InforMed is Accredited With Commendation by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

COMPLETE BY:SECOND LICENSE RENEWAL DATE ORWITHIN FOUR YEARS OF INITIAL LICENSE DATE.

CONTINUING MEDICAL EDUCATION

WWW.CA.CME.EDU

TARGETED SERIES OF CME FOR LICENSE RENEWAL

MEDICAL LICENSURE PROGRAM2018 CALIFORNIA

REQUIREDCME:

12CREDITSPAIN MANAGEMENT AND APPROPRIATETREATMENT OF TERMINALLY ILL

CALIFORNIA PHYSICIANS MANDATORY CME REQUIREMENTMust complete one-time requirement within the established minimum time period.

01 CONTROLLED SUBSTANCE EDUCATION FOR PRESCRIBERS COURSE ONE | 3 CREDITS

20 CDC OPIOID PRESCRIBING GUIDELINES FOR CHRONIC PAIN COURSE TWO | 4 CREDITS

61 CARING FOR PATIENTS AT THE END OF LIFE COURSE THREE | 2 CREDITS

79 PRESCRIBER EDUCATION FOR EXTENDED-RELEASE AND LONG-ACTING OPIOID ANALGESICS COURSE FOUR | 3 CREDITS

129 SELF-ASSESSMENT & EVALUATION SURVEY REQUIRED TO RECEIVE CREDIT

2018 CALIFORNIA

www.ca.cme.edu 1649 atlantic blvd #100jacksonville, fl 32207

f. 1.800.647.1356

Program Price 127

$135

Completion of entire CME series satisfies the

medical board’s 12 credit hour CME requirement

INFORMED TRACKSWHAT YOU NEED,WHEN YOU NEED IT

i

PHYSICIANSMANDATORY CONTINUING MEDICAL EDUCATION REQUIREMENT FOR LICENSE RENEWAL

PAIN MANAGEMENT/TERMINALLY ILL PATIENTSThe Medical Board of California requires that the number of credits of continuing medical education must include twelve credits in pain management and the treatment of terminally ill and dying patients. Physicians must complete this one time requirement by the second renewal of their medical license or within four years of their initial date of licensure, whichever occurs first. OTHER PHYSICIAN CME REQUIREMENTS The Medical Board of California requires 50 AMA PRA Category 1™ continuing medical education credits each biennium as a pre-requisite for physicians to renew their medical license.

The board mandates 12 credits be earned in pain management/terminally ill patients for physicians before their second renewal of their medical license or four years from the date of their initial license, whichever occurs first. This is a one-time requirement for all physicians (excluding pathologists and radiologists). When earned all of these credits count toward the total hours required during that biennium.

Also, under California’s law, the Medical Board requires that all general internal medicine and family practice physicians, that have a patient population of which 25 percent are age 65 years or older, complete at least twenty percent of their 50 credits each biennium in the field of geriatric medicine.

What does that means for you?

You must earn the mandatory 12 credits in pain management and the appropriate treatment of terminally ill and dying patients patients between the date you were granted an initial license and the earlier of your second license renewal or four years.

The Medical Board of California 2005 Evergreen Street, Suite 1200

Sacramento, CA 95815 E: webmaster@mbc.ca.gov

P: 1-800-633-2322

Disclaimer: The following information is provided by InforMed and is intended to summarize state CE/CME license requirements for informational purposes only. This is not intended as a comprehensive statement of the law on this topic, nor to be relied upon as authoritative. All information should be verified independently.

California Professional License Requirements

LICENSE RENEWAL INFORMATION

50 AMA PRA Category 1 Credit(s) TM including12 CREDITS in Pain Management / Terminally Ill*

*One-time mandatory CME requrement

ii

WWW.CA.CME.EDUVisit CA.CME.EDU, select NETPASS to begin.

Dear New California Medical Professionals,

InforMed is pleased to offer this collection of CME activities for physicians that are licensed by the state of California. The uniquely tailored curriculum is customized to the educational needs of California medical professional. Participants earn AMA PRA Category 1 Credit™ through these self-directed, on-demand courses.

The CME series is designed to streamline the education requirements of the Medical Board of California. For your license type it’s mandatory that you earn twelve (12) credit hours in approved CME courses for pain management and terminally ill patients that must be completed by your second license renewal date or within four years of your initial license date, whichever occurs first. Licensees who complete all the courses in this program satisfy this mandatory CME requirement. All activities are independently sponsored by InforMed Continuing Medical Education without commercial support.

-InforMed CME Team

45

1

This course is designed for all physicians, physician assistants, nurse practitioners and all other health care professionals managing patients on controlled substances.

The purpose of this course is to educate health care providers about the requirements of the Controlled Substances Act and safe prescribing practices for non-opioid controlled substances. In addition, some of the medical conditions for which non-opioid controlled substances are most commonly prescribed will be reviewed, along with recommendations for responsible management of these conditions with specific controlled substances.

InforMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

InforMed designates this enduring material for maximum of 3 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Completion of this course will better enable the course participant to:1. Explain the purpose and role of the Controlled Substances Act (CSA) as it relates to clinical practice.2. Name the 5 classes of drugs regulated by the CSA.3. Explain the similarities and differences between the 5 DEA schedules for controlled substances.4. Identify what pieces of information must be included on all prescriptions for controlled substances.5. Describe at least 4 signs that a controlled substance may be being inappropriately prescribed.6. Describe the 6 key steps generally recommended for the responsible prescribing of controlled substances.7. Discuss pharmacological treatment options for anxiety disorder, insomnia, narcolepsy, obesity, and attention deficit hyperactivity disorder.

TARGET AUDIENCE

COURSE OBJECTIVE

ACCREDITATION STATEMENT:

DESIGNATION STATEMENT:

LEARNING OBJECTIVE

HOW TO RECEIVE CREDIT:

MAXIMUM CREDITS: FORMAT:COURSE DATES:

Read the course materials

Complete the self-assessment questions at the end. A score of 70% is required.

Return your customer information/answer sheet, evaluation,and payment to Informed by mail, phone, fax or complete online at course website under NETPASS.

Release Date: 1/2016 Enduring Material (Self Study)Exp. Date: 12/2018

3 AMA PRA Category 1 CreditsTM

CONTROLLED SUBSTANCEEDUCATION FOR PRESCRIBERS

2

Anne M. Pylkas, MDAssistant Professor of MedicineAddiction and Internal MedicineUniversity of Minnesota

Melissa B. Weimer. DO, MCRAssistant Professor of MedicineDivision of General and Internal Medicine & GeriatricsOregon Health & Science University

V. Silverstein, MDMedical WriterEagle Creek Medical Communications

Stephen BraunMedical WriterBraun Medical Media

Elizabeth ThomasMSN, WHNP-BC, NP-C

Special Designation:

This course satisfies three (3) CME credit hours on Pain Management and the

Appropriate Treatment of the Terminally Ill

The Medical Board of California requires most physicians and surgeons to complete a one-time mandatory 12 hours of CME in the subjects of pain management and the treatment of terminally ill & dying patients

In accordance with the ACCME Standards for Commercial Support of CME, Informed implemented mechanisms, prior to the planning and implementation of this CME activity, to identify and resolve conflicts of interest for all individuals in a position to control content of this CME activity.

FACULTY/PLANNING COMMITTEE DISCLOSURE:The following faculty and/or planning committee members have indicated they have no relationship(s) with industry to disclose relative to the content of this CME activity:• Anne M. Pylkas, MD• Melissa B. Weimer. DO, MCR• V. Silverstein, MD• Stephen Braun• Elizabeth Thomas, MSN, WHNP-BC, NP-C

STAFF AND CONTENT REVIEWERS:Informed staff and all content validation reviewers involved with this activity have reported no relevant financial relationships with commercial interests.

DISCLAIMER* 2018. All rights reserved. These materials, except those in the public domain, may not be reproduced without permission from InforMed. This publication is designed to provide general information prepared by professionals in regard to the subject matter covered. It is provided with the understanding that InforMed, Inc. is not engaged in rendering legal, medical or other professional services. Although prepared by professionals, this publication should not be utilized as a substitute for professional services in specific situations. If legal advice, medical advice or other expert assistance is required, the service of a professional should be sought.

FACULTY:

ACTIVITY PLANNER:

DISCLOSURE OF INTEREST:

COURSE SATISFIES

3Pain Management

and Terminally Ill Patients

3

IntroductionIn the United States, the rate of prescription drug disorders use disorders has increased dramatically over the past three decades. For example, the Centers for Disease Control (CDC) report a 300% increase in the consumption of opioid analgesics between 1999 and 2010, with death rates associated with these agents tripling as well.1 Opioids, however, are not the only problematic class of controlled substances being prescribed by health care professionals. Benzodiazepines, barbiturates, stimulants, and sedative-hypnotics can also pose risks for abuse, addiction, and significant morbidity and mortality.2,3 It is estimated that more than 6 million Americans are misusing prescription drugs (including opioids), which is more than the number of Americans abusing cocaine, heroin, hallucinogens, and inhalants, combined.4

Non-opioid controlled substances are a diverse group of agents that include anxiolytics, hypnotics, depressants, and stimulants. Controlled anti-anxiety medications include benzodiazepines such as alprazolam, diazepam, and lorazepam. Controlled sedativehypnotics include zolpidem and eszopiclone. Controlled muscle relaxants include barbiturates such as carisoprodol. Appetite suppressants such as phentermine are also listed as non-opioid controlled substances. Controlled psychomotor stimulants include amphetamines and methylphenidate. Physicians and other health care providers play important roles in the nationwide effort to stem the tide of inappropriate drug use. Survey data from 2009 and 2010 show that over half of the non medical users of pain relievers, tranquilizers, stimulants, and sedatives got their prescription drugs “from a friend or relative for free.”5 In a follow-up question, three quarters or more of these respondents indicated that their friend or relative had obtained the drugs from one doctor.5

In order to be maximally effective in reducing the use of controlled substances by unauthorized users, health care providers must have a thorough understanding of both the regulatory frameworks surrounding controlled substances as well as an appreciation for the current acceptable medical practices for prescribing controlled substances in clinical situations. This monograph will review both of these broad areas, with the focus on the non-opioid classes of controlled substances, since guidelines and practices for the responsible prescribing of opioid medications is covered in significant detail in other monographs.

The Controlled Substances ActThe United State federal government’s first attempt at regulating medications was through the Harrison Act passed in 1914.6 The Harrison Act criminalized what, at that time, was considered to be the “recreational” use of opium, morphine, and cocaine. While these drugs could still be legally obtained, physicians, dentists and veterinary surgeons were now required to register, document, and pay taxes on any packages containing these drugs. Over the next few years, thousands of prescribers who did not comply with the law were arrested, convicted, and jailed. In 1970, the United States government passed the Federal Comprehensive Drug Abuse Prevention and Control Act. Now known as the Controlled Substances Act (CSA), the law consists of three parts, including rehabilitation services for people with substance use disorder, the regulation and distribution of controlled substances, and the importation and export of controlled substances.7 The Drug Enforcement Administration (DEA) administers all parts of the CSA. Associated laws include the Chemical Diversion and Trafficking Act of 1988, the Anabolic Steroids Act of 2004, and the Combat Methamphetamine Epidemic Act of 2000. Section 812 of the CSA lists the original controlled substances listed in the law. Over the past 45 years, the federal government has updated the CSA to add, remove, or transfer over 160 substances across schedules. This monograph reflects the most recent issue of Title 21 Code of Federal Regulations (CFR) Part 1300. It is limited to describing the controlled substances most frequently encountered by health care providers and is not a comprehensive list.8

The CSA addresses problems associated with the manufacture, distribution and abuse of substances with no recognized medical use in the United States (e.g. LSD, heroin, and MDMA/ecstasy) as well as those with currently accepted medical uses (e.g. morphine, amphetamine, and diazepam). Since many controlled drugs are important tools in the clinician’s pharmaceutical armamentarium, the CSA attempts to balance two competing needs: to maintain an adequate and uninterrupted supply of these controlled substances for legitimate purposes while simultaneously reducing their diversion and abuse.9

The CSA places all substances which were in some manner regulated under existing federal law into one of five schedules (with the exceptions of alcohol and tobacco). This placement is based on the substance’s perceived medical use, potential for abuse, safety, and dependence liability. The law also provides a mechanism for new substances to be

added to or transferred between schedules or for substances to be removed from control. In determining into which schedule a drug or other substance should be placed, or whether a substance should be decontrolled or rescheduled, certain factors are required to be considered, including:10

1. The drug’s actual or relative potential for abuse

2. Scientific evidence of the drug’s pharmacological effect, if known

3. Its history and current pattern of abuse4. The scope, duration, and significance of

abuse5. What, if any, risk there is to the public

health6. The drug’s psychic or physiological

dependence liability7. Whether the substance is an immediate

precursor of a substance already controlled After considering the above listed factors, the DEA administrator may make specific findings concerning the drug or other substance. This will determine into which schedule (if any) the drug or other substance will be placed.

Schedules of Controlled SubstancesControlled substances under the CSA are classified into one or more of five schedules.

Did You Know?Some drugs or substances appear in 2 or more schedules, depending on the specifics of their formulation. For example, raw cannabis is listed as Schedule I, although products containing one or more of the active ingredients in cannabis (i.e., tetrahydrocannabinol, or THC) are listed as Schedule III. Likewise, GHB as a street drug is Schedule I, although when formulated in a product for clinical use it is listed as Schedule III. Schedule I SubstancesSubstances in this schedule are deemed to have a high potential for abuse, have been determined to have no currently accepted medical use in the United States, and lack evidence for safe use under medical supervision. Some examples of substances listed in schedule I are: heroin, LSD, peyote, and MDMA (ecstasy). Schedule II SubstancesSubstances in this schedule have a high potential for abuse which may lead to severe psychological or physical dependence, and yet the drug or substance also has a currently accepted medical use in the United States. Examples include many opioid pain medications, and stimulants such as amphetamine, methamphetamine, methylphenidate, and cocaine.

4

Schedule III Substances Substances in this schedule have a potential for abuse less than substances in schedules I or II and abuse may lead to moderate or low physical dependence or high psychological dependence. These substances also have currently accepted medical uses in the United States. Examples include buprenorphine and products containing not more than 90 milligrams of codeine per dosage unit (i.e. Tylenol with codeine®). Examples of schedule III non-opioid drugs include benzphetamine, ketamine, and anabolic steroids such as oxandrolone. Schedule IV Substances Substances in this schedule are thought to have a low potential for abuse relative to substances in schedule III, and have currently accepted medical uses in the United States. Examples include alprazolam, clonazepam, diazepam, lorazepam, phenobarbital, temazepam, and triazolam. Schedule V Substances Substances in this schedule have a low potential for abuse relative to substances listed in schedule IV. These are generally used for antitussive, antidiarrheal, and analgesic purposes. Examples include cough preparations containing not more than 200 milligrams of codeine per 100 milliliters or per 100 grams.

Classes of Controlled SubstancesThe CSA regulates five classes of drugs:• Opioids• Sedative-Hypnotics• Stimulants• Hallucinogens• Anabolic steroids

Each class has distinguishing properties, and drugs within each class often produce similar effects. However, all controlled substances, regardless of class, share a number of common features. All controlled substances have abuse potential or are immediate precursors to substances with abuse potential.10

With the exception of anabolic steroids, controlled substances are abused to alter mood, thought, and feeling through their actions on the central nervous system (brain and spinal cord). Some of these drugs alleviate pain, anxiety, or depression. Some induce sleep and others energize. Though some controlled substances are therapeutically useful, the “feel good” effects of these drugs contribute to their potential for abuse. The extent to which a substance is reliably capable of producing intensely pleasurable feelings (euphoria) increases the likelihood of that substance being abused.10

Table 1. Commonly-Encountered Non-Opioid Controlled Substances11Schedule Substance Common Name

I 3,4-Methylenedioxymethamphetamine Ecstasy, MDMA, XTCI Gamma Hydroxybutyric Acid GHBI Lysergic acid diethylamide LSDI Cannabis Marijuana, PotI Methaqualone QuaaludeII Amphetamine Dexedrine, Adderalll, ObetrolII Lisdexamfetamine VyvanseII Methylphenidate Concerta, Ritalin, MethylinII Phenobarbital NembutalIII Anabolic steroids Anabolic SteroidsIII Chlorphentermine Pre-Sate, Lucofen, Aspedon, Desopimon

III Dronabinol MarinolIV Alprazolam XanaxIV Barbital Veronal, Plexonal, BarbitoneIV Carisoprodol SomaIV Chlordiazepoxide Librium, Libritabs, Limbitrol, SK-Lygen

IV Clonazepam Klonopin, ClonopinIV Diazepam Valium, DiastatIV Lorazepam AtivanIV Midazolam VersedIV Modafinil ProvigilIV Phentermine Ionamin, Fastin, Adipex-P, ZantrylIV Phenobarbital PhenobarbitalIV Temazepam RestorilIV Zaleplon SonataIV Zolpidem Ambien, Ivadal, Stilnoct, StilNoxIV Zopiclone LunestaV Pregabalin Lyrica

Table 1 lists some of the non-opioid controlled substances that are commonly encountered and/or prescribed in clinical settings. Note that some substances, such as many common products that emit fumes that can be inhaled to alter consciousness, are not scheduled because doing so would impede legitimate commerce.10 New substances are continually being either discovered or invented which have abuse potential and, thus, the list of controlled substances continues to grow.

Physical Signs Of Depressant Overdose:• Shallow respiration• Clammy skin• Dilated pupils• Weak and rapid pulse• Slurred speech• Loss of motor coordination• Blurred vision• Nausea• Vomiting• Low blood pressure

Drugs Causing Similar Effects:• Alcohol (ethanol)• Antihistamines• Certain antipsychotics Available Forms:• Tablets• Capsules• Syrups• Injectable liquids

QUICK SEDATIVE-HYPNOTICS FACTS

5

Sedative-Hypnotics Sedative-hypnotics, lower arousal levels and reduce nervous system excitability via a range of pharmacological mechanisms, the most prominent of which are facilitation of gamma-aminobutyric acid (GABA) receptors, opioid receptors, and inhibition of glutamatergic or catecholaminergic activity.12 Although widely prescribed for their anxiety relieving, muscle-relaxing, and sleep-inducing properties, sedative-hypnotics are also widely abused for these properties as well as their abilities to induce euphoria. Because ethanol acts on many of the same neuronal receptor targets as many of the sedative-hypnotics, adverse synergistic effects may occur that can result in death. Barbiturates were the first class of synthetic sedative-hypnotics to be introduced and many specific types with varying durations of action are FDA-approved for indications such as the relief of anxiety, the promotion of sleep, or epilepsy. Benzodiazepines were discovered in the 1950s and have largely eclipsed barbiturates for a range of indications including anxiety, insomnia, muscle spasms, alcohol withdrawal, and as a premedication for certain medical or dental procedures.13 Although initially thought to be less prone to induce tolerance and dependence than barbiturates, benzodiazepines are now recognized to be just as liable to diversion and abuse.14 Benzodiazepines are categorized as either short-, intermediate- or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are used for the treatment of anxiety, though they are not effective for long term treatment of anxiety.12

Flunitrazepam (RohypnolÒ) is a benzodiazepine that has never been approved by the FDA in the United States, but which is available by prescription in other countries and also as illegal preparations.10 Because it can impair judgment and induce amnesia, particularly when combined with ethanol, flunitrazepam has been associated with sexual assault.10

Non-benzodiazepines are molecularly distinct from benzodiazepines, although they act on the same GABA receptor sites and produce similar sedative effects.15 Common non-benzodiazepines include zolpidem (AmbienÒ), Zaleplon (SonataÒ) and Eszopiclone (LunestaÒ). Gamma-hydroxybutyric acid (GHB) and its chemical analogs are widely used, both as a prescription medicine (XyremÒ), and as industrial solvents or components in many commercial products. Sold as a liquid or as a powder that is dissolved in another liquid and

swallowed, GHB induces euphoric and calming effects as well as amnesia.

Stimulants Stimulants induce a range of effects on the body and mind by enhancing activity of the central and peripheral nervous systems. Common effects, which vary depending on the stimulant in question, may include: enhanced alertness, wakefulness, endurance, productivity, and motivation; increased sexual arousal, locomotion, heart rate, and blood pressure; and diminished appetite. Many stimulants improve mood or induce feelings of euphoria. Stimulants exert their effects through a number of different pharmacological mechanisms, the most prominent of which are facilitation of norepinephrine and/or dopamine activity, adenosine receptor antagonism, and nicotinic acetylcholine receptor agonism.12 Not all stimulants are listed as controlled substances. Caffeine, theophylline, and nicotine are widely used and legally available. Amphetamines and methylphenidate are controlled substances but are also widely-prescribed to treat attention-deficit disorders, sleep disorders such as narcolepsy and shift-work disorders, and as adjuvant medications for depression, especially treatment-resistant depression.12 Cocaine has limited medical uses as a topical local anesthetic and for reducing bleeding of mucous membranes in the mouth, throat, and nasal cavities. Other stimulants such as crack cocaine and methamphetamine have no approved medical uses The clandestine production of amphetamines in the past decade has increased dramatically, particularly the production of methamphetamine, which is a potent central nervous system stimulant and highly addictive.10 (Note that a single brand of methamphetamine, Desoxyn, Ò is approved by the FDA for the treatment of attention deficit disorders.) So-called “bath salts” are synthetic stimulants, also known as synthetic cathinones, which is the active chemical found naturally in the khat plant.10 “Bath salts” are sold as powders, tablets, or capsules under various brand names. They are usually ingested by sniffing/snorting, though they can also be taken orally, smoked, or put into a solution for injection. Tolerance to higher doses of stimulants can develop quickly, as can psychological dependence. Abrupt cessation of stimulants is typically followed by a “crash” of depression, anxiety, extreme fatigue, and drug craving. Accidental death may be caused by cardiovascular collapse, dehydration, or high fever (physical exertion increases the

hazards of stimulant use because of the effects of stimulants on the body’s hypothalamic temperature-regulation mechanisms).

TOLERANCE V. ADDICTION

Tolerance is an unavoidable neurophsyiologicalhysical adaptation of the brain to the presence of a drug. As a result, patients can be expected to need higher doses of medication to obtain the same effect over time. Tolerance also implies that a person will experience substance withdrawal symptoms if a drug is suddenly stopped. Addiction is the compulsive seeking and use of a drug despite continuing harm and dysfunction. Continued use of a substance by someone who has addictiontypically decreases their functioning over time; use of a substance by a person without addiction typically improves functioning, is marked by controlled and non-compulsive use.

Quick Stimulant Facts Physical Signs Of Stimulant Overdose:• Tremors• Headache• Flushed skin• Chest pain with palpitations• Excessive sweating• Vomiting• Abdominal cramps• Agitation Drugs Causing Similar Effects:• Although often classified as a

hallucinogen, MDMA (ecstasy) is a stimulant and can induce similar responses to classic stimulants

Available Forms:• Tablets• Capsules• Powder• “Rocks”• Injectable liquids

6

DefinitionsThe DEA describes controlled substances as “drugs that have a potential for abuse and dependence; these include substances classified as opioids, stimulants, depressants, hallucinogens, anabolic steroids, and drugs that are immediate precursors of these classes of substances.”16 Drugs with a significant risk of addiction and non medical use and lacking a medical indication in the United States are listed as schedule I controlled substances and cannot be prescribed by any health care provider. These agents are outside the scope of this monograph. The American Society of Addiction Medicine defines addiction as a primary, chronic disease of brain reward, motivation, and memory circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social, and spiritual manifestations. This is reflected in the pathological pursuit of reward and/or relief by substance use and other behaviors. Addiction is characterized by an inability to consistently abstain, impairment in behavioral control, craving, diminished recognition of the problems with behavior and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, addiction involves cycles of relapse and remission. Without treatment, addiction is a progressive disease that can result in disability and death. The Diagnostic and Statistical Manual 5th Edition (DSM 5) categorizes addictive disorders by the specific substance misused, i.e., alcohol use disorders, opioid use disorders, and others. The diagnostic criteria from the DSM 5 for substance use disorder are as follows: “A problematic pattern of substance use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period”:17

1. More of the substance taken or they are taken over a longer period than planned.

2. The patient has difficulty cutting down or controlling use.

3. Large amounts of time are invested in attempting to obtain, use, or recover from, using.

4. Craving.5. Use causes a failure to fulfill roles at work,

school, or home.6. Continued use despite having social or

interpersonal problems caused by use.7. Social, occupational, or recreational

activities given up because of use.8. Use even when physically hazardous.9. Use despite physical or psychological

problems caused by substance use.10. Tolerance, as defined by the need for an

increased amount to achieve intoxication, or decreased effect with continued use of

the same amount of a substance. (This criteria is exempted from consideration if a drug or substance is being taken taken as prescribed under the guidance of a medical professional.)

11. Withdrawal symptoms upon cessation of use, or substances taken to avoid withdrawal. (This criteria is exempted from consideration if a drug or substance is being taken as prescribed under the guidance of a medical professional.)

The severity of substance use disorders can be described by the number of criteria the patient meets. A patient with mild disorder meets 2-3 symptoms, moderate disorder meets 4-5 symptoms, and a patient with severe disorder meets 6 or more symptoms.17

There is no single definition of nonmedical use, or misuse, of prescription drugs. Large epidemiologic surveys define it as the use of these medications without a prescription or simply for the experience or feeling the drug causes. It can also mean use in a way that is not intended, such as via routes, frequencies, or dosages other than prescribed. The term “abuse” is an outdated term and will not be used in this monograph. Dependence is a confusing term with several meanings. In this monograph, we will use it to mean “physical dependence” or the occurrence of negative physical symptoms (i.e., withdrawal) upon cessation or reduction in dose of a drug. Diversion is a medico-legal term that implies the transfer of any legally prescribed controlled substance from the individual to whom it was prescribed to another person for any illicit use.In order to be eligible for DEA registration and legally prescribe controlled substances, a health care provider must meet certain requirements. He or she “must be a physician, dentist, veterinarian, hospital, or other person licensed, registered, or otherwise permitted by the United States or the State in which he or she practices to dispense controlled substances in the course of professional practice.”16 As a result, a prescriber who does not have a professional license or whose professional license has been temporarily suspended cannot hold a DEA license or legally prescribe controlled substances. Similarly, prescribers must have a DEA license in the state where they are professionally licensed. The Challenge of Controlled SubstancesPatients have long turned to physicians to relieve suffering. However, health care providers face difficulties when they prescribe controlled substances to their patients. The CDC describes prescribing practices, insurance benefit policies, insufficient governmental oversight, and the patient belief that all prescribed

substances are safe, as factors that lead to increased morbidity and mortality in patients who take controlled substances.18 Many health care providers regularly prescribe controlled substances to their patients, but treatment plans have become quite complex and the penalties for mismanagement can be dauntingly high. Providers find themselves balancing issues of safety, a complex array of therapeutic options, compliance with governmental regulation and a mandate to alleviate patient suffering. Since the Controlled Substances Act was passed in 1970, more than 160 medications have been added, transferred, or removed from the lists of controlled substances.11 As part of their obligation to be responsible health care providers, prescribers must be aware of new legislation and regulatory requirements associated with practicing medicine.19 However, prescribers are not always aware of the latest additions, changes, and deletions made in the schedules of non-opioid controlled substances. Nevertheless, the Drug Enforcement Agency can punish prescribers who fail to comply with the latest updates by revoking their prescribing license, closing their businesses, implementing fines, or inflicting prison time. These negative outcomes may be prevented by educating prescribers about which medications are on the controlled substances list and how to safely prescribe them to patients. Health care providers who prescribe non-opioid controlled substance to patients must understand all of the risks associated with dispensing controlled substances. For example, in one study examining the interaction between prescribing physicians and older patients on chronic anxiolytics, the prescribing physicians continued prescribing anxiolytic medications to their patients because they believed that elderly patients were at low risk of addiction.20 This practice is problematic, however, because even though the patients were at low risk of addiction they were also at increased risk of falls, motor vehicle collisions, and functional decline associated with the substances being prescribed. Before a provider prescribes a controlled substance, he or she must understand all alternative treatments and be able to justify why the patient requires a controlled substance. Once a physician accurately diagnoses a disease, he or she cannot simply prescribe a controlled substance, but must remain updated on all of the latest management options including lifestyle changes, medical management, and operative interventions. Moreover, health care providers are obligated to thoroughly document the patient history, physical examination and alternative treatments before prescribing a controlled substance.16

7

Case Study Exercise 1Instructions: Spend 10 minutes reviewing the case study below and considering the questions and commentary that follow. Jenny Cook is a 42 year old woman who has recently relocated and is establishing care with a new primary care physician. On her first visit to your clinic, she reports that her personal health has been quite good, except for an extra 100 pounds that she has been struggling to lose since she gained weight in college 20 years ago. She is sedentary and works at an office job, but she makes sure to walk around the high school track for at least 30 minutes, 3 times a week. In fact, now that she thinks about it, she has been feeling a strange “fluttering” in her chest during those walks for the past 6 months. She doesn’t think it is anything serious, but decided to mention it anyway. Question 1: What follow- up questions do you have about the patient’s chief complaint?

Commentary on Question 1: The patient’s chief complaint is the “fluttering” she has in her chest while exercising. Although she alludes to weight gain, it is important for you to investigate her palpitation symptoms as a possible arrhythmia first. As always, you must ask about the nature, timing, exacerbating and relieving factors associated with her “fluttering.” You should also ask her about any co-morbid conditions, past medical history, past surgical history, family history of heart disease or thyroid disease, and if she is taking any medications. When she tells you her medications, you must evaluate the side-effect profile of each medication.

Except for the extra weight, the patient denies any past medical or past surgical history. She does not have any allergies to medications, and she regularly takes a birth control pill, multivitamin, and phentermine. She requests re-fills on all of her medications. When you ask her how long she has been taking phentermine, she responds that she has been taking it on and off since it was initially prescribed for her by the health care provider at University Health Services. She stopped taking medication for weight loss when fen-phen was taken off the market. However, a friend of hers, who is a nurse practitioner, began prescribing phentermine to Jenny again 5 years ago. Now that Jenny has moved to a different state, her friend told her that she could no longer prescribe phentermine because it is a controlled substance. Question 2: Describe any concerns you have about the patient’s health history.

Commentary on Question 2: Although the patient denies any past medical problems, she has been taking phentermine for many years. Phentermine is a non-opioid stimulant controlled substance used for weight loss. It was previously approved as a combination medication with the drug fenfluramine to create fen-phen, Fen-phen was taken off the market when several studies showed that its side-effect profile included significant cardiac complications, with valvular regurgitation impacting over 20% of patients.21 Although the combination drug was taken off the market, patients who used to take the medication are still at-risk for adverse events. You should be concerned that this patient did not undergo a cardiac evaluation after discontinuing fen-phen. In addition, phentermine is not meant to be used long-term, and patients who are currently taking this drug should be carefully monitored. This patient was taking the drug chronically, and she was not monitored appropriately by a health care provider.

DEA REQUIREMENTS FOR PRESCRIBING CONTROLLED SUBSTANCES

Legislative and Regulatory Developments Providers must be aware of regulatory developments and legislation associated with the prescribing requirements for controlled substances.19 This section will review the appropriate documentation for writing prescriptions, DEA prescriber registration, renewal, and revocation of registration. Rules for Documentation22

All prescriptions for controlled substances must be either typed or written in ink or indelible pencil. Although a designated individual may write the prescription, it must be manually signed by the responsible provider. All prescriptions must contain the following elements:• Prescriber’s name, address, and DEA

registration number• Manual signature of prescriber• Patient’s name and address• Date of issue• Drug name• Drug strength• Dosage• Quantity prescribed• Number of refills (may be 0)• Directions for use Schedule II controlled substance prescriptions must be written and signed by the prescriber. Under certain very strict circumstances, they can be e-prescribed, but the electronic medical record is required to have specific authentication steps. Some states require e-prescription such as New York. Schedule II medications cannot be refilled; they require a new prescription

each time they are filled. In case of emergency, the prescriber may telephone the prescription for a schedule II controlled substance into the pharmacy but the prescriber must follow up with a written prescription within seven days. Schedule III and IV controlled substance prescriptions may be written, called in or faxed to the pharmacy, and they have a maximum of five refills in six months. Prescriptions for schedule V controlled substances do not have a limit on refills. Registration, Renewal, and Termination of DEA License4

In order to prescribe controlled substances, practitioners must be registered with the DEA. There are three ways to obtain DEA Form 224 and apply for registration:• DEA Diversion Web Site: www.DEAdiversion.

usdoj.gov• DEA field office• Registration Call Center: 1-800-882-9539 Once obtained, the Certificate of Registration, DEA Form 223, must be kept at the registered location and be easily retrieved for official inspection. DEA registration should be renewed every three years using DEA Form 224a. The DEA will mail the renewal form to the address listed on the current registration 45 days before the expiration date. The renewal can be completed online at www.DEAdiversion.usdoj.gov, or the printed renewal form can be mailed to:

Drug Enforcement AdministrationRegistration UnitCentral StationP.O. Box 28083Washington, D.C. 20038-8083

Prescribers are required to update the DEA if they change their business address or discontinue their business. Revoking the DEA License4

Per the CSA, the DEA can deny, suspend, or revoke registration if the prescriber has committed any of the following acts:1. Falsified the DEA application2. Has been convicted of a felony associated

with a controlled substance3. Lacks a state practitioner license or

registration4. Cannot participate in Medicaid or Medicare5. Acted in a way that is inconsistent with public

interest, including sustaining state licensing or professional disciplinary society sanctions or being convicted of a federal or state crime associated with controlled substances

Locum Tenens23

Health care providers who are working in a locum tenens capacity must understand the laws surrounding their DEA registration. Physicians who function in a locum tenens capacity temporarily substitute for a permanently employed physician

8

while he or she is on leave. Some locum tenens physicians may also provide temporary care in a short-staffed hospital or clinic. If these practitioners work within a single state, they must be licensed and registered within that state. If they register at one location in the state but practice at a different location, they are not required to re-register with the DEA. However, if they work throughout the U.S. and administer, dispense, or prescribe controlled substances in several states, they must obtain a separate DEA registration in each state where they work, use the hospital’s DEA if the hospital agrees, or transfer their DEA registration from one state to another. General Risk Management Strategies for Controlled Substances A Universal Precautions approach to prescribing all controlled substances presupposes that all patients are capable of prescription drug misuse and that procedures should be implemented to mitigate this risk. These procedures include making a clear diagnosis of the disorder being treated, assessing risk of drug misuse, obtaining informed consent regarding the abuse liability of controlled substances, and continually re-evaluating treatment effectiveness and patient adherence.24

Health care providers must perform and document a complete history and physical in accordance with the usual course of professional practice before legally prescribing any controlled substances. The documented history should include a description of the patient’s chief complaint, attempted treatments, and co-morbid conditions. The physical examination should be used to identify co-morbid conditions and should include a neurological assessment. About the Symptoms:• What are the symptoms?• When did the symptoms start?• Was there an inciting event?• How do the symptoms impact daily life?

What did the patient do in response to the symptoms?

• Have they been treated for this problem in the past?

• If so, were they prescribed a controlled substance?

• Who prescribed the controlled substance and at what doses?

History• Does the patient have any other medical

disorders?• Specifically for sedatives, any respiratory

disorders, frequent falls, cognitive issues?• Specifically for stimulants, any

cardiovascular issues?• Does the patient have a history of

substance use disorders, including tobacco use?

• Is there evidence in the chart of a history of a substance use disorder that the patient may not be disclosing? Do they have a collateral contact, such as a spouse, to verify this? Is a urine drug screening (UDS) needed to confirm?

• Does the patient have a history of psychiatric disorders, how active is it, and is the patient acutely suicidal? See screening tests below.

• Is the patient prescribed other CNS depressants?

• Is there evidence of diversion in the past?• Is there a family history of substance use

disorders?• Are there children in the household and

how will the medications be secured?• Is there a history of trauma or abuse? If the patient is currently taking a controlled substance, the provider should ask for the name and location of the previously treating physician and, if available, check the prescription monitoring program (PMP) to corroborate that information. The health care provider must learn if the patient has attempted other treatment modalities, including dietary modification, physical therapy, behavioral therapies, medical management with a non-controlled substance, or operative intervention. The provider should also ask if the patient’s symptoms improved or deteriorated in response to prior interventions.

In order to safely manage the patient, the health care provider should find out if the patient is suffering from any co-morbid diseases or conditions, including a history of substance use disorders or harm related to substance use.

To safely treat patients with controlled substances, providers should be aware of risk factors for unintentional drug overdose and addiction. Addiction risk factors include a personal or family history of any substance use disorder (including current tobacco use), young age, and psychiatric comorbidity.25 Chronic respiratory illness, acute psychiatric instability, uncontrolled suicidality, active substance use disorder, concomitant use of benzodiazepines or other known central nervous system (CNS) depressants (including alcohol) and known diversion in the past are other relative contraindications to controlled substance prescribing.26

Providers should also perform a directed physical exam and review any additional diagnostic studies or labs the patients may have required in the past. urine drug screen may need to undergo additional imaging or diagnostic testing. As above, a UDS may be needed at baseline when there is a high suspicion of an active substance use disorder. On physical examination, the health care provider should be vigilant for signs of intoxication or withdrawal, track marks, bruising from needles, and physical exam findings that do not fit with the presenting complaint (for example, the patient is at an appropriate weight but seeking weight reduction).27

Once a rigorous clinical assessment has established a clear indication for the prescription, the clinician and patient must balance the potential benefit of the medication in treating the diagnosis with the risks inherent to the medication including addiction and overdose. Although risk-management screening tools are designed for prescribing opioids, they can also be modified and applied to screen patients for risk of misuse of non-opioid controlled substances. The most common of these are the Opioid Risk Tool (ORT), the DIRE Score, and the Screener and Opioid Assessment for Patients with Pain (SOAPP). It should be noted that these tools assess risk and should not be used to determine whether or not opioids should be prescribed. Several mental health assessment tools are available and may be prudent to use if there is suspicion of an underlying psychiatric disorder, which may enhance risk of misuse of controlled substances, if left untreated. Mental Health Assessment Tools 1. Patient Health Questionnaire –2 (PHQ-2). This is a simple two-item screening tool. If it is positive on either item, the clinician should offer another more detailed questionnaire to better assess the presence or absence of a depressive disorder. One link to this screening tool: http://www.cqaimh.org/pdf/tool_phq2.pdf.

2. Patient Health Questionnaire–9 (PHQ-9). This nine-item tool screens for a depressive disorder, and often is used as a follow-up to the PHQ-2. It’s easy to score and use. Here’s one link to a copy: http://www.integration.samhsa.gov/images/res/PHQ%20-%20Questions.pdf.

3. Zung Self-Rating Depression Scale (Zung). This is a 20-item written questionnaire. One copy is at http://healthnet.umassmed.edu/mhealth/ZungSelfRatedDepressionScale.pdf.

4. Hamilton Depression Rating Scale (Ham-D). This is 21-item screening questionnaire. Cutoff scores is <7 is normal. http://img.medscape.com/pi/emed/ckb/psychiatry/79926-1889862-1859039-2124408.pdf

9

Once the patient has been selected for management with any controlled substance, a robust treatment agreement should be used to build trust in the patient-physician relationship and to clarify expectations for medication adherence and management.. Treatment agreements consist of informed consent, which includes the nature of the treatment, what to expect, responsibility of both parties, reasonable alternatives, benefits, and risks. While data supporting the effectiveness of treatment agreements are lacking, they are considered a standard practice. Providers must be diligent about discussing the risk of possible side effects, such as addiction and overdose, associated with use of controlled substances, and documenting all discussions, consent, and response to therapy.Continual assessment of adherence and effectiveness of the treatment with a controlled substance is crucial. A functional assessment of changes in daily activities, quality of life, and medication side effects is helpful in weighing the effectiveness of the prescribed medication. Medication adherence and other drug use can be assessed using regular urine drug screenings PMP queries, and pill counts. Urine drug screening is inexpensive, easily obtained, noninvasive, and widely available. Urine drug testing should be used to screen for the presence of prescribed and non-prescribed medications and illicit drugs. Urine drug screening is generally a 2-step process. First an ELISA immunoassay (IA) is used, which is highly sensitive but not very specific. Second, a confirmatory gas or liquid chromatography and mass spectroscopy can confirm IA results, which have high sensitivity and specificity. Urine drug testing does not definitively confirm whether prescription drug misuse has occurred and does not diagnose the presence of a substance use disorder, and, thus, should be used only as one tool to assess adherence. A PMP is a useful tool to detect prescribing by other providers, doctor shopping, and medications not disclosed during patient interview. Currently there is no nationwide PMP, so patients obtaining prescriptions across state lines can go undetected. Querying the PMP prior to prescribing opioids and intermittently thereafter based on patient risk and history is recommended.Pill counts are useful to address whether the patient is using more medication than prescribed or diverting medication to other sources. Pill counts should include 24 hour notice to return to clinic with their medications. Failure to bring the expected number of pills may be an indication of misuse and for closer patient assessment and monitoring.

The most difficult part of managing controlled substances is identifying and managing aberrant behaviors. They include non-medical use, addiction, diversion, prescription forgery, and recurrent prescription loss. In addition to signaling the presence of a substance use disorder, aberrant

e disorder, aberrant behaviors may indicate pathology progression, a new or worsened psychiatric diagnosis, cognitive dysfunction, or pseudoaddiction (addiction-like behaviors that result from inadequately treated pain, anxiety, or other symptoms). Regardless of cause, the presence of aberrant behavior will influence the plan and discontinuation of the medication may be appropriate. A flexible approach is warranted. A patient misusing medication to self-treat depressive symptoms may be handled differently than a patient selling medications, for example. Case Study Exercise 2 Instructions: Spend 10 minutes reviewing the continuation case study below and considering the questions and commentary that follow. You explain to Jenny that you will perform a full evaluation, including a thorough history and physical examination. Jenny agrees and provides the following history. She reports that she was of normal weight as a child, but then gained the “freshman 15” every year for 4 years while in college. She tried to lose the weight at age 21 by decreasing her alcohol intake, but continued to

eat poorly and not exercise. When she went to her school’s health clinic, the health care provider wrote her a prescription for “diet pills.” The patient thinks she was taking fen-phen at some point. She continued taking the pills on and off for 3 years and her weight fluctuated 10 pounds in either direction. In the past, Jenny has tried multiple diets, including Atkins, paleo, and Master Cleanse. Most recently, she has gone vegan and gluten-free for weeks at a time. Unfortunately, she loses 10-15 pounds at most and quickly gains it all back with additional weight. Five years ago, the patient’s father suddenly died of a heart attack and she realized that she was at-risk for an early death. So she quit smoking, joined

a gym, spoke with her friend, who is a nurse practitioner, and obtained a prescription for phentermine. She says she rarely drinks alcohol and does not smoke or use illicit substances. Question 1: Has this patient appropriately attempted to manage her weight? Commentary on Question 1: Jenny acknowledges that she is overweight and appears motivated to reduce her weight to a healthy range. In the past, she reduced her alcohol consumption and discussed her weight gain with a health care provider at her school’s health clinic. More recently, she has addressed some aspects of a comprehensive lifestyle program, including dietary changes and exercise.28 The patient is also knowledgeable about her increased cardiovascular risk due to family history and obesity, and she improved her overall health when she quit smoking. Question 2: What concerns do you have about h ow this patient has managed her weight? Comment

10

Question 4: Under what circumstances can a health care provider lose his or her DEA privileges to prescribe non-opioid controlled substances? Commentary on Question 4: The DEA describes circumstances where health care providers lost their prescribing licenses permanently or temporarily after violating the requirements for maintaining a license.19 Examples of violations include the following actions by providers: loss of their provider practice licenses or registration; committed and were convicted of a felony involving controlled substances; falsified their DEA application; were ineligible to participate in Medicaid/Medicare; or acted in a way that was not in the public’s interest. Some health care providers were also cited because they failed to follow CSA evaluation and documentation requirements. To meet these requirements, health care providers must perform appropriate history and physical examinations, consider treatment options that do not involve controlled substances, and carefully monitor patients throughout treatment. They must carefully document all the steps of the evaluation, completely fill out all the parts of the written prescription, and maintain careful clinic records. Failing to meet these basic DEA requirements can result in the provider losing his or her prescribing license. When prescribing any medication, controlled or not, it is important that you maintain a professional boundary with the patient and maintain adequate records. In this case, it is not clear if the patient saw her NP as a friend or as a patient. Prescribing for friends is a breach of professional ethics.

APPROPRIATE AND INAPPROPRIATE PRESCRIBING PRACTICES

The legal standard that a controlled substance may only be prescribed, administered, or dispensed for a legitimate medical purpose by a provider acting in the usual course of professional practice has been construed to mean that the prescription must be “in accordance with a standard of medical practice generally recognized and accepted in the United States.”4

Federal courts have long recognized that it is not possible to define the phrase “legitimate medical purpose in the usual course of professional practice” precisely enough to cover all of the varied situations providers may encounter in clinical practice.4 There are, however, recurring patterns that suggest inappropriate prescribing of controlled substances by a clinician:4

• An inordinately large quantity of controlled substances prescribed or large numbers of prescriptions issued compared to other providers in an area

• No physical examination given• Warnings to the patient to fill prescriptions at

different drug stores• Issuing prescriptions knowing that the patient

was diverting the drugs to others• Issuing prescriptions in exchange for sexual

favors or for money

• Prescribing controlled drugs at intervals inconsistent with legitimate medical treatment

• The use of street slang rather than medical terminology for the drugs prescribed

• No logical relationship between the drugs prescribed and treatment of the condition allegedly existing

Each case must be evaluated on its own merits in view of the totality of circumstances particular to the provider and patient. Regulatory agencies, for example, are typically aware that what constitutes “an inordinately large quantity of controlled substances,” can vary greatly from patient to patient. A particular quantity of a powerful Schedule II opioid might be blatantly excessive for the treatment of a particular patient’s mild temporary pain, and yet be insufficient to treat the severe unremitting pain of a cancer patient.4

REGULATIONS PERTAINING TOINTERNET ACCESS TO CONTROLLED SUBSTANCES

In 2008, an amendment to the CSA was passed to add new regulatory requirements and criminal provisions designed to combat the proliferation of so-called “rogue Internet sites.”10 The Ryan Haight Act made it illegal to dispense controlled substances in all schedules via the Internet. An online pharmacy is defined as a person, entity, or Internet site, whether in the United States or abroad, that knowingly or intentionally delivers, distributes, dispenses, or offers to deliver, distribute, or dispense, a controlled substance by means of the Internet.

This law became effective April 13, 2009. As of that date, it is illegal under federal law to deliver, distribute, or dispense a controlled substance by means of the Internet unless the online pharmacy holds a modification of DEA registration authorizing it to operate as an online pharmacy.

SECURITY REQUIREMENTS RELATED TO CONTROLLED SUBSTANCES

The CFR requires all registrants to provide effective controls and procedures to guard against theft and diversion of the controlled substances they store or handle. Factors used to determine the adequacy of these security controls include:4

1. The location of the premises and the relationship such location bears on security needs.

2. The type of building and office construction.3. The type and quantity of controlled

substances stored on the premises.4. The type of storage medium (safe, vault, or

steel cabinet).5. The control of public access to the facility.

6. The adequacy of registrant’s monitoring system (alarms and detection systems).

7. The availability of local police protection.

Registered health care providers are required to store Schedule II through V controlled substances in a securely locked, substantially constructed cabinet (usually double locked cabinet). In order to maximize security related to controlled substances, DEA recommends that health care providers not employ any of the following persons if they will have potential access to controlled substances:1. Any person who has been convicted of

a felony offense related to controlled substances.

2. Any person who has been denied a DEA registration.

3. Any person who has had a DEA registration revoked.

4. Any person who has surrendered a DEA registration for cause.

Lastly, practitioners should notify the DEA field office in their area of the theft or significant loss of any controlled substances upon discovery.4

DISPOSAL OF CONTROLLED SUBSTANCES

A practitioner may dispose of out-of-date, damaged, or otherwise unusable or unwanted controlled substances, including samples, by transferring them to a registrant who is authorized to receive such materials.4 These registrants are referred to as “Reverse Distributors.” The practitioner should contact their local DEA field office for a list of authorized Reverse Distributors. [For addresses and telephone numbers of field offices, please see the DEA website: www.deadiversion.usdoj.gov/offices_n_dirs/index.html]. Schedule I and II controlled substances should be transferred via the DEA Form 222, while Schedule III–V compounds may be transferred via invoice. The practitioner should maintain copies of the records documenting the transfer and disposal of controlled substances for a period of two years.4

PATIENT EDUCATION ABOUTCONTROLLED SUBSTANCES

Responsible prescribing of controlled substances requires clinicians to fully educate patients about the many issues related to safe use, storage, and disposal of such substances. Not only will educating patients possibly improve their adherence to any medication regimen, it may prevent accidental overdose or inadvertent diversion to non-authorized users.

11

Controlled substances of all kinds require a higher level of care and responsibility on the part of patients due to their potential for misuse or abuse. Hence, education about safe use, storage, and disposal should be part of every provider-patient interaction involving these substances. This education may include verbal instructions delivered by a prescriber, nurse or other trained clinic staff person, written handouts, guidance through other media (such as DVDs or the Internet), or referral to other resources (such as a local clinic webpage or national resources). Patients should be instructed about the proper use and administration of any prescribed controlled substances, including special directions about timing of doses, whether to administer the medication with food or without, and any foods or other medications to avoid while administering. Here are some other key ideas to convey to patients about proper use:• Read the prescription container label each

time to check dosage.• Never use medicines after the expiration

date.• Never share medicines with others.• Do not take a medicine with alcohol or other

sedatives.• Do not take a medicine to promote sleep

(unless it has been specifically prescribed for that use).

• Never break, chew, or crush medicines.• Transdermal products may be affected by

external heat, fever, and exertion, which can increase absorption of a medication, leading to a potentially fatal overdose. In addition, transdermal products with metal foil backings are not safe for use in MRI scanners.

Patients should be continually reminded that sharing, selling, or giving away controlled substances is against the law and poses significant hazards not just to the recipient of the medications, but to society at large.

Physicians must also educate patients about the importance of proper storage of controlled substances. Even children or close relatives can be tempted to use medications they have not been prescribed, and these are often the way controlled substances become available to non-authorized uses. It is best if all controlled substances are stored in a locked cabinet or other secure storage unit. Storage areas should be cool, dry, and out of direct sunlight. Remind patients not to store medications in their car, to keep medications in the original containers, and to avoid storing medications in the refrigerator or freezer unless specifically directed to do so by a healthcare provider or pharmacist. Patients, family members, or caregivers should also monitor pill containers so they will know if any pills are missing.

Educating patients about proper disposal of unused controlled substances is also important. The U.S. Food and Drug Administration recommends a variety of disposal methods, depending on the specific drug being disposed.30 Some states, however, may have different or more stringent guidelines. California, for example, instructs consumers not to flush any medicines down the toilet or drain. If flushing medicines is not allowed in your state, instruct patients to follow the instructions of a pharmacist for disposal or to mix the medicines with an undesirable substance, such as used coffee grounds, put the mixture into a disposable container with a lid or a sealable bag, and place it in the trash. The DEA sponsors the National Take Back Initiative which coordinates periodic take-back programs at thousands of state and local law enforcement agencies across the country. More information about these programs can be found at: http://www.deadiversion.usdoj.gov/drug_disposal/takeback/index.html. CONDITION-SPECIFIC RECOMMENDATIONS TO REDUCE HARM AND SAFELY PRESCRIBE AND

MONITOR CONTROLLED SUBSTANCES

General Considerations Non-opioid controlled substances are a heterogeneous group of medications. The pharmacologic effects of frequently misused drugs include euphoria, sedation, and anxiolysis. Drugs with the highest risk for subsequent addiction rapidly elicit dopamine release in the midbrain. Here both the magnitude and rapidity of dopamine release are of importance. Therefore, potent high-dose immediate-onset medications have greater abuse liability than do their less-potent lower-dose extended-release counterparts.

Unlike opioid controlled substances prescribed for pain relief, health care providers prescribe non-opioid controlled substances for a wide range of disorders. These disorders include psychiatric illnesses, neurological diseases, and obesity. This monograph will review how these agents are used within specific disease states. These discussions are not comprehensive, and it should be remembered that controlled substances are often the last therapeutic option that should be considered to manage a disease or condition, with behavioral, non-pharmacologic, and non-controlled medications tried prior a trial of any controlled substances. Health care providers should be aware of all of the available treatment options for each disease and be able to justify why they believe that a controlled substance is the best therapeutic intervention. Providers should also understand the side-effects of each medication and how to monitor controlled substances for signs of misuse, addiction or abuse.

Anxiety31

The CSA lists numerous anxiolytics as controlled substances. Scheduled drugs include the benzodiazepines, barbiturates, and so called “z-drugs” such as zolpidem, zaleplon and eszopiclone. Benzodiazepines such as alprazolam, clonazepam, diazepam and lorazepam have largely replaced barbiturates for the short-term treatment of anxiety. Because many anxiolytics have sedating properties, these medications are also commonly used as sleep-inducing (hypnotic) agents. Anxiety disorders share features of excessive fear and anticipation of future threat. Fear leads to autonomic arousal, a feeling of imminent danger, and an impulse to escape. In contrast to fear, anxiety leads to hypervigilance, muscle tension, and avoidant behaviors. Physical symptoms associated with anxiety include chest pain, dyspnea, tachycardia, flushing, dry mouth, tremor, dizziness, blurry vision, nausea or vomiting, abdominal pain, diarrhea, and urinary symptoms.32

Fear and anxiety can be non-pathologic, transient emotions. In contrast, pathologic anxiety disorders persist for longer than six months, exist when certain behaviors are no longer developmentally appropriate, and are out of proportion to the threatening event or object. They must also cause distress, significantly alter the patient’s routine, and diminish his or her functioning in everyday life. Examples of anxiety disorders include separation anxiety disorder, specific phobias, social anxiety disorder, panic disorder, agoraphobia, substance/medication-induced anxiety disorder, and generalized anxiety disorder (GAD). Obsessive compulsive disorders and trauma-related disorders are also common causes of anxiety symptoms, though DSM 5 has separated them from other anxiety disorders. Although anxiety disorders are very common, little progress has been made in developing new anxiolytics over the past 50 years.33 Primary care providers prescribe the majority of anxiolytic medications, so there is an urgent need to train them about how to safely prescribe these medications and when to prescribe alternative agents.34 Anxiolytics form a heterogeneous group of agents with a wide range of efficacy and some of these medications are controlled substances with a high potential for morbidity and mortality. Barbiturates and benzodiazepines are controlled substances commonly prescribed for patients suffering from anxiety. However, selective-serotonin uptake inhibitors (SSRI) and behavioral interventions are more effective, have better long-term solutions for anxiety with significantly smaller misuse potential.Barbiturates: Barbiturates were commonly used in the past as sedatives and hypnotics. However, they have serious safety problems and have been replaced by benzodiazepines outside the operating room.

12

Barbiturates are notorious for causing coma in high doses, inducing tolerance, possessing drug-interfering metabolites, creating physical dependency, and inciting severe withdrawal symptoms. Barbiturates work by interfering with sodium and potassium transport and inhibiting the esencephalic reticular activating system. Side-effects of these agents include drowsiness, decreased concentration, drug hangover, nausea, and dizziness. CNS, cardiovascular and respiratory depression may cause overdose death. Withdrawal from barbiturates can cause seizures, delirium, anxiety, weakness, restlessness, tremors, nausea, vomiting, cardiac arrest, and death. Barbiturates are still being used during anesthesia and phenobarbital is used cautiously as an anticonvulsant. Carisoprodol is still prescribed as a muscle relaxantbut it lacks effectiveness as a long term agent and should be used sparingly for short periods of time and only in rare instances.It should be avoided in the elderly, and avoided in patients with substance use disorders. It is metabolized to meprobamate, which, though it was marketed as safer than barbiturates, has most of the pharmacological effects and dangers of barbiturates. It has high abuse and misuse potential.Benzodiazepines: Benzodiazepines have largely replaced barbiturates for short-term anxiolysis because they are safer and more effective, though the evidence for their use long term is also weak. They work by increasing hyperpolarization and inhibiting neuronal firing through the GABA receptors. The selective inhibition of neuronal circuits in the limbic system reduces anxiety. Benzodiazepines have high addiction potential and should only be used for short-term relief of severe anxiety. They are controlled substances, and providers who mis-prescribe them can be held accountable by the DEA. Although they are commonly prescribed, benzodiazepines have a significant risk of morbidity and mortality, including addiction, injuries due to side-effects, deadly interaction with other substances, and death from overdose. In 2010, 29% of overdose deaths in the United States involved benzodiazepines, though 77% of those deaths also involved opioid analgesics. When not used in combination with other drugs, benzodiazepines are implicated in only 3.7% of drug overdoses.35 In 2010, 2.2% of Americans misused tranquilizers, of which benzodiazepines were the major constituent. Nearly 10% of these individuals met criteria for a benzodiazepine use disorder.5 In a case-control study, risk factors for death from prescribed drug overdose included one or more sedative/hypnotic medication prescriptions, male sex, older age, increased number of prescriptions, higher dose of opioid analgesics, and a prescription for buprenorphine, fentanyl, hydromorphone, methadone, or oxycodone.2 Benzodiazepines produce behavioral disinhibition and amnesia

and can work synergistically with opioids to enhance opioid-induced euphoria. Thus patients misusing both benzodiazepines and opioids may lose track of how much they have taken and be inclined to take more. The main side-effects of long-term benzodiazepine use is severe physical dependence and the risk of rebound anxiety. Benzodiazepine withdrawal mimics alcohol withdrawal and is marked by tachycardia, hypertension, anxiety, agitation, disorientation, hallucinations, and seizures.36

Before prescribing benzodiazepines, providers must obtain a current list of medications, and discuss and document the patient’s drug and alcohol history. Concomitant use of benzodiazepines and alcohol can increase the risk of overdose death and the provider will be held liable for unsafe prescribing practices if he or she has failed to document and address these risk factors.37 Physicians should know the patient’s alcohol use patterns before prescribing benzodiazepines. Benzodiazepines should only be prescribed with extreme caution in patients who currently meet criteria, or have met criteria in the past, of an alcohol use disorder. Benzodiazepines should not be used to treat alcohol use disorder. In fact, benzodiazepines can worsen alcohol use disorder and put patients at larger risk for seizure during withdrawal. In one pilot study, an audit of medical clinic records showed that 57% of the records did not contain any information about the patients’ alcohol use and the remaining records only provided limited information that was insufficient to safely prescribe benzodiazepines.37 If a health care provider does not document alcohol use in the history of a patient before prescribing benzodiazepines, he or she is not documenting an appropriate history. Approximately one-third of patients who have long term use of benzodiazepines will experience withdrawal symptoms within two to ten days of stopping use. Some patients will experience withdrawal symptoms on tapering benzodiazepines to a lower dose. Withdrawal symptoms include hyperarousal symptoms, such as insomnia, anxiety, photophobia, heightened sensitivity to sound, unsteadiness, and seizures.38 Patients in a nationwide study in Switzerland who abused benzodiazepines described self-medication for anxiety and insomnia as the primary motivation for misusing this controlled substance. Most patients began taking benzodiazepines after their provider prescribed the medication, and the prescribing provider usually detected the misuse.39

Benzodiazepines should be prescribed for short-term use only and very cautiously in older adults. Side-effects of benzodiazepine use in older adults include motor vehicle collisions, falls, cognitive difficulties, delirium, sleep disturbances, drug-drug interactions, and impaired function.20 However, studies of older adults reveal that health care providers prescribe chronic benzodiazepines

for anxiolysis in this vulnerable population, and 9.5% to 20% of community-dwelling older adults are taking a benzodiazepine.20 Studies of older patients who are taking benzodiazepines show that they come to rely on them for any anxious symptoms, deny the presence of side-effects and are reluctant to taper or discontinue use even when they understand the risks of continued use.40 Health care providers prescribe these medications because they view them as effective, rapidly acting, and eliciting strong patient satisfaction.41 Providers minimize risks of these medications and do not view them as problematic in the older patient population because there is a view that older patients are at lower risk of addiction . As a result, they do not monitor these patients stringently or try to taper them off of long-term use of these drugs. These beliefs contradict practice guidelines and do not meet standard of care.Flumazenil: Flumazenil is the reversal agent for benzodiazepine overdose.42 It is a GABA receptor antagonist that can be administered intravenously. This medication has rapid but short duration and may need to be repeatedly re-administered. It can cause withdrawal symptoms in benzodiazepine dependent patients, including nausea, vomiting, dizziness, agitation and seizures. If flumazenil is administered to patients who are taking Phenobarbital to control their seizures, it may result in onset of seizure activity. Insomnia The American Academy of Sleep defines insomnia as “the subjective perception of difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity for sleep, and that results in some form of daytime impairment.”43 Insomnia is the most common sleep disorder and chronic insomnia is described as insomnia that lasts for longer than one month. Insomnia is primarily a clinical diagnosis. The routine evaluation of insomnia involves obtaining a thorough history and performing a physical examination. In obtaining a history, the health care provider should make sure to ask questions about medical and psychiatric comorbidities including sleep apnea (the STOP-Bang questionnaire (available at: http://www.stopbang.ca/ ) is a good sleep apnea screening tool in primary care), substance use disorders, and stress. The provider may want to discuss the patient’s sleep habits with the patient’s partner or caregiver in case he or she has noticed any sleep abnormalities such as snoring, sleep apnea, sleepwalking, or unusual limb movements. Physical examination should include a neurological exam and an assessment for comorbidities. The provider should ask the patient about prescribed medications, caffeine intake, alcohol intake, and herbal supplements. Initial treatment for insomnia should involve behavioral and lifestyle interventions.

13

Once underlying comorbid conditions have been ruled out or managed, health care providers can recommend improved sleep hygiene, exercise, and cognitive behavioral therapy as first-line treatment. Some patients take over-the-counter antihistamines, opioids, or drink alcohol in an effort to treat insomnia. Providers should discourage patients from using opioids or alcohol as sleep agents. Antihistamines reduce sleep quality and produce residual daytime drowsiness, making them a poor choice for treating insomnia. Although benzodiazepines are commonly prescribed for their hypnotic properties, patients should not rely on benzodiazepines to treat chronic insomnia, and providers should preferentially prescribe non-benzodiazepine sleep agents. Pharmaceutical intervention for treating insomnia should be used when non-pharmaceutical treatments are ineffective, when insomnia significantly interferes with function, or when the underlying cause is addressed but insomnia persists.44 Health care providers should prescribe the lowest effective dose and for a short duration. The provider should avoid prescribing hypnotics for patients who have an underlying history of respiratory depression, myasthenia gravis, substance use disorder, or acute cerebrovascular accident. Temazepam: Temazepam is a benzodiazepine used to treat patients with insomnia who wake up frequently during the night.42 Its peak sedative effect occurs 2-3 hours after it is taken, so patients must take this medication several hours before bedtime. It is a schedule IV controlled substance. Z-Drugs: Zolpidem, Zaleplon, and Eszopiclone: Like benzodiazepines, the Z-drugs enhance the effect of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter. Because they modulate a more specific GABA receptor subtype, the Z-drugs were thought to be less addictive and have less abuse potential than benzodiazepines. Evidence shows, however, that they elicit a similar behavioral profile including reinforcing effects, abuse potential, tolerance, physical dependence, and subjective effects.45 While Z-drug addiction is uncommon, the risk increases at higher doses and in patients with a history of substance use disorders.45 They can all cause withdrawal symptoms if abruptly discontinued after prolonged use. Side-effects are similar in all three and can include nightmares, agitation, hallucinations, complex sleep-related behavior, dizziness, daytime drowsiness, headache and gastrointestinal problems. Narcolepsy: Narcolepsy is characterized by the brain’s inability to regulate the sleep-wake cycle. As a result, individuals with narcolepsy suddenly fall asleep in the middle of the day in “sleep attacks” and experience episodes of extreme daytime sleepiness.46 Approximately 1

in 3,000 Americans has narcolepsy with cataplexy. Males and females are equally affected, and narcolepsy is a life-long chronic condition that often begins between the ages of 7 and 25 years old. Associated symptoms include vivid dreams, hallucinations, and total paralysis immediately before falling asleep or after waking. Some people with narcolepsy also have cataplexy, a loss of voluntary muscle tone that makes the sufferer limp and unable to move. These patients suffer from poor sleep in general and often enter REM sleep several minutes after falling asleep, in contrast to people with normal sleep cycles who enter REM sleep 80-100 minutes after falling asleep. Most people with narcolepsy have low levels of hypocretin, a neurotransmitter which promotes wakefulness. The most likely cause of narcolepsy is through the autoimmune-mediated destruction of hypocretin-containing brain cells in genetically susceptible individuals. Exposures to an early H1N1 vaccine in 2009, certain toxins, dietary factors, hormonal changes, stress, and changes in sleep cycle have all been implicated in the development of narcolepsy. Brain injury and tumor growth into sleep centers of the brain involved in REM sleep have also been associated with this disease. In order to diagnose narcolepsy, health care providers must take a careful sleep history from the patient to determine if shift-work, circadian rhythm abnormalities or pre-existing sleep deprivation are present. The provider should make sure to note any symptoms consistent with cataplexy. Excessive daytime sleepiness and cataplexy are pathognomonic for this disease. Approximately half of patients have all four symptoms of hallucinations, sleep paralysis, cataplexy, and excessive daytime sleepiness.47 Preschool-age children may have different symptoms, including inattentiveness, emotional lability, and hyperactivity.48

Patients may be sent home with a sleep journal and asked to keep track of their sleep patterns for several weeks.46 A thorough physical examination must be performed to exclude any other underlying disease state that may cause similar symptoms, although cataplexy is rarely found outside of narcolepsy. Patient may undergo two tests in the sleep lab: a polysomnogram (PSG) and the multiple sleep latency test (MSLT). At this point, patients are usually referred to neurologists and sleep specialists who can evaluate the results. The PSG records abnormalities in the sleep cycle, and uses electroencephalography and electromyography as part of the evaluation. The MSLT is performed during the day and measures sleep latency, abnormally timed REM episodes, and nerve activity during, and in between, naps. It remains the most important test for diagnosing narcolepsy without cataplexy.49 Measurements of hypocretin levels may also be useful.

Treating narcolepsy is difficult because this disease is due to permanently low hypocretin levels.46 Although bench scientists aim to provide curative intervention through the use of stem-cell therapies to replace hypocretin-producing cells, currently-approved treatments focus on alleviating symptoms. Patients with narcolepsy find this disease highly disruptive to their everyday function. They may fall asleep during work or school, in the middle of a conversation, or during a meal. More dangerously, they may fall asleep while driving or operating heavy machinery. While they are awake, many patients describe persistent mental cloudiness, loss of concentration, fatigue, and extreme exhaustion. Therefore, health care providers prescribe treatments such as modafinil/armodafinil, amphetamines, SSRI’s, and TCA’s to improve wakefulness during the day. At night, patients with narcolepsy experience disrupted sleep, with hallucinations, paralysis, insomnia, and other sleep difficulties. Consequently, other treatments, including behavioral interventions, attempt to improve duration and quality of sleep. Sodium oxybate is the only medication approved in the United States to treat cataplexy. First-line agents for patients with excessive daytime sleepiness are modafinil/armodafinil alone or in combination with sodium oxybate.50 Alternative treatments include amphetamines (including methylphenidate), SSRI’s, and TCA’s. Modafinil/Armodafinil: Modafinil and armodafinil (r-enantiomer) have replaced amphetamines to become the first-line stimulants for patients with narcolepsy.51 These medications reduce excessive daytime drowsiness and improve alertness with a better side-effect profile than amphetamines. They share a mechanism of action with amphetamines, namely blocking dopamine reuptake, though the observed effects are much milder.52 Modafinil is a scheduled IV controlled substance, given the shared mechanisms with addictive stimulant drugs. It has been shown to have similar mood elevating properties, though to a lower degree.52 Also, monkeys trained to self-administer cocaine will self-administer modafinil as well.52 Withdrawal symptoms include anhedonia, lethargy, anxiety and insomnia. Sodium Oxybate: Sodium oxybate (gamma hydroxybutyrate, GHB, Xyrem) is a sedative approved to decrease daytime sleepiness and cataplexy in the United States.51 It restores sleep continuity, decreases hallucinations, and reduces sleep paralysis. Sodium oxybate must be administered twice per night because of its short half-life, and dose titration can be challenging. Side-effects include nocturnal confusion, sleepwalking, dizziness, nausea and enuresis. Patients who are taking this medication should avoid alcohol and other sedating medications because overdose of sodium oxybate can lead to fatal respiratory depression. These safety

14

concerns mean that the medication is tightly restricted and classified as a schedule III controlled substance . though in a recent analysis, rates of addiction are relatively low, <1%.53

Methylphenidate and Amphetamine-Like Stimulants: Amphetamines indirectly act on the central nervous system (CNS) and peripheral nervous system (PNS) by blocking monoamine oxidase and releasing intracellular catecholamine into synaptic spaces.42 In the CNS, amphetamines stimulate the cerebrospinal axis, cortex, brain stem and medulla. As a result, the patient experiences improved alertness, decreased appetite, and less daytime drowsiness. Side-effects include neurological, cardiovascular, and gastrointestinal symptoms. Neurological symptoms range from insomnia, irritability, tremor, and dizziness to confusion, delirium, panic, and suicidal ideation. Cardiovascular side-effects can be serious, including cardiac arrhythmias, hypertension, angina, and circulatory collapse. Amphetamines should not be prescribed or administered to patients with cardiovascular disease or who are taking MAO-inhibitors. Lastly, patients taking amphetamines may experience anorexia, nausea/vomiting, abdominal pain or diarrhea as a result of taking this medication. Chlorpromazine, an alpha-blocker, is the antidote for amphetamine overdose. The 2010 National Survey on Drug Use Health estimates that of the 7 million current nonmedical users of prescription medications, 1.1 million use stimulants.54 Though the percentage of past month users of prescription stimulants has remained stable, the Drug Abuse Warning Network data show that the number of emergency room visits related to nonmedical use of prescription stimulants has increased 189% since 2004.54 The misuse of stimulants is most common in adolescents and is often associated with the desire for cognitive enhancement and euphoria.14 Use patterns tend to coincide with examination periods and as a means to counter the effects of binge drinking and marijuana use.55 As with opioids, immediate-release formulations have more abuse liability, and long acting and tamper-resistant formulations have been developed to discourage misuse. Stimulants should be prescribed with caution and closely monitored in patients with a history of substance use disorder. Alternative, non-addictive treatments should be tried first. Attention-Deficit/Hyperactivity Disorder (ADHD) A t ten t ion-Def i c i t /Hyper-ac t i v i ty Disorder is one of the most commonly-diagnosed disorders of childhood. According to the CDC, 11% of children between the ages of 4 and 17 (6.4 million children) have been diagnosed with ADHD in the United States.56 Boys are twice as likely as girls to receive a diagnosis and the average age of diagnosis is 7 years old. Furthermore, the rate of diagnosis has been increasing 5% per year since 2003.

ADHD treatment involves both medical and behavioral interventions, with about half of preschoolers with ADHD taking a medication for this disease in 2011.56 Health care providers frequently prescribe amphetamines and methylphenidate, schedule II controlled substances, for the management of ADHD. Neurobiological findings in children with ADHD include delayed brain maturation, inhibitory control defects, noradrenergic dysfunction, and dopaminergic dysfunction.57 However, the diagnosis of ADHD remains a clinical diagnosis. The American Academy of Pediatrics recommends that primary care providers consider evaluating pediatric patients between the ages of 4 and 18 who present with academic or behavioral problems and symptoms of inattention, hyperactivity, and impulsivity.58 Providers should use the criteria for a diagnosis of ADHD as described in the DSM 5. These criteria for diagnosing ADHD require a persistent pattern of inattention and/or hyperactivity-impulsivity. For a diagnosis of inattention, at least six out of nine symptoms must have been present for the past six months in children younger than 17. These symptoms must be developmentally inappropriate and disrupt school/work and social life. ADHD can have predominantly inattentive presentation, predominantly hyperactive/impulsive presentation, or combined presentation. Providers should document the severity of ADHD, ranging from mild to severe depending on the number of symptoms and impairment of social or occupational functioning. They should also make sure to assess the child and rule out other causes of symptoms or co-morbid conditions, such as deafness or cognitive delay. Guidelines suggest that health care providers should take an interdisciplinary approach to treating ADHD. Educational interventions, behavioral approaches, and medication all may have roles in managing this disorder. The American Academy of Pediatrics has written recommendations for treatment based on age. For children ages 4-5, the health care provider should prescribe behavior therapy to be administered by the parent and/or teacher as first-line intervention. If the child continues to have moderate or severe functional disturbance or there is no improvement in behavior, the provider may prescribe methylphenidate. For older children, ages 6-11, the health care provider should prescribe teacher and/or parent administered behavioral intervention, FDA approved medication, or both. Evidence is strongest for prescribing stimulants, followed by, in descending order of efficacy for adolescents, atomoxetine, extended release guanfacine, and extended release clonidine. Adolescents ages 12-18 do well with FDA approved medication and behavioral interventions. The values and preferences of the

patient and family are critical factors in deciding whether or not to initiate medication.59

Behavioral interventions are preferred to medication as the initial intervention for preschool children with ADHD and are adjuncts to medication for school-aged children and adolescents.59

Medical management of ADHD includes treatment with stimulants (methylphenidate, amphetamine), atomoxetine, extended release (ER) guanfacine, and extended release (ER) clonidine. The choice of the initial medication depends upon a number of factors, including:59,60

• The duration of desired coverage (completion of homework or driving may require coverage into the evening)

• The ability of the child to swallow pills or capsules

• The time of day when the target symptoms occur

• The desire to avoid administration at school• Coexisting tic disorder• Coexisting emotional or behavioral condition• Potential adverse effects• History of substance use disorders in patient

or household member: avoid stimulants or use stimulants with less potential for abuse (Slow-release, long acting)

• Preference of the child/adolescent and his/her parent/guardian

• Expense (in general, short acting stimulants are least expensive)

Methylphenidate And Amphetamine: In one study evaluating the role of psychostimulants (such as methylphenidate, dexamphetamine, and modafinil) in managing co-morbid ADHD and non-ADHD disorders, these medications improved concentration, mood, and cognitive function while decreasing fatigue.61 Side-effects include anorexia, sleep difficulties, abdominal pain, and headaches. Some children have diminished height with long-term use.58 Psychiatric symptoms in younger children may include mood lability and dysphoria. Although rare, hallucinations and psychotic symptoms have been reported as a side-effect of stimulant use. Health care providers and parents are most concerned about reported cases of sudden cardiac death in previously healthy children who had been prescribed stimulants to treat ADHD. Providers must make sure to ask the child and parents about any specific cardiac symptoms or history of cardiovascular disease in the child. Furthermore, providers must obtain a thorough family history and ask about any cases of sudden death in the family, hypertrophic cardiomyopathy, Wolf-Parkinson-White syndrome, or long QT syndrome. Health care providers should avoid prescribing stimulants if they are concerned about increased risk of side-effects or potential for substance misuse or diversion.62

When prescribing stimulants, it is not only important to establish an accurate diagnosis

15

of ADHD, but also to monitor symptoms and for evidence of misuse.59 Stimulant diversion and misuse can be preventedto some extent, by prescribing long-acting stimulants with less potential for abuse, and by keeping track of prescription dates.63,64 Having open discussions with parents and patients about the risk of misuse and diversion is helpful, such that patients can be prepared if they are asked to sell their medications and so that parents are aware of the risks.63

The non-medical use of prescription stimulants represents the second most-common form of illicit drug use in college, second only to marijuana use.65 A 2008 study showed that lifetime rates of diversion ranged from 16% to 29% of students with stimulant prescriptions who were asked to give, sell, or trade their medications.64 Risk factors for diversion in this study included white race, being a members of a fraternity or sorority, individuals with lower grade point averages, use of immediate-release compared to extended-release preparations. Reported reasons for use, misuse, and diversion of stimulants include to concentrate, improve alertness, “get high,” or to experiment.64

Evaluation for substance use disorders and binge drinking should also be undertaken when prescribing stimulants for ADHD. Although there is a higher risk of misuse and diversion of stimulants in those with a history of substance use disorders, it should be noted that a critical risk factor for having ongoing substance use disorders in adulthood is the persistence of ADHD symptoms and adequate treatment of ADHD in childhood is associated with a lower risk of subsequent drug and alcohol use disorders.64

Atomoxetine: Atomoxitine is generally less effective than stimulants for ADHD symptoms.58 It is a non-stimulant norepinephrine reuptake inhibitor that can be used as second-line medical management of ADHD. Side-effects include gastrointestinal distress, somnolence, and anorexia. Rare side-effects include increase in suicidal ideation and drug-induced hepatitis. Atomoxitine may be more appropriate than stimulants for patients with a personal or family history of substance use disorders, or if there is concern for misuse or diversion.ER Guanfacine: Extended release guanfacine is a non-stimulant adrenergic agonist.58 It is used to treat hypertension, anxiety, and ADHD. Side-effects include somnolence and dry mouth.ER Clonidine: Like guanfacine, clonidine is an alpha-agonist that can be used to treat mild to moderate hypertension, as well as ADHD.42 Side-effects include mild sedation and dry mouth, but the patient may experience rebound hypertension if clonidine is abruptly withdrawn. Alpha-2-adrenergic agonists usually are used when children respond poorly to a trial of stimulants or atomoxetine, have unacceptable side effects, or have significant coexisting conditions

Obesity Obesity is a complex chronic disease that is becoming increasingly common internationally and in the United States. The World Health Organization (WHO) reports that more than 1.9 billion people worldwide are obese or overweight, and the worldwide prevalence of obesity doubled between 1980 and 2014.66 In the United States, approximately 34.9% of adults, or 78.6 million people, are obese.67 People who suffer from obesity have significant increases in morbidity and mortality.66

Weight loss can significantly improve obesity-associated morbidity and mortality. In obese or overweight patients at risk for type 2 diabetes, weight loss of 2.5-5 kg over at least two years can decrease the risk of obesity-associated type 2 diabetes by 30-60%.28 Similarly, in overweight or obese adults with or without cardiovascular risk factors, lipid levels improve in a dose-response manner with weight loss. In order to effectively treat obesity, health care providers should understand the appropriate behavioral and dietary changes patients must make in order to lose weight and maintain weight loss. They should also understand when it is appropriate to recommend medical management or surgical intervention, and the risks and benefits of those interventions. Obesity can be very challenging to treat, in part because of physiological mechanisms that cause the human body to resist weight loss. Providers must learn the necessary skills for how to motivate patients while also respecting their autonomy. Effective management often involves interdisciplinary teamwork with nutritionists and other trained consultants. Treatment for obesity includes dietary restriction, comprehensive lifestyle intervention, medical management, and surgical intervention. Here we focus just on medical management with controlled substances. In 2011, 2.74 million patients were having their morbid obesity treated pharmacologically.68 Pharmaceutical interventions for weight reduction may suppress appetite, reduce absorption, or increase energy expenditure.69 Medications currently approved for pharmacological weight management include short-term use of phentermine, orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion, and liraglutide.70 Studies show that different proportions of patients achieve clinically meaningful weight loss relative to placebo. Thus, the ranges were 37–47% for lorcaserin, 35–73% for orlistat, and 67–70% for maximally dosed phentermine/topiramate-ER.68 Phentermine, an anorexic agent used to treat obesity, is classified as a schedule III controlled substance.Phentermine: Phentermine is an anorexic agent. It reduces food intake by causing early satiety. It is an amphetamine-like drug that interferes

with norepinephrine release. A similar drug, sibutramine was withdrawn from the market in 2010 because of its association with increased risk of cardiovascular events and stroke. Phentermine/topiramate was approved by the Food and Drug Administration (FDA) in 2012. It is well-tolerated with dose-dependent adverse events. Safety concerns include tachycardia, teratogenicity, metabolic acidosis, psychiatric disorders, and cognitive adverse events.71 It should not be used in patients with cardiovascular disease (hypertension or coronary heart disease) or in pregnant women because of an increased risk of orofacial clefts in infants exposed to the combination drug during the first trimester of pregnancy.

Case Study Exercise 3Instructions: Spend 10 minutes reviewing the continuation case study below and considering the questions and commentary that follow. Jenny returns for a follow-up visit with you after completing her cardiovascular evaluation. Even though her cardiovascular evaluation was negative for abnormalities, she has thought about the risks of phentermine and decided that she would like to consider alternative interventions for managing her obesity. In particular, she is concerned that her history of fen-phen use and a family history of heart disease might lead to cardiac problems in the future. You agree and stop the phentermine. Question 1: If the patient can no longer safely take phentermine, describe alternative options she may have for weight loss. Options may include pharmaceutical and non-pharmaceutical alternatives. Commentary on Question 1: The patient’s non-pharmaceutical weight loss options include dietary, exercise, behavioral, and surgical interventions. Dietary interventions for morbidly obese women may entail caloric reduction producing at least a 500 kcal/day deficit, resulting in a goal of 1,200-1,500 kcal consumed per day. Exercise goals include at least 150 minutes of aerobic activity per week, and behavioral therapy is meant to encourage adherence to dietary changes and physical activity.28

The patient should discuss whether or not she is a good candidate for surgical intervention with her primary care provider and a bariatric surgeon in order to decide if any surgical interventions may help her with weight loss. You refer Jenny to a comprehensive lifestyle intervention program located at a local academic center. There, the patient begins taking orlistat, goes on an AHA diet, and starts walking and jogging for 30 minutes 6 times a week. She is carefully monitored by the medical team at her

16

comprehensive lifestyle intervention program. Two months later, Jenny returns to your clinic. She has lost 10 lbs, and she is determined to continue on her program. However, she has been having difficulty sleeping for the past month, and was wondering if you could prescribe a medication she saw advertised on television to help her sleep. Question 2: You note that the sleep agent the patient would like you to prescribe is a schedule IV controlled substance. How would you proceed with your insomnia evaluation? Commentary on Question 2: First, obtain a thorough history, including a sleep history, and review the patient’s medical and psychiatric co-morbid conditions. The provider should ask the patient about prescribed medications, caffeine intake, alcohol intake, and herbal supplements. If anyone else knows about the patient’s sleep habits, ask that person if he or she has noticed any unusual patient sleep patterns, including snoring, sleep apnea, sleepwalking, or unusual limb movements. Next, perform a physical examination including a neurological assessment to identify any co-morbidities. Consider administering an Epworth Sleepiness Scale or the STOP-Bang test to assess for sleep apnea during the clinic visit. Finally, request that the patient keep a sleep log for 2 weeks to identify patterns of sleep disruption. She should follow up in 3 weeks with the results. In the meantime, review and encourage behavioral interventions to improve sleep, include exercise, relaxation therapy, and good sleep habits.44

Jenny returns to see you for a follow-up visit. She is excited to be losing weight and feeling healthier than she has ever felt in her adult life. However, she has recently been considering bariatric surgery and would like to discuss her options with you. After reviewing the risks and benefits of surgical intervention with her, you both agree to wait to see if she makes significant weight-loss progress through her current program. If she changes her mind, you plan to refer her to a bariatric surgeon affiliated with the local academic center. The patient also brings the results of her sleep journal and reports that her insomnia is getting worse, despite her adherence to sleep inducing behaviors and diligent use of melatonin. She is frustrated and exhausted. Question 3: You decide to prescribe a schedule IV controlled substance for a short time to treat the patient’s insomnia. What 6 additional steps must you take to ensure you are following best practices for prescribing a controlled substance?

Commentary on Question 3: Here are the recommended steps for ensuring best practices for prescribing a controlled substance:

1. Document a thorough history and complete physical examination.

2. Discuss the side-effects and addictive potential of the controlled substance with the patient.

3. Check the electronic prescription-monitoring database to corroborate the patient’s controlled substance history.

4. Document that you have discussed any history of substance use, concerns from the patient’s family members, and details about the patient’s treatment plan in the chart. Advise the patient to not use concomitant alcohol.

5. Establish guidelines and describe the duration of treatment.

6. Carefully monitor the patient for any evidence of misuse during treatment.

CONCLUSIONS

This CME monograph on best practices for managing non-opioid controlled substances summarized the United States federal legislation governing the prescription of controlled substances and offered suggestions for how health care providers can comply with those regulations. The monograph provided a list of frequently encountered non-opioid controlled substances grouped by schedule. It reviewed the legal requirements for compliance in prescribing these substances, including how to perform critical components of the history and physical examination, assessing patients for substance use disorder risk, and documenting risk stratification. Before prescribing controlled substances, health care providers are obligated to document how they made the diagnosis and why a controlled substance is the best treatment for the patient. This monograph also reviewed some common conditions that may be treated with controlled substances. The current epidemic of opioid use disorder has brought to light the responsibility of medical providers to responsibly and safety prescribe opioids, as well as controlled substances. The monograph reviewed screening tools for substance use disorder, methods to assess for substance use disorder, and responsibility of the provider to refer for treatment when appropriate

The government frequently changes the federal requirements for compliance with controlled substances. Substances are added, removed, or transferred between schedules in the controlled substance list. For example, the American Medical Association, the Institute of Medicine, and the American College of Physicians have petitioned the DEA to shift cannabis from Schedule I to Schedule II in light of the voluminous testimony that this substance does have valid medical uses and to facilitate research on more effective therapeutic uses of the relevant compounds contained in raw

cannabis.72

In order to maintain compliance, responsible health care providers must be aware of changes in legislation and regulatory requirements associated with commonly prescribed substances. They must maintain current DEA licensure for the state in which they practice and ensure that the DEA has their most current mailing address. When prescribers fill out a prescription for a controlled substance, they must ensure that all parts of the prescription are filled out properly, and they should take schedules into account when sending prescriptions to the pharmacy or ordering re-fills. Lastly, health care providers should closely monitor patients who are taking controlled substances for signs of addiction, overdose, side-effects, and drug-drug interactions. Clearly, the rise of prescription drug abuse, and the wider use of controlled substances, is related to social, cultural, and economic forces both larger and more powerful than any role that clinicians have in their day-to-day work with controlled substances.73 But at the same time, clinicians can take simple steps to insure that controlled substances are prescribed safely and transparently. By so doing, those prescribers protect not only their patients, but society at large and, also, themselves should they encounter the scrutiny of regulators. References1. Centers for Disease Control & Prevention. Vital signs: overdoses of prescription opioid pain relievers---United States, 1999--2008. MMWR. Morbidity and mortality weekly report. 2011;60(43):1487-1492.2. Paulozzi LJ, Kilbourne EM, Shah NG, et al. A history of being prescribed controlled substances and risk of drug overdose death. Pain medicine. 2012;13(1):87-95.3. Gwira Baumblatt JA, Wiedeman C, Dunn JR, Schaffner W, Paulozzi LJ, Jones TF. High-risk use by patients prescribed opioids for pain and its role in overdose deaths. JAMA internal medicine. 2014;174(5):796-801.4. Drug Enforcement Agency. Practitioner’s Manual: Section II. 2015; http://www.deadiversion.usdoj.gov/pubs/manuals/pract/section2.htm. Accessed June 13, 2015.5. Substance Abuse and Mental Health Services Administration. National survey on drug use and health 2010. 2010; http://archive.samhsa.gov/data/NSDUH/2k10nsduh/2k10results.htm. Accessed December 7, 2015.6. Faguet GB. Pain Control and Drug Policy: A Time for Change. Santa Barbara, CA: Praeger; 2010.7. Abood R. Pharmacy Practice and the Law, 5th Ed. Sudbury, MA: Jones and Bartlett Publishers; 2008.8. Drug Enforcement Agency. Federal regulations. 2015; http://www.deadiversion.usdoj.gov/fed_regs/actions/2015/fr0519_2.htm. Accessed June 11, 2015.9. Sapienza FL. Abuse deterrent formulations and the Controlled Substances Act (CSA). Drug and alcohol dependence. 2006;83 Suppl 1:S23-30.10. US Department of Justice DEA. Drugs of Abuse, 2011 Edition: A DEA Resource Guide. 2011.11. Drug Enforcement Agency. DEA List of Controlled Substances 2015. 2015; http://www.deadiversion.usdoj.gov/drug_chem_info/index.html. Accessed December 7, 2015.12. Katzung BG. Basic Clinical Pharmacology 6th Ed.

17

Norwalk, CT: Appleton & Lange; 1995.13. Olkkola KT, Ahonen J. Midazolam and other benzodiazepines. Handb Exp Pharmacol. 2008(182):335-360.14. Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry. 2005;18(3):249-255.15. Lemmer B. The sleep-wake cycle and sleeping pills. Physiol Behav. 2007;90(2-3):285-293.16. Drug Enforcement Agency. Role of authorized agents in communicating controlled substance prescriptions. 2015; http://www.deadiversion.usdoj.gov/fed_regs/rules/2010/fr1006.htm. Accessed June 11, 2015.17. American Psychiatric Association. DSM-5, Diagnostic and Statistical Manual of Mental Disorders: Fifth ed. Washington DC: American Psychiatric Association; 2013.18. Centers for Disease Control & Prevention. Prescription Drug Abuse Report. 2015; http://www.cdc.gov/drugoverdose/pdf/hhs_prescription_drug_abuse_report_09.2013.pdf. Accessed June 12, 2015.19. Drug Enforcement Agency. Registrant Actions. 2015; http://www.deadiversion.usdoj.gov/fed_regs/actions/2015/fr0520_2.htm. Accessed June 11, 2015.20. Llorente MD, David D, Golden AG, Silverman MA. Defining patterns of benzodiazepine use in older adults. J Geriatr Psychiatry Neurol. 2000;13(3):150-160.21. Surapaneni P, Vinales KL, Najib MQ, Chaliki HP. Valvular heart disease with the use of fenfluramine-phentermine. Tex Heart Inst J. 2011;38(5):581-583.22. Drug Enforcement Agency. Prescriptions. 2015; http://www.deadiversion.usdoj.gov/faq/prescriptions.htm. Accessed June 13, 2015.23. Drug Enforcement Agency. What is the DEA’s Policy on Locum Tenens? 2015; http://www.deadiversion.usdoj.gov/faq/locum_tenens.htm. Accessed June 13, 2015.24. Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain medicine. 2005;6(2):107-112.25. Liebschutz JM, Saitz R, Weiss RD, et al. Clinical factors associated with prescription drug use disorder in urban primary care patients with chronic pain. J Pain. 2010;11(11):1047-1055.26. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance. Pain physician. 2012;15(3 Suppl):S67-116.27. American Academy of Family Practice. Guidelines for the use of opioid therapy in patients with chronic noncancer pain. 2012; http://www.aafp.org/dam/AAFP/documents/patient_care/pain_management/opioid-abuse-position-paper.pdf. Accessed June 15, 2015.28. National Heart Lung & Blood Institute. Obesity Evidence Review. 2015; https://www.nhlbi.nih.gov/sites/www.nhlbi.nih.gov/files/obesity-evidence-review.pdf. Accessed June 27, 2015.29. Obesity Society. Executive Summary: Guidelines for the management of overweight and obesity in adults. 2013; http://onlinelibrary.wiley.com/doi/10.1002/oby.20821/pdf. Accessed June 27, 2015.30. Food and Drug Administration. How to dispose of unused medicines. 2015; http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm101653.htm. Accessed January 5, 2016.31. von Moltke LL, Greenblatt DJ. Medication dependence and anxiety. Dialogues Clin Neurosci. 2003;5(3):237-245.32. Lyness JM. Psychiatric Pearls. Philadelphia, PA: F.A. Davis Company; 1997.

33. Stewart AM, Nguyen M, Poudel MK, et al. The failure of anxiolytic therapies in early clinical trials: what needs to be done. Expert Opin Investig Drugs. 2015;24(4):543-556.34. Strain JJ, Pincus HA, Gise LH, Houpt JL. The role of psychiatry in the training of primary care physicians. Gen Hosp Psychiatry. 1986;8(5):372-385.35. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. Jama. 2013;309(7):657-659.36. Marino PL, Sutkin KM. The ICU Book. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.37. Graham AV, Parran TV, Jr., Jaen CR. Physician failure to record alcohol use history when prescribing benzodiazepines. J Subst Abuse. 1992;4(2):179-185.38. Lader M. Anxiolytic drugs: dependence, addiction and abuse. Eur Neuropsychopharmacol. 1994;4(2):85-91.39. Ladewig D. Abuse of benzodiazepines in western European society--incidence and prevalence, motives, drug acquisition. Pharmacopsychiatria. 1983;16(4):103-106.40. Cook JM, Biyanova T, Masci C, Coyne JC. Older patient perspectives on long-term anxiolytic benzodiazepine use and discontinuation: a qualitative study. Journal of general internal medicine. 2007;22(8):1094-1100.41. Cook JM, Marshall R, Masci C, Coyne JC. Physicians’ perspectives on prescribing benzodiazepines for older adults: a qualitative study. Journal of general internal medicine. 2007;22(3):303-307.42. Mycek M, Harvey A, Champe PC. Pharmacology, 2nd Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2000.43. American Academy of Sleep Medicine. Clinical guideline for the evaluation and management of chronic insomnia in adults. 2015; http://aasmnet.org/practiceparameters.aspx?cid=109. Accessed December 30, 2015.44. Ramakrishnan K, Scheid DC. Treatment options for insomnia. Am Fam Physician. 2007;76(4):517-526.45. Victorri-Vigneau C, Dailly E, Veyrac G, Jolliet P. Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. British journal of clinical pharmacology. 2007;64(2):198-209.46. National Institute of Neurological Disorders and Stroke. Narcolepsy Fact Sheet. 2015; http://www.ninds.nih.gov/disorders/narcolepsy/detail_narcolepsy.htm. Accessed June 22, 2015.47. Babiker MO, Prasad M. Narcolepsy in children: a diagnostic and management approach. Pediatr Neurol. 2015;52(6):557-565.48. Nevsimalova S. The diagnosis and treatment of pediatric narcolepsy. Curr Neurol Neurosci Rep. 2014;14(8):469.49. Baumann CR, Mignot E, Lammers GJ, et al. Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. Sleep. 2014;37(6):1035-1042.50. Thorpy MJ. Update on therapy for narcolepsy. Curr Treat Options Neurol. 2015;17(5):347.51. Wozniak DR, Quinnell TG. Unmet needs of patients with narcolepsy: perspectives on emerging treatment options. Nat Sci Sleep. 2015;7:51-61.52. Food and Drug Administration. Provigial Full Prescribing Information Cephalon, Inc. 2015.53. Wang YG, Swick TJ, Carter LP, Thorpy MJ, Benowitz NL. Safety overview of postmarketing and clinical experience of sodium oxybate (Xyrem): abuse, misuse, dependence, and diversion. J Clin Sleep Med. 2009;5(4):365-371.54. Substance A, Mental Health Services Administration Public Health Service USDoH, Human S. Summary of the 2009 National Survey on Drug Use and Health.

Journal of pain & palliative care pharmacotherapy. 2010;24(4):434-438.55. McCabe SE, Knight JR, Teter CJ, Wechsler H. Non-medical use of prescription stimulants among US college students: prevalence and correlates from a national survey. Addiction. 2005;100(1):96-106.56. Centers for Disease Control & Prevention. ADHD Data and Statistics. 2015; http://www.cdc.gov/ncbddd/adhd/data.html. Accessed June 24, 2015.57. Dopheide JA, Pliszka SR. Attention-deficit-hyperactivity disorder: an update. Pharmacotherapy. 2009;29(6):656-679.58. American Academy of Pediatrics. ADHD: Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescent. 2015; http://pediatrics.aappublications.org/content/ear ly/2011/10/14/peds.2011-2654.full.pdf. Accessed June 27, 2015.59. Subcommittee on Attention-Deficit/Hyperactivity D, Steering Committee on Quality I, Management, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007-1022.60. Pliszka S, Issues AWGoQ. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921.61. Sinita E, Coghill D. The use of stimulant medications for non-core aspects of ADHD and in other disorders. Neuropharmacology. 2014;87:161-172.62. Wilens TE, Morrison NR. The intersection of attention-deficit/hyperactivity disorder and substance abuse. Curr Opin Psychiatry. 2011;24(4):280-285.63. Schonwald A. Update: attention deficit/hyperactivity disorder in the primary care office. Current opinion in pediatrics. 2005;17(2):265-274.64. Wilens TE, Adler LA, Adams J, et al. Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature. J Am Acad Child Adolesc Psychiatry. 2008;47(1):21-31.65. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE. Monitoring the Future national survey results on drug use, 1975–2010: Volume I, Secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan 2011.66. World Health Organization. Obesity. 2015; http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed June 23, 2015.67. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. Jama. 2014;311(8):806-814.68. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. Jama. 2014;311(1):74-86.69. American Family Physician. Medical Management of Obesity. 2015; http://www.aafp.org/afp/2000/0715/p419.html. Accessed June 27, 2015.70. Fujioka K. Current and emerging medications for overweight or obesity in people with comorbidities. Diabetes Obes Metab. 2015;17(11):1021-1032.71. Hainer V, Aldhoon-Hainerova I. Tolerability and safety of the new anti-obesity medications. Drug Saf. 2014;37(9):693-702.72. Bostwick JM. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin Proc. 2012;87(2):172-186.73. Fishman SM. Responsible Opioid Prescribing: A Clinician’s Guide, 2nd Ed. Washington, DC: Waterford Life Sciences; 2012.

18

CONTROLLED SUBSTANCE EDUCATION FOR PRESCRIBERSSelf-Assessment

Choose the best possible answer for each question and mark your answers on the Self-Assessment answer sheet at the end of this book. There is a required score of 70% or better to receive a Certificate of completion.

1. The regulations set forth in the CSA are primarily enforced by _______________.

A. The Department of Justice and the DEAB. The National Institutes of HealthC. The Food and Drug AdministrationD. The Substance Abuse and Mental Health Services

Administration

2. What two competing needs must the CSA and regulators attempt to balance?

A. The need to contain the spiraling costs of prescription medications while also supporting the pharmaceutical industry’s need to support expensive research and development efforts.

B. The need to maintain an adequate supply of controlled substances for legitimate purposes while simultaneously reducing their diversion and abuse.

C. The need to regulate the pharmaceutical industry while also supporting law enforcement agencies.

D. The need to punish those abusing prescription medications with the need to provide adequate social support for addicts.

3. Which of the following factors might be used to determine into which schedule a drug or other substance should be placed?

A. The history and current pattern of abuse of a drugB. Scientific evidence of the drug’s pharmacological

effectC. The drug’s actual or relative potential for abuseD. All of the above

4. Into how many classes does the CSA assign drugs or other substances?

A. 4B. 5C. 6D. 10

5. Heroin, LSD, MDMA, and cannabis are currently listed in which CSA schedule?

A. IB. IIC. IIID. IV

6. Drugs in which schedule are deemed to have a high potential for abuse or dependence but also have a currently accepted medical use in the US?

A. IB. IIC. IIID. IV

7. Substances in which schedule have a low potential for abuse, and also have currently accepted medical uses in the United States?

A. IB. IIC. IIID. IV

8. Any person who handles or intends to handle controlled substances must obtain what?

A. A registration from their state Medical BoardB. A registration from the Drug Enforcement

AdministrationC. A registration from the FDAD. A registration from the Department of Homeland

Security

9. If a physician is filling in for another physician in another state as part of a locum tenens arrangement, the substitute physician can legally prescribe controlled substances as long as he or she is legitimately registered with the DEA in his or her home state.

A. TRUE B. FALSE

10. In an emergency, a prescriber may phone or electronically submit a prescription for a Schedule II drug to a pharmacy, but must follow up with a written prescription within 7 days.

A. TRUE B. FALSE

19

11. Which of the following items does not need to be contained in any prescription for a controlled substance?

A. Proof of informed consentB. Patient’s name and addressC. Drug strengthD. Number of refills (if any)

12. Which of the following might suggest inappropriate prescribing of controlled substances by a clinician?

A. Prescribing a drug for which no logical relationship exists with the alleged condition of a patient

B. Prescribing a substance without performing a physical examination

C. Prescribing the substance at intervals inconsistent with legitimate medical treatment

D. All of the above

13. The Ryan Haight Act made it illegal to _________________.

A. Dispense controlled substances in all schedules via the Internet

B. Dispense controlled substances in a state different from the one in which a practitioner is registered

C. Dispense Schedule I substances to patients for any reasonD. Dispense controlled substances to minors

14. Although initially thought to be less prone to induce tolerance and dependence than barbiturates, benzodiazepines are now recognized to be just as liable to diversion and abuse.

A. TRUE B. FALSE

15. Drugs with the highest risk for subsequent addiction slowly elicit dopamine release in the midbrain.

A. TRUE B. FALSE

20

This course is designed for all physicians (MD/DO), physician assistants, and nurse practitioners.

Physicians, nurses, and other health care professionals must better understand their competing responsibilities related to the prescription of opioids and be able to effectively evaluate all patients for their level of risk for misuse or abuse of opioids. This course reviews the 2016 CDC guidelines for prescribing opioids to patients with chronic non-cancer pain. An expert panel formed to create guidelines for the use of opioids in the treatment of chronic, non-cancer pain concluded that adequate patient risk assessment and risk management for opioid abuse, addiction, and diversion is essential.

InforMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

InforMed designates this enduring material for maximum of 4 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Completion of this course will better enable the course participant to:1. Discuss the current scope of prescription opioid abuse, addiction, and overdose deaths.2. Recognize recommended time frames for clinician evaluation of risks and benefits following initiation of an opioid

prescription.3. Describe the contrasting levels of evidence for the effectiveness of opioids for long-term treatment of chronic non-

cancer pain and for the severity of the potential risks posed by such treatment.4. Explain the value of function-based treatment goals as opposed to pain-relief goals.5. Identify the 50 milligrams morphine equivalent/day (MMED) level that is recommended as a point to reassess benefits

and risks of an opioid prescription.6. Explain why special care must be taken with extended-release/long-acting (ER/LA) opioid formulations.7. Discuss why methadone must be prescribed with particular caution.8. Describe the recommendations about the prescription of opioid analgesics to pregnant women.9. Identify the potential value of using PDMPs and the recommended frequency for consulting a PDMP for patients on

long-term opioid therapy.

TARGET AUDIENCE

COURSE OBJECTIVE

ACCREDITATION STATEMENT:

DESIGNATION STATEMENT:

LEARNING OBJECTIVE

HOW TO RECEIVE CREDIT:

MAXIMUM CREDITS: FORMAT:COURSE DATES:

Read the course materials

Complete the self-assessment questions at the end. A score of 70% is required.

Return your customer information/answer sheet, evaluation,and payment to Informed by mail, phone, fax or complete online at course website under NETPASS.

Release Date: 12/2016 Enduring Material (Self Study)Exp. Date: 12/2019

4 AMA PRA Category 1 CreditsTM

CDC OPIOID PRESCRIBING GUIDELINES FOR CHRONIC PAIN

21

Stephen BraunMedical WriterBraun Medical Media

Elizabeth ThomasMSN, WHNP-BC, NP-C

Elizabeth ThomasMSN, WHNP-BC, NP-C

Special Designation:

This course satisfies four (4) CME credit hours on Pain Management and the Appropriate

Treatment of the Terminally Ill

The Medical Board of California requires most physicians and surgeons to complete a one-time mandatory 12 hours of CME in the subjects of pain management and the treatment of terminally ill & dying patients

In accordance with the ACCME Standards for Commercial Support of CME, Informed implemented mechanisms, prior to the planning and implementation of this CME activity, to identify and resolve conflicts of interest for all individuals in a position to control content of this CME activity.

FACULTY/PLANNING COMMITTEE DISCLOSURE:The following faculty and/or planning committee members have indicated they have no relationship(s) with industry to disclose relative to the content of this CME activity:• Stephen Braun• Elizabeth Thomas, MSN, WHNP-BC, NP-C

STAFF AND CONTENT REVIEWERS:Informed staff and all content validation reviewers involved with this activity have reported no relevant financial relationships with commercial interests.

SourcesMaterial from the following sources was used, with permission, in the creation of this monograph:

Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep 2016;65 (No. RR-1):1–49. DOI: http://dx.doi.org/10.15585/mmwr.rr6501e1.

DISCLAIMER* 2018. All rights reserved. These materials, except those in the public domain, may not be reproduced without permission from InforMed. This publication is designed to provide general information prepared by professionals in regard to the subject matter covered. It is provided with the understanding that InforMed, Inc. is not engaged in rendering legal, medical or other professional services. Although prepared by professionals, this publication should not be utilized as a substitute for professional services in specific situations. If legal advice, medical advice or other expert assistance is required, the service of a professional should be sought.

FACULTY:

ACTIVITY PLANNER:

DISCLOSURE OF INTEREST:

COURSE SATISFIES

4Pain Management

and Terminally Ill Patients

22

Summary This guideline provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses 1) when to initiate or continue opioids for chronic pain; 2) opioid selection, dosage, duration, followup, and discontinuation; and 3) assessing risk and addressing harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, and recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. CDC obtained input from experts, stakeholders, the public, peer reviewers, and a federally chartered advisory committee. It is important that patients receive appropriate pain treatment with careful consideration of the benefits and risks of treatment options. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death. CDC has provided a checklist for prescribing opioids for chronic pain (http://stacks.cdc.gov/view/cdc/38025) as well as a website (http://www.cdc.gov/drugoverdose/prescribingresources.html) with additional tools to guide clinicians in implementing the recommendations.

Introduction

Background Opioids are commonly prescribed for pain. An estimated 20% of patients presenting to physician offices with non-cancer pain symptoms or pain-related diagnoses (including acute and chronic pain) receive an opioid prescription1. In 2012, health care providers wrote 259 million prescriptions for opioid pain medication, enough for every adult in the United States to have a bottle of pills.2 Opioid prescriptions per capita increased 7.3% from 2007 to 2012, with opioid prescribing rates increasing more for family practice, general practice, and internal medicine compared with other specialties.3 Rates of opioid prescribing vary greatly across states in ways that cannot be explained by the underlying health status of the population, highlighting the lack of consensus among clinicians on how to use opioid pain medication.2

Prevention, assessment, and treatment of chronic pain are challenges for health providers and systems. Pain might go unrecognized, and patients, particularly members of racial and ethnic minority groups, women, the elderly, persons with

cognitive impairment, and those with cancer and at the end of life, can be at risk for inadequate pain treatment.4 Patients can experience persistent pain that is not well controlled. There are clinical, psychological, and social consequences associated with chronic pain including limitations in complex activities, lost work productivity, reduced quality of life, and stigma, emphasizing the importance of appropriate and compassionate patient care.4 Patients should receive appropriate pain treatment based on a careful consideration of the benefits and risks of treatment options. Chronic pain has been variably defined but is defined within this guideline as pain that typically lasts >3 months or past the time of normal tissue healing.5 Chronic pain can be the result of an underlying medical disease or condition, injury, medical treatment, inflammation, or an unknown cause.4 Estimates of the prevalence of chronic pain vary, but it is clear that the number of persons experiencing chronic pain in the United States is substantial. The 1999–2002 National Health and Nutrition Examination Survey estimated that 14.6% of adults have current widespread or localized pain lasting at least 3 months.6 Based on a survey conducted during 2001–20037, the overall prevalence of common, predominantly musculoskeletal pain conditions (e.g., arthritis, rheumatism, chronic back or neck problems, and frequent severe headaches) was estimated at 43% among adults in the United States, although minimum duration of symptoms was not specified. Most recently, analysis of data from the 2012 National Health Interview Study showed that 11.2% of adults report having daily pain.8 Clinicians should consider the full range of therapeutic options for the treatment of chronic pain. However, it is hard to estimate the number of persons who could potentially benefit from opioid pain medication long term. Evidence supports short-term efficacy of opioids for reducing pain and improving function in non-cancer nociceptive and neuropathic pain in randomized clinical trials lasting primarily ≤12 weeks9-10, and patients receiving opioid therapy for chronic pain report some pain relief when surveyed11-13. However, few studies have been conducted to rigorously assess the long-term benefits of opioids for chronic pain (pain lasting >3 months) with outcomes examined at least 1 year later.14 On the basis of data available from health systems, researchers estimate that 9.6–11.5 million adults, or approximately 3%–4% of the adult U.S. population, were prescribed long-term opioid therapy in 2005.15

Opioid pain medication use presents serious risks, including overdose and opioid use disorder. From 1999 to 2014, more than 165,000 persons died from overdose related to opioid pain medication in the United States.16 In the past decade, while the death rates for the top leading causes of death such as heart disease and cancer have decreased substantially,

the death rate associated with opioid pain medication has increased markedly.17 Sales of opioid pain medication have increased in parallel with opioid-related overdose deaths.18 The Drug Abuse Warning Network estimated that >420,000 emergency department visits were related to the misuse or abuse of narcotic pain relievers in 2011, the most recent year for which data are available.19 Although clinical criteria have varied over time, opioid use disorder is a problematic pattern of opioid use leading to clinically significant impairment or distress. This disorder is manifested by specific criteria such as unsuccessful efforts to cut down or control use and use resulting in social problems and a failure to fulfill major role obligations at work, school, or home.20 This diagnosis has also been referred to as “abuse or dependence” and “addiction” in the literature, and is different from tolerance (diminished response to a drug with repeated use) and physical dependence (adaptation to a drug that produces symptoms of withdrawal when the drug is stopped), both of which can exist without a diagnosed disorder. In 2013, on the basis of DSM-IV diagnosis criteria, an estimated 1.9 million persons abused or were dependent on prescription opioid pain medication.21 Having a history of a prescription for an opioid pain medication increases the risk for overdose and opioid use disorder22–24, highlighting the value of guidance on safer prescribing practices for clinicians. For example, a recent study of patients aged 15–64 years receiving opioids for chronic non-cancer pain and followed for up to 13 years revealed that one in 550 patients died from opioid-related overdose at a median of 2.6 years from their first opioid prescription, and one in 32 patients who escalated to opioid dosages >200 morphine milligram equivalents (MME) died from opioid-related overdose.25

This guideline provides recommendations for the prescribing of opioid pain medication by primary care clinicians for chronic pain (i.e., pain conditions that typically last >3 months or past the time of normal tissue healing) in outpatient settings outside of active cancer treatment, palliative care, and end-of-life care. Although the guideline does not focus broadly on pain management, appropriate use of long-term opioid therapy must be considered within the context of all pain management strategies (including non-opioid pain medications and nonpharmacologic treatments). CDC’s recommendations are made on the basis of a systematic review of the best available evidence, along with input from experts, and further review and deliberation by a federally chartered advisory committee. The guideline is intended to ensure that clinicians and patients consider safer and more effective treatment, improve patient outcomes such as reduced pain and improved function, and reduce

23

the number of persons who develop opioid use disorder, overdose, or experience other adverse events related to these drugs. Clinical decision making should be based on a relationship between the clinician and patient, and an understanding of the patient’s clinical situation, functioning, and life context. The recommendations in the guideline are voluntary, rather than prescriptive standards. They are based on emerging evidence, including observational studies or randomized clinical trials with notable limitations. Clinicians should consider the circumstances and unique needs of each patient when providing care.

Rationale Primary care clinicians report having concerns about opioid pain medication misuse, find managing patients with chronic pain stressful, express concern about patient addiction, and report insufficient training in prescribing opioids.26 Across specialties, physicians believe that opioid pain medication can be effective in controlling pain, that addiction is a common consequence of prolonged use, and that long-term opioid therapy often is overprescribed for patients with chronic non-cancer pain.27 These attitudes and beliefs, combined with increasing trends in opioid-related overdose, underscore the need for better clinician guidance on opioid prescribing. Clinical practice guidelines focused on prescribing can improve clinician knowledge, change prescribing practices28, and ultimately benefit patient health. Professional organizations, states, and federal agencies (e.g., the American Pain Society/American Academy of Pain Medicine, 2009; the Washington Agency Medical Directors Group, 2015; and the U.S. Department of Veterans Affairs/Department of Defense, 2010) have developed guidelines for opioid prescribing.29–31 Existing guidelines share some common elements, including dosing thresholds, cautious titration, and risk mitigation strategies such as using risk assessment tools, treatment agreements, and urine drug testing. However, there is considerable variability in the specific recommendations (e.g., range of dosing thresholds of 90 MME/day to 200 MME/day), audience (e.g., primary care clinicians versus specialists), use of evidence (e.g., systematic review, grading of evidence and recommendations, and role of expert opinion), and rigor of methods for addressing conflict of interest.32 Most guidelines, especially those that are not based on evidence from scientific studies published in 2010 or later, also do not reflect the most recent scientific evidence about risks related to opioid dosage. This CDC guideline offers clarity on recommendations based on the most recent scientific evidence, informed by expert opinion and stake-holder and public input. Scientific research has identified high-risk prescribing practices that have contributed to the overdose epidemic (e.g., high-dose prescribing, overlapping

opioid and benzodiazepine prescriptions, and extended-release/long-acting [ER/LA] opioids for acute pain).24,33,34 Using guidelines to address problematic prescribing has the potential to optimize care and improve patient safety based on evidence-based practice28, as well as reverse the cycle of opioid pain medication misuse that contributes to the opioid overdose epidemic.

Scope and Audience This guideline is intended for primary care clinicians (e.g., family physicians and internists) who are treating patients with chronic pain (i.e., pain lasting >3 months or past the time of normal tissue healing) in outpatient settings. Prescriptions by primary care clinicians account for nearly half of all dispensed opioid prescriptions, and the growth in prescribing rates among these clinicians has been above average.3 Primary care clinicians include physicians as well as nurse practitioners and physician assistants. Although the focus is on primary care clinicians, because clinicians work within team based care, the recommendations refer to and promote integrated pain management and collaborative working relationships with other providers (e.g., behavioral health providers, pharmacists, and pain management specialists). Although the transition from use of opioid therapy for acute pain to use for chronic pain is hard to predict and identify, the guideline is intended to inform clinicians who are considering prescribing opioid pain medication for painful conditions that can or have become chronic. This guideline is intended to apply to patients aged ≥18 years with chronic pain outside of palliative and end-of-life care. For this guideline, palliative care is defined in a manner consistent with that of the Institute of Medicine as care that provides relief from pain and other symptoms, supports quality of life, and is focused on patients with serious advanced illness. Palliative care can begin early in the course of treatment for any serious illness that requires excellent management of pain or other distressing symptoms.35 End-of-life care is defined as care for persons with a terminal illness or at high risk for dying in the near future in hospice care, hospitals, long-term care settings, or at home. Patients within the scope of this guideline include cancer survivors with chronic pain who have completed cancer treatment, are in clinical remission, and are under cancer surveillance only. The guideline is not intended for patients undergoing active cancer treatment, palliative care, or end-of-life care because of the unique therapeutic goals, ethical considerations, opportunities for medical supervision, and balance of risks and benefits with opioid therapy in such care. The recommendations address the use of opioid pain medication in certain special populations (e.g., older adults and pregnant women) and in populations with conditions posing

special risks (e.g., a history of substance use disorder). The recommendations do not address the use of opioid pain medication in children or adolescents aged <18 years. The available evidence concerning the benefits and harms of long-term opioid therapy in children and adolescents is limited, and few opioid medications provide information on the label regarding safety and effectiveness in pediatric patients. However, observational research shows significant increases in opioid prescriptions for pediatric populations from 2001 to 201036, and a large proportion of adolescents are commonly prescribed opioid pain medications for conditions such as headache and sports injuries (e.g., in one study, 50% of adolescents presenting with headache received a prescription for an opioid pain medication).37,38 Adolescents who misuse opioid pain medication often misuse medications from their own previous prescriptions39, with an estimated 20% of adolescents with currently prescribed opioid medications reporting using them intentionally to get high or increase the effects of alcohol or other drugs.40 Use of prescribed opioid pain medication before high school graduation is associated with a 33% increase in the risk of later opioid misuse.41 Misuse of opioid pain medications in adolescence strongly predicts later onset of heroin use.42 Thus, risk of opioid medication use in pediatric populations is of great concern. Additional clinical trial and observational research is needed, and encouraged, to inform development of future guidelines for this critical population. The recommendations are not intended to provide guidance on use of opioids as part of medication-assisted treatment for opioid use disorder. Some of the recommendations might be relevant for acute care settings or other specialists, such as emergency physicians or dentists, but use in these settings or by other specialists is not the focus of this guideline. Readers are referred to other sources for prescribing recommendations within acute care settings and in dental practice, such as the American College of Emergency Physicians’ guideline for prescribing of opioids in the emergency department43; the American Society of Anesthesiologists’ guideline for acute pain management in the perioperative setting44; the Washington Agency Medical Directors’ Group Interagency Guideline on Prescribing Opioids for Pain, Part II: Prescribing Opioids in the Acute and Subacute Phase30; and the Pennsylvania Guidelines on the Use of Opioids in Dental Practice45. In addition, given the challenges of managing the painful complications of sickle cell disease, readers are referred to the NIH National Heart, Lung, and Blood Institute’s Evidence Based Management of Sickle Cell Disease Expert Panel Report formanagement of sickle cell disease.46

24

Guideline Development Methods

Guideline Development Using the Grading of Recommendations Assessment, Development, and Evaluation Method CDC developed this guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method (http://www.gradeworkinggroup.org). This method specifies the systematic review of scientific evidence and offers a transparent approach to grading quality of evidence and strength of recommendations. The method has been adapted by the CDC Advisory Committee on Immunization Practices (ACIP).47 CDC has applied the ACIP translation of the GRADE framework in this guideline. Within the ACIP GRADE framework, the body of evidence is categorized in a hierarchy. This hierarchy reflects degree of confidence in the effect of a clinical action on health outcomes. The categories include type 1 evidence (randomized clinical trials or overwhelming evidence from observational studies), type 2 evidence (randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies), type 3 evidence (observational studies or randomized clinical trials with notable limitations), and type 4 evidence (clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations). Type of evidence is categorized by study design as well as limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects, dose response gradient, and a constellation of plausible biases that could change observations of effects. Type 1 evidence indicates that one can be very confident that the true effect lies close to that of the estimate of the effect; type 2 evidence means that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; type 3 evidence means that confidence in the effect estimate is limited and the true effect might be substantially different from the estimate of the effect; and type 4 evidence indicates that one has very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of the effect.47,48 When no studies are present, evidence is considered to be insufficient. The ACIP GRADE framework places recommendations in two categories, Category A and Category B. Four major factors determine the category of the recommendation: the quality of evidence, the balance between desirable and undesirable effects, values and preferences, and resource allocation (cost). Category A recommendations apply to all persons in a specified group and indicate that most patients should receive the recommended course

of action. Category B recommendations indicate that there should be individual decision making; different choices will be appropriate for different patients, so clinicians must help patients arrive at a decision consistent with patient values and preferences, and specific clinical situations.47 According to the GRADE methodology, a particular quality of evidence does not necessarily imply a particular strength of recommendation.48–50

Category A recommendations can be made based on type 3 or type 4 evidence when the advantages of a clinical action greatly outweigh the disadvantages based on a consideration of benefits and harms, values and preferences, and costs. Category B recommendations are made when the advantages and disadvantages of a clinical action are more balanced. GRADE methodology is discussed extensively elsewhere.47,51 The U.S. Preventive Services Task Force (USPSTF) follows different methods for developing and categorizing recommendations (http://www.uspreventiveservicestaskforce.org). USPSTF recommendations focus on preventive services and are categorized as A, B, C, D, and I. Under the Affordable Care Act, all “non-grandfathered” health plans (that is, those health plans not in existence prior to March 23, 2010 or those with significant changes to their coverage) and expanded Medicaid plans are required to cover preventive services recommended by USPSTF with a category A or B rating with no cost sharing. The coverage requirements went into effect September 23, 2010. Similar requirements are in place for vaccinations recommended by ACIP, but do not exist for other recommendations made by CDC, including recommendations within this guideline. A previously published systematic review sponsored by the Agency for Healthcare Research and Quality (AHRQ) on the effectiveness and risks of long-term opioid treatment of chronic pain14,52 initially served to directly inform the recommendation statements. This systematic clinical evidence review addressed the effectiveness of long-term opioid therapy for outcomes related to pain, function, and quality of life; the comparative effectiveness of different methods for initiating and titrating opioids; the harms and adverse events associated with opioids; and the accuracy of risk prediction instruments and effectiveness of risk mitigation strategies on outcomes related to overdose, addiction, abuse, or misuse. For the current guideline development, CDC conducted additional literature searches to update the evidence review to include more recently available publications and to answer an additional clinical question about the effect of opioid therapy for acute pain on long-term use. More details about the literature search strategies and GRADE methods applied are provided in the Clinical Evidence Review (http://stacks.cdc.gov/view/cdc/38026). CDC developed GRADE evidence tables to illustrate the quality of the evidence for

each clinical question. As identified in the AHRQ sponsored clinical evidence review, the overall evidence base for the effectiveness and risks of long-term opioid therapy is low in quality per the GRADE criteria. Thus, contextual evidence is needed to provide information about the benefits and harms of nonpharmacologic and non-opioid pharmacologic therapy and the epidemiology of opioid pain medication overdose and inform the recommendations. Further, as elucidated by the GRADE Working Group, supplemental information on clinician and patient values and preferences and resource allocation can inform judgments of benefits and harms and be helpful for translating the evidence into recommendations. CDC conducted a contextual evidence review to supplement the clinical evidence review based on systematic searches of the literature. The review focused on the following four areas: effectiveness of nonpharmacologic and non-opioid pharmacologic treatments; benefits and harms related to opioid therapy (including additional studies not included in the clinical evidence review such as studies that evaluated outcomes at any duration or used observational study designs related to specific opioid pain medications, high-dose opioid therapy, co-prescription of opioids with other controlled substances, duration of opioid use, special populations, risk stratification/mitigation approaches, and effectiveness of treatments for addressing potential harms of opioid therapy); clinician and patient values and preferences; and resource allocation. CDC constructed narrative summaries of this contextual evidence and used the information to support the clinical recommendations. More details on methods for the contextual evidence review are provided in the Contextual Evidence Review (http://stacks.cdc.gov/view/cdc/38027). On the basis of a review of the clinical and contextual evidence (review methods are described in more detail in subsequent sections of this report), CDC drafted recommendation statements focused on determining when to initiate or continue opioids for chronic pain; opioid selection, dosage, duration, follow up, and discontinuation; and assessing risk and addressing harms of opioid use. To help assure the draft guideline’s integrity and credibility, CDC then began a multi-step review process to obtain input from experts, stakeholders, and the public to help refine the recommendations.

Solicitation of Expert Opinion CDC sought the input of experts to assist in reviewing the evidence and providing perspective on how CDC used the evidence to develop the draft recommendations. These experts, referred to as the “Core Expert Group” (CEG) included subject matter experts, representatives of primary care professional societies and state agencies, and an expert in guideline development methodology.

25

CDC identified subject matter experts with high scientific standing; appropriate academic and clinical training and relevant clinical experience; and proven scientific excellence in opioid prescribing, substance use disorder treatment, and pain management. CDC identified representatives from leading primary care professional organizations to represent the audience for this guideline. Finally, CDC identified state agency officials and representatives based on their experience with state guidelines for opioid prescribing that were developed with multiple agency stakeholders and informed by scientific literature and existing evidence-based guidelines. Prior to their participation, CDC asked potential experts to reveal possible conflicts of interest such as financial relationships with industry, intellectual preconceptions, or previously stated public positions. Experts could not serve if they had conflicts that might have a direct and predictable effect on the recommendations. CDC excluded experts who had a financial or promotional relationship with a company that makes a product that might be affected by the guideline. CDC reviewed potential nonfinancial conflicts carefully (e.g., intellectual property, travel, public statements or positions such as congressional testimony) to determine if the activities would have a direct and predictable effect on the recommendations. CDC determined the risk of these types of activities to be minimal for the identified experts. All experts completed a statement certifying that there was no potential or actual conflict of interest. Activities that did not pose a conflict (e.g., participation in Food and Drug Administration [FDA] activities or other guideline efforts) are disclosed. CDC provided to each expert written summaries of the scientific evidence (both the clinical and contextual evidence reviews conducted for this guideline) and CDC’s draft recommendation statements. Experts provided individual ratings for each draft recommendation statement based on the balance of benefits and harms, evidence strength, certainty of values and preferences, cost, recommendation strength, rationale, importance, clarity, and ease of implementation. CDC hosted an in person meeting of the experts that was held on June 23–24, 2015, in Atlanta, Georgia, to seek their views on the evidence and draft recommendations and to better understand their premeeting ratings. CDC sought the experts’ individual opinions at the meeting. Although there was widespread agreement on some of the recommendations, there was disagreement on others. Experts did not vote on the recommendations or seek to come to a consensus. Decisions about recommendations to be included in the guideline, and their rationale, were made by CDC. After revising the guideline, CDC sent written copies of it to each of the experts for review and asked for any additional comments;

CDC reviewed these written comments and considered them when making further revisions to the draft guideline. The experts have not reviewed the final version of the guideline.

Federal Partner Engagement Given the scope of this guideline and the interest of agencies across the federal government in appropriate pain management, opioid prescribing, and related outcomes, CDC invited its National Institute of Occupational Safety and Health and CDC’s federal partners to observe the expert meeting, provide written comments on the full draft guideline after the meeting, and review the guideline through an agency clearance process; CDC reviewed comments and incorporated changes. Interagency collaboration will be critical for translating these recommendations into clinical practice. Federal partners included representatives from the Substance Abuse and Mental Health Services Administration, the National Institute on Drug Abuse, FDA, the U.S. Department of Veterans Affairs, the U.S. Department of Defense, the Office of the National Coordinator for Health Information Technology, the Centers for Medicare and Medicaid Services, the Health Resources and Services Administration, AHRQ, and the Office of National Drug Control Policy. Stakeholder Comment Given the importance of the guideline for a wide variety of stakeholders, CDC also invited review from a Stakeholder Review Group (SRG) to provide comment so that CDC could consider modifications that would improve the recommendations’ specificity, applicability, and ease of implementation. The SRG included representatives from professional organizations that represent specialties that commonly prescribe opioids (e.g., pain medicine, physical medicine and rehabilitation), delivery systems within which opioid prescribing occurs (e.g., hospitals), and representation from community organizations with interests in pain management and opioid prescribing.* Representatives from each of the SRG organizations were provided a copy of the guideline for comment. Each of these representatives provided written comments. Once input was received from the full SRG, CDC reviewed all comments and carefully considered them when revising the draft guideline.

Constituent Engagement To obtain initial perspectives from constituents on the recommendation statements, including clinicians and prospective patients, CDC convened a constituent engagement webinar and circulated information about the webinar in advance through announcements to partners. CDC hosted the webinar on September 16 and 17, 2015, provided information about the methodology for developing the guideline, and presented the key

recommendations. A fact sheet was posted on the CDC Injury Center website (http://www.cdc.gov/injury) summarizing the guideline development process and clinical practice areas addressed in the guideline; instructions were included on how to submit comments via email. CDC received comments during and for 2 days following the first webinar. Over 1,200 constituent comments were received. Comments were reviewed and carefully considered when revising the draft guideline.

Peer Review Per the final information quality bulletin for peer review (https://www.whitehouse.gov/sites/default/files/omb/memoranda/fy2005/m05-03.pdf), peer review requirements applied to this guideline because it provides influential scientific information that could have a clear and substantial impact on public and private sector decisions. Three experts independently reviewed the guideline to determine the reasonableness and strength of recommendations; the clarity with which scientific uncertainties were clearly identified; and the rationale, importance, clarity, and ease of implementation of the recommendations.* CDC selected peer reviewers based on expertise, diversity of scientific viewpoints, and independence from the guideline development process. CDC assessed and managed potential conflicts of interest using a process similar to the one as described for solicitation of expert opinion. No financial interests were identified in the disclosure and review process, and non-financial activities were determined to be of minimal risk; thus, no significant conflict of interest concerns were identified. CDC placed the names of peer reviewers on the CDC and the National Center for Injury Prevention and Control Peer Review Agenda websites that are used to provide information about the peer review of influential documents. CDC reviewed peer review comments and revised the draft guideline accordingly.

Public Comment To obtain comments from the public on the full guideline, CDC published a notice in the Federal Register (80 FR 77351) announcing the availability of the guideline and the supporting clinical and contextual evidence reviews for public comment. The comment period closed January 13, 2016. CDC received more than 4,350 comments from the general public, including patients with chronic pain, clinicians, families who have lost loved ones to overdose, medical associations, professional organizations, academic institutions, state and local governments, and industry. CDC reviewed each of the comments and carefully considered them when revising the draft guideline.

26

Federal Advisory Committee Review and Recommendation The National Center for Injury Prevention and Control (NCIPC) Board of Scientific Counselors (BSC) is a federal advisory committee that advises and makes recommendations to the Secretary of the Department of Health and Human Services, the Director of CDC, and the Director of NCIPC.* The BSC makes recommendations regarding policies, strategies, objectives, and priorities, and reviews progress toward injury and violence prevention. CDC sought the BSC’s advice on the draft guideline. BSC members are special government employees appointed as CDC advisory committee members; as such, all members completed an OGE Form 450 to disclose relevant interests. BSC members also reported on their disclosures during meetings. Disclosures for the BSC are reported in the guideline. To assist in guideline review, on December 14, 2015, via Federal Register notice, CDC announced the intent to form an Opioid Guideline Workgroup (OGW) to provide observations on the draft guideline to the BSC. CDC provided the BSC with the draft guideline as well as summaries of comments provided to CDC by stakeholders, constituents, and peer reviewers, and edits made to the draft guideline in response. During an open meeting held on January 7, 2016, the BSC recommended the formation of the OGW. The OGW included a balance of perspectives from audiences directly affected by the guideline, audiences that would be directly involved with implementing the recommendations, and audiences qualified to provide representation. The OGW comprised clinicians, subject matter experts, and a patient representative, with the following perspectives represented: primary care, pain medicine, public health, behavioral health, substance abuse treatment, pharmacy, patients, and research.* Additional sought after attributes were appropriate academic and clinical training and relevant clinical experience; high scientific standing; and knowledge of the patient, clinician, and caregiver perspectives. In accordance with CDC policy, two BSC committee members also served as OGW members, with one serving as the OGW Chair. The professional credentials and interests of OGW members were carefully reviewed to identify possible conflicts of interest such as financial relationships with industry, intellectual preconceptions, or previously stated public positions. Only OGW members whose interests were determined to be minimal were selected. When an activity was perceived as having the potential to affect a specific aspect of the recommendations, the activity was disclosed, and the OGW member was recused from discussions related to that specific aspect of the recommendations (e.g., urine drug testing and abuse-deterrent formulations). Disclosures for the OGW are reported. CDC and the OGW identified

ad-hoc consultants to supplement the workgroup expertise, when needed, in the areas of pediatrics, occupational medicine, obstetrics and gynecology, medical ethics, addiction psychiatry, physical medicine and rehabilitation, guideline development methodology, and the perspective of a family member who lost a loved one to opioid use disorder or overdose. The BSC charged the OGW with reviewing the quality of the clinical and contextual evidence reviews and reviewing each of the recommendation statements and accompanying rationales. For each recommendation statement, the OGW considered the quality of the evidence, the balance of benefits and risks, the values and preferences of clinicians and patients, the cost feasibility, and the category designation of the recommendation (A or B). The OGW also reviewed supplementary documents, including input provided by the CEG, SRG, peer reviewers, and the public. OGW members discussed the guideline accordingly during virtual meetings and drafted a summary report of members’ observations, including points of agreement and disagreement, and delivered the report to the BSC. NCIPC announced an open meeting of the NCIPC BSC in the Federal Register on January 11, 2016. The BSC met on January 28, 2016, to discuss the OGW report and deliberate on the draft guideline itself. Members of the public provided comments at this meeting. After discussing the OGW report, deliberating on specific issues about the draft guideline identified at the meeting, and hearing public comment, the BSC voted unanimously: to support the observations made by the OGW; that CDC adopt the guideline recommendations that, according to the workgroup’s report, had unanimous or majority support; and that CDC further consider the guideline recommendations for which the group had mixed opinions. CDC carefully considered the OGW observations, public comments, and BSC recommendations, and revised the guideline in response.

Summary of the Clinical Evidence Review

Primary Clinical Questions CDC conducted a clinical systematic review of the scientific evidence to identify the effectiveness, benefits, and harms of long-term opioid therapy for chronic pain, consistent with the GRADE approach.47,48 Long-term opioid therapy is defined as use of opioids on most days for >3 months. A previously published AHRQ funded systematic review on the effectiveness and risks of long-term opioid therapy for chronic pain comprehensively addressed four clinical questions.14,52 CDC, with the assistance of a methodology expert, searched the literature to identify newly published studies on these four original questions. Because long-term opioid use might be affected by use of opioids for acute pain, CDC subsequently developed a fifth

clinical question (last in the series below), and in collaboration with a methodologist conducted a systematic review of the scientific evidence to address it. In brief, five clinical questions were addressed:• The effectiveness of long-term opioid

therapy versus placebo, no opioid therapy, or non-opioid therapy for long term (≥1 year) outcomes related to pain, function, and quality of life, and how effectiveness varies according to the type/cause of pain, patient demographics, and patient comorbidities (Key Question [KQ] 1).

• The risks of opioids versus placebo or no opioids on abuse, addiction, overdose, and other harms, and how harms vary according to the type/cause of pain, patient demographics, patient comorbidities, and dose (KQ2).

• The comparative effectiveness of opioid dosing strategies (different methods for initiating and titrating opioids; immediate release versus ER/LA opioids; different ER/LA opioids; immediate release plus ER/LA opioids versus ER/LA opioids alone; scheduled, continuous versus as-needed dosing; dose escalation versus dose maintenance; opioid rotation versus maintenance; different strategies for treating acute exacerbations of chronic pain; decreasing opioid doses or tapering off versus continuation; and different tapering protocols and strategies) (KQ3).

• The accuracy of instruments for predicting risk for opioid overdose, addiction, abuse, or misuse; the effectiveness of risk mitigation strategies (use of risk prediction instruments); effectiveness of risk mitigation strategies including opioid management plans, patient education, urine drug testing, prescription drug monitoring program (PDMP) data, monitoring instruments, monitoring intervals, pill counts, and abuse-deterrent formulations for reducing risk for opioid overdose, addiction, abuse, or misuse; and the comparative effectiveness of treatment strategies for managing patients with addiction (KQ4).

• The effects of prescribing opioid therapy versus not prescribing opioid therapy for acute pain on long-term use (KQ5).

The review was focused on the effectiveness of long-term opioid therapy on long-term (>1 year) outcomes related to pain, function, and quality of life to ensure that findings are relevant to patients with chronic pain and long-term opioid prescribing. The effectiveness of short-term opioid therapy has already been established.10 However, opioids have unique effects such as tolerance and physical dependence that might influence assessments of benefit over time.

27

These effects raise questions about whether findings on short-term effectiveness of opioid therapy can be extrapolated to estimate benefits of long-term therapy for chronic pain. Thus, it is important to consider studies that provide data on long-term benefit. For certain opioid-related harms (overdose, fractures, falls, motor vehicle crashes), observational studies were included with outcomes measured at shorter intervals because such outcomes can occur early during opioid therapy, and such harms are not captured well in short-term clinical trials. A detailed listing of the key questions is provided in the Clinical Evidence Review (http://stacks.cdc.gov/view/cdc/38026).

Clinical Evidence Systematic Review Methods Complete methods and data for the 2014 AHRQ report, upon which this updated systematic review is based, have been published previously.14,52 Study authors developed the protocol using a standardized process53 with input from experts and the public and registered the protocol in the PROSPERO database.54 For the 2014 AHRQ report, a research librarian searched MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PsycINFO, and CINAHL for English language articles published January 2008 through August 2014, using search terms for opioid therapy, specific opioids, chronic pain, and comparative study designs. Also included were relevant studies from an earlier review10 in which searches were conducted without a date restriction, reference lists were reviewed, and ClinicalTrials.gov was searched. CDC updated the AHRQ literature search using the same search strategies as in the original review including studies published before April, 2015. Seven additional studies met inclusion criteria and were added to the review. CDC used the GRADE approach outlined in the ACIP Handbook for Developing Evidence-Based Recommendations47 to rate the quality of evidence for the full body of evidence (evidence from the 2014 AHRQ review plus the update) for each clinical question. Evidence was categorized into the following types: type 1 (randomized clinical trials or overwhelming evidence from observational studies), type 2 (randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies), type 3 (observational studies, or randomized clinical trials with notable limitations), or type 4 (clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations). When no studies were present, evidence was considered to be insufficient. Per GRADE methods, type of evidence was categorized by study design as well as a function of limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects,

dose-response gradient, and constellation of plausible biases that could change effects. Results were synthesized qualitatively, highlighting new evidence identified during the update process. Meta-analysis was not attempted due to the small numbers of studies, variability in study designs and clinical heterogeneity, and methodological shortcomings of the studies. More detailed information about data sources and searches, study selection, data extraction and quality assessment, data synthesis, and update search yield and new evidence for the current review is provided in the Clinical Evidence Review (http://stacks.cdc.gov/view/cdc/38026).

Summary of Findings for Clinical Questions The main findings of this updated review are consistent with the findings of the 2014 AHRQ report.14 In summary, evidence on long-term opioid therapy for chronic pain outside of end-of-life care remains limited, with insufficient evidence to determine long-term benefits versus no opioid therapy, though evidence suggests risk for serious harms that appears to be dose-dependent. These findings supplement findings from a previous review of the effectiveness of opioids for adults with chronic non-cancer pain. In this previous review, based on randomized trials predominantly ≤12 weeks in duration, opioids were found to be moderately effective for pain relief, with small benefits for functional outcomes; although estimates vary, based on uncontrolled studies, a high percentage of patients discontinued long-term opioid use because of lack of efficacy and because of adverse events.10

The GRADE evidence summary with type of evidence ratings for the five clinical questions for the current evidence review are outlined (Table 1). This summary is based on studies included in the AHRQ 2014 review (35 studies) plus additional studies identified in the updated search (seven studies). Additional details on findings from the original review are provided in the full 2014 AHRQ report.14,52 Full details on the clinical evidence review findings supporting this guideline are provided in the Clinical Evidence Review (http://stacks.cdc.gov/view/cdc/38026).

Effectiveness For KQ1, no study of opioid therapy versus placebo, no opioid therapy, or non-opioid therapy for chronic pain evaluated long-term (≥1 year) outcomes related to pain, function, or quality of life. Most placebo controlled randomized clinical trials were ≤6 weeks in duration. Thus, the body of evidence for KQ1 is rated as insufficient (0 studies contributing).14

Harms For KQ2, the body of evidence is rated as type 3 (12 studies contributing; 11 from the original review plus one new study). One fair quality

cohort study found that long-term opioid therapy is associated with increased risk for an opioid abuse or dependence diagnosis (as defined by ICD-9-CM codes) versus no opioid prescription.22 Rates of opioid abuse or dependence diagnosis ranged from 0.7% with lower dose (≤36 MME) chronic therapy to 6.1% with higher dose (≥120 MME) chronic therapy, versus 0.004% with no opioids prescribed. Ten fair quality uncontrolled studies reported estimates of opioid abuse, addiction, and related outcomes.55–65 In primary care settings, prevalence of opioid dependence (using DSMIV criteria) ranged from 3% to 26% (55,56,59). In pain clinic settings, prevalence of addiction ranged from 2% to 14%.57,58,60,61,63–65

Factors associated with increased risk for misuse included history of substance use disorder, younger age, major depression, and use of psychotropic medications.55,62 Two studies reported on the association between opioid use and risk for overdose.66,67 One large fair quality retrospective cohort study found that recent opioid use was associated with increased risk for any overdose events and serious overdose events versus non use.66 It also found higher doses associated with increased risk. Relative to 1–19 MME/day, the adjusted hazard ratio (HR) for any overdose event (consisting of mostly nonfatal overdose) was 1.44 for 20 to 49 MME/day, 3.73 for 50–99 MME/day, and 8.87 for ≥100 MME/day. A similar pattern was observed for serious overdose. A good quality population-based, nested case-control study also found a dose-dependent association with risk for overdose death.67 Relative to 1–19 MME/day, the adjusted odds ratio (OR) was 1.32 for 20–49 MME/day, 1.92 for 50–99 MME/day, 2.04 for 100–199 MME/day, and 2.88 for ≥200 MME/day. Findings of increased fracture risk for current opioid use, versus non use, were mixed in two studies.68,69 Two studies found an association between opioid use and increased risk for cardiovascular events.70,71 Indirect evidence was found for endocrinologic harms (increased use of medications for erectile dysfunction or testosterone from one previously included study; laboratory-defined androgen deficiency from one newly reviewed study).72,73 One study found that opioid dosages ≥20 MME/day were associated with increased odds of road trauma among drivers.74

Opioid Dosing Strategies For KQ3, the body of evidence is rated as type 4 (14 studies contributing; 12 from the original review plus two new studies). For initiation and titration of opioids, the 2014 AHRQ report found insufficient evidence from three fair-quality, open label trials to determine comparative effectiveness of ER/LA versus immediate-release opioids

28

for titrating patients to stable pain control.75,76 One new fair-quality cohort study of Veterans Affairs patients found initiation of therapy with an ER/LA opioid associated with greater risk for nonfatal overdose than initiation with an immediate-release opioid, with risk greatest in the first 2 weeks after initiation of treatment.77

For comparative effectiveness and harms of ER/LA opioids, the 2014 AHRQ report included three randomized, head-to-head trials of various ER/LA opioids that found no clear differences in 1-year outcomes related to pain or function78–80 but had methodological shortcomings. A fair-quality retrospective cohort study based on national Veterans Health Administration system pharmacy data found that methadone was associated with lower overall risk for all-cause mortality versus morphine81, and a fair-quality retrospective cohort study based on Oregon Medicaid data found no statistically significant differences between methadone and long-acting morphine in risk for death or overdose symptoms.82 However, a new observational study83 found methadone associated with increased risk for overdose versus sustained release morphine among Tennessee Medicaid patients. The observed inconsistency in study findings suggests that risks of methadone might vary in different settings as a function of different monitoring and management protocols, though more research is needed to understand factors associated with safer methadone prescribing. For dose escalation, the 2014 AHRQ report included one fair-quality randomized trial that found no differences between more liberal dose escalation and maintenance of current doses after 12 months in pain, function, all-cause withdrawals, or withdrawals due to opioid misuse.84 However, the difference in opioid dosages prescribed at the end of the trial was relatively small (mean 52 MME/day with more liberal dosing versus 40 MME/day). Evidence on other comparisons related to opioid dosing strategies (ER/LA versus immediate-release opioids; immediate-release plus ER/LA opioids versus ER/LA opioids alone; scheduled continuous dosing versus as-needed dosing; or opioid rotation versus maintenance of current therapy; long-term effects of strategies for treating acute exacerbations of chronic pain) was not available or too limited to determine effects on long-term clinical outcomes. For example, evidence on the comparative effectiveness of opioid tapering or discontinuation versus maintenance, and of different opioid tapering strategies, was limited to small, poor quality studies.85–87

Risk Assessment and Mitigation For KQ4, the body of evidence is rated as type 3 for the accuracy of risk assessment tools and insufficient for the effectiveness of use of risk assessment tools and mitigation strategies

in reducing harms (six studies contributing; four from the original review plus two new studies). The 2014 AHRQ report included four studies88–91

on the accuracy of risk assessment instruments, administered prior to opioid therapy initiation, for predicting opioid abuse or misuse. Results for the Opioid Risk Tool (ORT)89–91 were extremely inconsistent; evidence for other risk assessment instruments was very sparse, and studies had serious methodological shortcomings. One additional fair-quality92 and one poor quality93 study identified for this update compared the predictive accuracy of the ORT, the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R), and the Brief Risk Interview. For the ORT, sensitivity was 0.58 and 0.75 and specificity 0.54 and 0.86; for the SOAPP-R, sensitivity was 0.53 and 0.25 and specificity 0.62 and 0.73; and for the Brief Risk Interview, sensitivity was 0.73 and 0.83 and specificity 0.43 and 0.88. For the ORT, positive likelihood ratios ranged from non-informative (positive likelihood ratio close to 1) to moderately useful (positive likelihood ratio >5). The SOAPP-R was associated with non-informative likelihood ratios (estimates close to 1) in both studies. No study evaluated the effectiveness of risk mitigation strategies (use of risk assessment instruments, opioid management plans, patient education, urine drug testing, use of PDMP data, use of monitoring instruments, more frequent monitoring intervals, pill counts, or use of abuse-deterrent formulations) for improving outcomes related to overdose, addiction, abuse, or misuse.

Effects of Opioid Therapy for Acute Pain on Long-Term Use For KQ5, the body of evidence is rated as type 3 (two new studies contributing). Two fair-quality retrospective cohort studies found opioid therapy prescribed for acute pain associated with greater likelihood of long-term use. One study evaluated opioid-naïve patients who had undergone low-risk surgery, such as cataract surgery and varicose vein stripping.94 Use of opioids within 7 days of surgery was associated with increased risk for use at 1 year. The other study found that among patients with a workers’ compensation claim for acute low back pain, compared to patients who did not receive opioids early after injury (defined as use within 15 days following onset of pain), patients who did receive early opioids had an increased likelihood of receiving five or more opioid prescriptions 30–730 days following onset that increased with greater early exposure. Versus no early opioid use, the adjusted OR was 2.08 (95% CI = 1.55–2.78) for 1-140 MME/day and increased to 6.14 (95% confidence interval [CI] = 4.92–7.66) for ≥450 MME/day.95

Summary of the Contextual Evidence Review

Primary Areas of Focus Contextual evidence is complementary information that assists in translating the clinical research findings into recommendations. CDC conducted contextual evidence reviews on four topics to supplement the clinical evidence review findings:• Effectiveness of nonpharmacologic

(e.g., cognitive behavioral therapy [CBT], exercise therapy, interventional treatments, and multimodal pain treatment) and non-opioid pharmacologic treatments (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs], antidepressants, and anticonvulsants), including studies of any duration.

• Benefits and harms of opioid therapy (including additional studies not included in the clinical evidence review, such as studies that were not restricted to patients with chronic pain, evaluated outcomes at any duration, performed ecological analyses, or used observational study designs other than cohort and case-cohort control studies) related to specific opioids, high-dose therapy, co-prescription with other controlled substances, duration of use, special populations, and potential usefulness of risk stratification/mitigation approaches, in addition to effectiveness of treatments associated with addressing potential harms of opioid therapy (opioid use disorder).

• Clinician and patient values and preferences related to opioids and medication risks, benefits, and use.

• Resource allocation including costs and economic efficiency of opioid therapy and risk mitigation strategies.

CDC also reviewed clinical guidelines that were relevant to opioid prescribing and could inform or complement the CDC recommendations under development (e.g., guidelines on nonpharmacologic and non-opioid pharmacologic treatments and guidelines with recommendations related to specific clinician actions such as urine drug testing or opioid tapering protocols).

Contextual Evidence Review Methods CDC conducted a contextual evidence review to assist in developing the recommendations by providing an assessment of the balance of benefits and harms, values and preferences, and cost, consistent with the GRADE approach. Given the public health urgency for developing opioid prescribing recommendations, a rapid review was required for the contextual evidence review for the current guideline. Rapid reviews are used when

29

there is a need to stream-line the systematic review process to obtain evidence quickly.96 Methods used to streamline the process include limiting searches by databases, years, and languages considered, and truncating quality assessment and data abstraction protocols. CDC conducted “rapid reviews” of the contextual evidence on nonpharmacologic and non-opioid pharmacologic treatments, benefits and harms, values and preferences, and resource allocation. Detailed information about contextual evidence data sources and searches, inclusion criteria, study selection, and data extraction and synthesis are provided in the Contextual Evidence Review (http://stacks.cdc.gov/view/cdc/38027). In brief, CDC conducted systematic literature searches to identify original studies, systematic reviews, and clinical guidelines, depending on the topic being searched. CDC also solicited publication referrals from subject matter experts. Given the need for a rapid review process, grey literature (e.g., literature by academia, organizations, or government in the forms of reports, documents, or proceedings not published by commercial publishers) was not systemically searched. Database sources, including MEDLINE, PsycINFO, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, varied by topic. Multiple reviewers scanned study abstracts identified through the database searches and extracted relevant studies for review. CDC constructed narrative summaries and tables based on relevant articles that met inclusion criteria, which are provided in the Contextual Evidence Review (http://stacks.cdc.gov/view/cdc/38027). Findings from the contextual reviews provide indirect evidence and should be interpreted accordingly. CDC did not formally rate the quality of evidence for the studies included in the contextual evidence review using the GRADE method. The studies that addressed benefits and harms, values and preferences, and resource allocation most often employed observational methods, used short follow up periods, and evaluated selected samples. Therefore the strength of the evidence from these contextual review areas was considered to be low, comparable to type 3 or type 4 evidence. The quality of evidence for non-opioid pharmacologic and nonpharmacologic pain treatments was generally rated as moderate, comparable to type 2 evidence, in systematic reviews and clinical guidelines (e.g., for treatment of chronic neuropathic pain, low back pain, osteoarthritis, and fibromyalgia). Similarly, the quality of evidence on pharmacologic and psychosocial opioid use disorder treatment was generally rated as moderate, comparable to type 2 evidence, in systematic reviews and clinical guidelines.

Summary of Findings for Contextual Areas Full narrative reviews and tables that summarize key findings from the contextual

evidence review are provided in the Contextual Evidence Review (http://stacks.cdc.gov/view/cdc/38027).

Effectiveness of Nonpharmacologic and Non-opioid Pharmacologic Treatments Several nonpharmacologic and non-opioid pharmacologic treatments have been shown to be effective in managing chronic pain in studies ranging in duration from 2 weeks to 6 months. For example, CBT that trains patients in behavioral techniques and helps patients modify situational factors and cognitive processes that exacerbate pain has small positive effects on disability and catastrophic thinking.97 Exercise therapy can help reduce pain and improve function in chronic low back pain98, improve function and reduce pain in osteoarthritis of the knee99 and hip100, and improve wellbeing, fibromyalgia symptoms, and physical function in fibromyalgia101. Multimodal and multidisciplinary therapies (e.g., therapies that combine exercise and related therapies with psychologically based approaches) can help reduce pain and improve function more effectively than single modalities.102,103 Non-opioid pharmacologic approaches used for pain include analgesics such as acetaminophen, NSAIDs, and cyclooxygenase 2 (COX-2) inhibitors; selected anticonvulsants; and selected antidepressants (particularly tricyclics and serotonin and norepinephrine reuptake inhibitors [SNRIs]). Multiple guidelines recommend acetaminophen as first-line pharmacotherapy for osteoarthritis104–109 or for low back pain110 but note that it should be avoided in liver failure and that dosage should be reduced in patients with hepatic insufficiency or a history of alcohol abuse.109 Although guidelines also recommend NSAIDs as first-line treatment for osteoarthritis or low back pain106,110, NSAIDs and COX-2 inhibitors do have risks, including gastrointestinal bleeding or perforation as well as renal and cardiovascular risks.111 FDA has recently strengthened existing label warnings that NSAIDs increase risks for heart attack and stroke, including that these risks might increase with longer use or at higher doses.112 Several guidelines agree that first and second-line drugs for neuropathic pain include anticonvulsants (gabapentin or pregabalin), tricyclic antidepressants, and SNRIs.113–116 Interventional approaches such as epidural injection for certain conditions (e.g., lumbar radiculopathy) can provide short-term improvement in pain.117–119 Epidural injection has been associated with rare but serious adverse events, including loss of vision, stroke, paralysis, and death.120

Benefits and Harms of Opioid Therapy Balance between benefits and harms is a critical factor influencing the strength of clinical recommendations. In particular, CDC considered what is known from the epidemiology

research about benefits and harms related to specific opioids and formulations, high dose therapy, co-prescription with other controlled substances, duration of use, special populations, and risk stratification and mitigation approaches. Additional information on benefits and harms of long-term opioid therapy from studies meeting rigorous selection criteria is provided in the clinical evidence review (e.g., see KQ2). CDC also considered the number of persons experiencing chronic pain, numbers potentially benefiting from opioids, and numbers affected by opioid-related harms. A review of these data is presented in the background section of this document, with detailed information provided in the Contextual Evidence Review (http://stacks.cdc.gov/view/cdc/38027). Finally, CDC considered the effectiveness of treatments that addressed potential harms of opioid therapy (opioid use disorder). Regarding specific opioids and formulations, as noted by FDA, there are serious risks of ER/LA opioids, and the indication for this class of medications is for management of pain severe enough to require daily, around-the-clock, long-term opioid treatment in patients for whom other treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.121 Time-scheduled opioid use was associated with substantially higher average daily opioid dosage than as-needed opioid use in one study.122 Methadone has been associated with disproportionate numbers of overdose deaths relative to the frequency with which it is prescribed for pain. Methadone has been found to account for as much as a third of opioid related overdose deaths involving single or multiple drugs in states that participated in the Drug Abuse Warning Network, which was more than any opioid other than oxycodone, despite representing <2% of opioid prescriptions outside of opioid treatment programs in the United States; further, methadone was involved in twice as many single drug deaths as any other prescription opioid.123

Regarding high-dose therapy, several epidemiologic studies that were excluded from the clinical evidence review because patient samples were not restricted to patients with chronic pain also examined the association between opioid dosage and overdose risk.23,24,124–126 Consistent with the clinical evidence review, the contextual review found that opioid-related overdose risk is dose-dependent, with higher opioid dosages associated with increased overdose risk. Two of these studies23,24, as well as the two studies in the clinical evidence review66,67, evaluated similar MME/day dose ranges for association with overdose risk. In these four studies, compared with opioids prescribed at <20 MME/day, the odds of overdose

30

among patients prescribed opioids for chronic nonmalignant pain were between 1.367 and 1.924

for dosages of 20 to <50 MME/day, between 1.967 and 4.624 for dosages of 50 to <100 MME/day, and between 2.067 and 8.966 for dosages of ≥100 MME/day. Compared with dosages of 1-<20 MME/day, absolute risk difference approximation for 50-<100 MME/day was 0.15% for fatal overdose24 and 1.40% for any overdose66, and for ≥100 MME/day was 0.25% for fatal overdose24 and 4.04% for any overdose.66 A recent study of Veterans Health Administration patients with chronic pain found that patients who died of overdoses related to opioids were prescribed higher opioid dosages (mean: 98 MME/day; median: 60 MME/day) than controls (mean: 48 MME/day, median: 25 MME/day.127 Finally, another recent study of overdose deaths among state residents with and without opioid prescriptions revealed that prescription opioid-related overdose mortality rates rose rapidly up to prescribed doses of 200 MME/day, after which the mortality rates continued to increase but grew more gradually.128 A listing of common opioid medications and their MME equivalents is provided (Table 2). Regarding co-prescription of opioids with benzodiazepines, epidemiologic studies suggest that concurrent use of benzodiazepines and opioids might put patients at greater risk for potentially fatal overdose. Three studies of fatal overdose deaths found evidence of concurrent benzodiazepine use in 31%–61% of decedents.67,128,129 In one of these studies67, among decedents who received an opioid prescription, those whose deaths were related to opioids were more likely to have obtained opioids from multiple physicians and pharmacies than decedents whose deaths were not related to opioids. Regarding duration of use, patients can experience tolerance and loss of effectiveness of opioids over time.130 Patients who do not experience clinically meaningful pain relief early in treatment (i.e., within 1 month) are unlikely to experience pain relief with longer-term use.131

Regarding populations potentially at greater risk for harm, risk is greater for patients with sleep apnea or other causes of sleep disordered breathing, patients with renal or hepatic insufficiency, older adults, pregnant women, patients with depression or other mental health conditions, and patients with alcohol or other substance use disorders. Interpretation of clinical data on the effects of opioids on sleep-disordered breathing is difficult because of the types of study designs and methods employed, and there is no clear consensus regarding association with risk for developing obstructive sleep apnea syndrome.132 However, opioid therapy can decrease respiratory drive, a high percentage of patients on long-term opioid therapy have been reported to have an abnormal apneahypopnea index133, opioid therapy can worsen central sleep apnea in obstructive

sleep apnea patients, and it can cause further desaturation in obstructive sleep apnea patients not on continuous positive airway pressure (CPAP).31 Reduced renal or hepatic function can result in greater peak effect and longer duration of action and reduce the dose at which respiratory depression and overdose occurs.134 Age-related changes in patients aged ≥65 years, such as reduced renal function and medication clearance, even in the absence of renal disease135, result in a smaller therapeutic window between safe dosages and dosages associated with respiratory depression and overdose. Older adults might also be at increased risk for falls and fractures related to opioids.136–138 Opioids used in pregnancy can be associated with additional risks to both mother and fetus. Some studies have shown an association of opioid use in pregnancy with birth defects, including neural tube defects139,140, congenital heart defects140, and gastroschisis140; preterm delivery141, poor fetal growth141, and stillbirth.141 Importantly, in some cases, opioid use during pregnancy leads to neonatal opioid withdrawal syndrome.142 Patients with mental health comorbidities and patients with histories of substance use disorders might be at higher risk than other patients for opioid use disorder.62,143,144 Recent analyses found that depressed patients were at higher risk for drug overdose than patients without depression, particularly at higher opioid dosages, although investigators were unable to distinguish unintentional overdose from suicide attempts.145 In case-control and case-cohort studies, substance abuse/dependence was more prevalent among patients experiencing overdose than among patients not experiencing overdose (12% versus 6% [66], 40% versus 10% [24], and 26% versus 9% [23]). Regarding risk stratification approaches, limited evidence was found regarding benefits and harms. Potential benefits of PDMPs and urine drug testing include the ability to identify patients who might be at higher risk for opioid overdose or opioid use disorder, and help determine which patients will benefit from greater caution and increased monitoring or interventions when risk factors are present. For example, one study found that most fatal overdoses could be identified retrospectively on the basis of two pieces of information, multiple prescribers and high total daily opioid dosage, both important risk factors for overdose124,146 that are available to prescribers in the PDMP.124 However, limited evaluation of PDMPs at the state level has revealed mixed effects on changes in prescribing and mortality outcomes.28 Potential harms of risk stratification include underestimation of risks of opioid therapy when screening tools are not adequately sensitive, as well as potential overestimation of risk, which could lead to inappropriate clinical decisions. Regarding risk mitigation approaches, limited evidence was found regarding benefits

and harms. Although no studies were found to examine prescribing of naloxone with opioid pain medication in primary care settings, naloxone distribution through community-based programs providing prevention services for substance users has been demonstrated to be associated with decreased risk for opioid overdose death at the community level.147

Concerns have been raised that prescribing changes such as dose reduction might be associated with unintended negative consequences, such as patients seeking heroin or other illicitly obtained opioids48 or interference with appropriate pain treatment.149 With the exception of a study noting an association between an abuse deterrent formulation of OxyContin and heroin use, showing that some patients in qualitative interviews reported switching to another opioid, including heroin, for many reasons, including cost and availability as well as ease of use150, CDC did not identify studies evaluating these potential outcomes. Finally, regarding the effectiveness of opioid use disorder treatments, methadone and buprenorphine for opioid use disorder have been found to increase retention in treatment and to decrease illicit opioid use among patients with opioid use disorder involving heroin.151–153

Although findings are mixed, some studies suggest that effectiveness is enhanced when psychosocial treatments (e.g., contingency management, community reinforcement, psychotherapeutic counseling, and family therapy) are used in conjunction with medication assisted therapy; for example, by reducing opioid misuse and increasing retention during maintenance therapy, and improving compliance after detoxification.154,155

Clinician and Patient Values and Preferences Clinician and patient values and preferences can inform how benefits and harms of long-term opioid therapy are weighted and estimate the effort and resources required to effectively provide implementation support. Many physicians lack confidence in their ability to prescribe opioids safely156, to predict157 or detect158 prescription drug abuse, and to discuss abuse with their patients.158 Although clinicians have reported favorable beliefs and attitudes about improvements in pain and quality of life attributed to opioids 59, most consider prescription drug abuse to be a “moderate” or “big” problem in their community, and large proportions are “very” concerned about opioid addiction (55%) and death (48%).160 Clinicians do not consistently use practices intended to decrease the risk for misuse, such as PDMPs161,162, urine drug testing163, and opioid treatment agreements.164 This is likely due in part to challenges related to registering for PDMP access and logging into the PDMP (which can

31

interrupt normal clinical work-flow if data are not integrated into electronic health record systems)165, competing clinical demands, perceived inadequate time to discuss the rationale for urine drug testing and to order confirmatory testing, and feeling unprepared to interpret and address results.166

Many patients do not have an opinion about “opioids” or know what this term means.167 Most are familiar with the term “narcotics.” About a third associated “narcotics” with addiction or abuse, and about half feared “addiction” from long-term “narcotic” use.168 Most patients taking opioids experience side effects (73% of patients taking hydrocodone for non-cancer pain11, 96% of patients taking opioids for chronic pain12), and side effects, rather than pain relief, have been found to explain most of the variation in patients’ preferences related to taking opioids.12 For example, patients taking hydrocodone for non-cancer pain commonly reported side effects including dizziness, headache, fatigue, drowsiness, nausea, vomiting, and constipation.11 Patients with chronic pain in focus groups emphasized effectiveness of goal setting for increasing motivation and functioning.168 Patients taking high dosages report reliance on opioids despite ambivalence about their benefits169 and regardless of pain reduction, reported problems, concerns, side effects, or perceived helpfulness.13

Resource Allocation Resource allocation (cost) is an important consideration in understanding the feasibility of clinical recommendations. CDC searched for evidence on opioid therapy compared with other treatments; costs of misuse, abuse, and overdose from prescription opioids; and costs of specific risk mitigation strategies (e.g., urine drug testing). Yearly direct and indirect costs related to prescription opioids have been estimated (based on studies published since 2010) to be $53.4 billion for non medical use of prescription opioids170; $55.7 billion for abuse, dependence (i.e., opioid use disorder), and misuse of prescription opioids171; and $20.4 billion for direct and indirect costs related to opioid-related overdose alone.172 In 2012, total expenses for outpatient prescription opioids were estimated at $9.0 billion, an increase of 120% from 2002.173 Although there are perceptions that opioid therapy for chronic pain is less expensive than more time-intensive nonpharmacologic management approaches, many pain treatments, including acetaminophen, NSAIDs, tricyclic antidepressants, and massage therapy, are associated with lower mean and median annual costs compared with opioid therapy.174 COX-2 inhibitors, SNRIs, anticonvulsants, topical analgesics, physical therapy, and CBT are also associated with lower median annual costs compared with opioid therapy.174 Limited information was found on costs of strategies to decrease risks associated

with opioid therapy; however, urine drug testing, including screening and confirmatory tests, has been estimated to cost $211–$363 per test.175

Recommendations The recommendations are grouped into three areas for consideration:• Determining when to initiate or continue

opioids for chronic pain.• Opioid selection, dosage, duration, follow-

up, and discontinuation.• Assessing risk and addressing harms of

opioid use.

There are 12 recommendations (Box 1). Each recommendation is followed by a rationale for the recommendation, with considerations for implementation noted. In accordance with the ACIP GRADE process, CDC based the recommendations on consideration of the clinical evidence, contextual evidence (including benefits and harms, values and preferences, resource allocation), and expert opinion. For each recommendation statement, CDC notes the recommendation category (A or B) and the type of the evidence (1, 2, 3, or 4) supporting the statement (Box 2). Expert opinion is reflected within each of the recommendation rationales. While there was not an attempt to reach consensus among experts, experts from the Core Expert Group and from the Opioid Guideline Workgroup (“experts”) expressed overall, general support for all recommendations. Where differences in expert opinion emerged for detailed actions within the clinical recommendations or for implementation considerations, CDC notes the differences of opinion in the supporting rationale statements. Category A recommendations indicate that most patients should receive the recommended course of action; category B recommendations indicate that different choices will be appropriate for different patients, requiring clinicians to help patients arrive at a decision consistent with patient values and preferences and specific clinical situations. Consistent with the ACIP47 and GRADE process48, category A recommendations were made, even with type 3 and 4 evidence, when there was broad agreement that the advantages of a clinical action greatly outweighed the disadvantages based on a consideration of benefits and harms, values and preferences, and resource allocation. Category B recommendations were made when there was broad agreement that the advantages and disadvantages of a clinical action were more balanced, but advantages were significant enough to warrant a recommendation. All recommendations are category A recommendations, with the exception of recommendation 10, which is rated as category B. Recommendations were associated with a range of evidence types, from type 2 to type 4. In summary, the categorization of recommendations was based on the following

assessment:• No evidence shows a long-term benefit

of opioids in pain and function versus no opioids for chronic pain with outcomes examined at least 1 year later (with most placebo-controlled randomized trials ≤6 weeks in duration).

• Extensive evidence shows the possible harms of opioids (including opioid use disorder, overdose, and motor vehicle injury).

• Extensive evidence suggests some benefits of nonpharmacologic and non-opioid pharmacologic treatments compared with long-term opioid therapy, with less harm.

BOX 1. CDC recommendations for prescribing opioids for chronic pain outside of active cancer, palliative, and

end-of-life care

Determining When to Initiate or Continue Opioids for Chronic Pain1. Nonpharmacologic therapy and non-

opioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate.

2. Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety.

3. Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy.

Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation4. When starting opioid therapy for

chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids.

continued on the following page

32

Determining When to Initiate or Continue Opioids for Chronic Pain

1. Nonpharmacologic therapy and non-opioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate (recommendation category: A, evidence type: 3).

Patients with pain should receive treatment that provides the greatest benefits relative to risks. The contextual evidence review found that many nonpharmacologic therapies,

including physical therapy, weight loss for knee osteoarthritis, psychological therapies such as CBT, and certain interventional procedures can ameliorate chronic pain. There is high quality evidence that exercise therapy (a prominent modality in physical therapy) for hip100 or knee99 osteoarthritis reduces pain and improves function immediately after treatment and that the improvements are sustained for at least 2–6 months. Previous guidelines have strongly recommended aerobic, aquatic, and/or resistance exercises for patients with osteoarthritis of the knee or hip.176 Exercise therapy also can help reduce pain and improve function in low back pain and can improve global wellbeing and physical function in fibromyalgia.98,101 Multimodal therapies and multidisciplinary biopsychosocial rehabilitation combining approaches (e.g., psychological therapies with exercise) can reduce

long-term pain and disability compared with usual care and compared with physical treatments (e.g., exercise) alone. Multimodal therapies are not always available or reimbursed by insurance and can be time consuming and costly for patients. Interventional approaches such as arthrocentesis and intra-articular glucocorticoid injection for pain associated with rheumatoid arthritis117 or osteoarthritis118 and subacromial corticosteroid injection for rotator cuff disease119 can provide short-term improvement in pain and function. Evidence is insufficient to determine the extent to which repeated glucocorticoid injection increases potential risks such as articular cartilage changes (in osteoarthritis) and sepsis.118 Serious adverse events are rare but have been reported with epidural injection.120

BOX 2. Interpretation of recommendation categories and evidence type

Recommendation CategoriesBased on evidence type, balance between desirable and undesirable effects, values and preferences, and resource allocation (cost).Category A recommendation: Applies to all persons; most patients should receive the recommended course of action.Category B recommendation: Individual decision making needed; different choices will be appropriate for different patients. Clinicians help patients arrive at a decision consistent with patient values and preferences and specific clinical situations.

Evidence TypeBased on study design as well as a function of limitations in study design or implementation, imprecision of estimates, variability in findings, indirectness of evidence, publication bias, magnitude of treatment effects, dose-response gradient, and constellation of plausible biases that could change effects.Type 1 evidence: Randomized clinical trials or overwhelming evidence from observational studies.Type 2 evidence: Randomized clinical trials with important limitations, or exceptionally strong evidence from observational studies.Type 3 evidence: Observational studies or randomized clinical trials with notable limitations.Type 4 evidence: Clinical experience and observations, observational studies with important limitations, or randomized clinical trials with several major limitations.

BOX 1. CDC recommendations for prescribing opioids for chronic pain outside of active cancer, palliative, and end-of-life care

(continued)

5. When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day.

6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed.

7. Clinicians should evaluate benefits and harms with patients within 1 to 4 weeks of starting opioid therapy for chronic pain or of dose escalation. Clinicians should evaluate benefits and harms of continued therapy with patients every 3 months or more frequently. If benefits do not outweigh harms of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue opioids.

Assessing Risk and Addressing Harms of Opioid Use8. Before starting and periodically during continuation of opioid therapy, clinicians should evaluate

risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use, are present.

9. Clinicians should review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months.

10. When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs.

11. Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible.

12. Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder.

* All recommendations are category A (apply to all patients outside of active cancer treatment, palliative care, and end-of-life care) except recommendation 10 (designated category B, with individual decision making required); see full guideline for evidence ratings.

33

Several non-opioid pharmacologic therapies (including acetaminophen, NSAIDs, and selected antidepressants and anticonvulsants) are effective for chronic pain. In particular, acetaminophen and NSAIDs can be useful for arthritis and low back pain. Selected anticonvulsants such as pregabalin and gabapentin can improve pain in diabetic neuropathy and post-herpetic neuralgia (contextual evidence review). Pregabalin, gabapentin, and carbamazepine are FDA approved for treatment of certain neuropathic pain conditions, and pregabalin is FDA approved for fibromyalgia management. In patients with or without depression, tricyclic antidepressants and SNRIs provide effective analgesia for neuropathic pain conditions including diabetic neuropathy and post-herpetic neuralgia, often at lower dosages and with a shorter time to onset of effect than for treatment of depression (see contextual evidence review). Tricyclics and SNRIs can also relieve fibromyalgia symptoms. The SNRI duloxetine is FDA approved for the treatment of diabetic neuropathy and fibromyalgia. Because patients with chronic pain often suffer from concurrent depression144, and depression can exacerbate physical symptoms including pain177, patients with co-occurring pain and depression are especially likely to benefit from antidepressant medication (see Recommendation 8). Non-opioid pharmacologic therapies are not generally associated with substance use disorder, and the numbers of fatal overdoses associated with non-opioid medications are a fraction of those associated with opioid medications (contextual evidence review). For example, acetaminophen, NSAIDs, and opioid pain medication were involved in 881, 228, and 16,651 pharmaceutical overdose deaths in the United States in 2010178. However, non-opioid pharmacologic therapies are associated with certain risks, particularly in older patients, pregnant patients, and patients with certain co-morbidities such as cardiovascular, renal, gastrointestinal, and liver disease (see contextual evidence review). For example, acetaminophen can be hepatotoxic at dosages of > 3-4 grams/day and at lower dosages in patients with chronic alcohol use or liver disease (109). NSAID use has been associated with gastritis, peptic ulcer disease, cardiovascular events111,112, and fluid retention, and most NSAIDs (choline magnesium trilisate and selective COX-2 inhibitors are exceptions) interfere with platelet aggregation.179 Clinicians should review FDA approved labeling including boxed warnings before initiating treatment with any pharmacologic therapy. Although opioids can reduce pain during short-term use, the clinical evidence review found insufficient evidence to determine whether pain relief is sustained and whether function or quality of life improves with long-term opioid therapy (KQ1). While benefits for pain relief, function, and quality of life with long-term opioid use for

chronic pain are uncertain, risks associated with long-term opioid use are clearer and significant. Based on the clinical evidence review, long-term opioid use for chronic pain is associated with serious risks including increased risk for opioid use disorder, overdose, myocardial infarction, and motor vehicle injury (KQ2). At a population level, more than 165,000 persons in the United States have died from opioid pain medication-related overdoses since 1999 (see Contextual Evidence Review). Integrated pain management requires coordination of medical, psychological, and social aspects of health care and includes primary care, mental health care, and specialist services when needed.180 Nonpharmacologic physical and psychological treatments such as exercise and CBT are approaches that encourage active patient participation in the care plan, address the effects of pain in the patient’s life, and can result in sustained improvements in pain and function without apparent risks. Despite this, these therapies are not always or fully covered by insurance, and access and cost can be barriers for patients. For many patients, aspects of these approaches can be used even when there is limited access to specialty care. For example, previous guidelines have strongly recommended aerobic, aquatic, and/or resistance exercises for patients with osteoarthritis of the knee or hip176 and maintenance of activity for patients with low back pain.110 A randomized trial found no difference in reduced chronic low back pain intensity, frequency or disability between patients assigned to relatively low-cost group aerobics and individual physiotherapy or muscle reconditioning sessions.181 Low-cost options to integrate exercise include brisk walking in public spaces or use of public recreation facilities for group exercise. CBT addresses psychosocial contributors to pain and improves function97 Primary care clinicians can integrate elements of a cognitive behavioral approach into their practice by encouraging patients to take an active role in the care plan, by supporting patients in engaging in beneficial but potentially anxiety-provoking activities, such as exercise179, or by providing education in relaxation techniques and coping strategies. In many locations, there are free or low-cost patient support, self-help, and educational community-based programs that can provide stress reduction and other mental health benefits. Patients with more entrenched anxiety or fear related to pain, or other significant psychological distress, can be referred for formal therapy with a mental health specialist (e.g., psychologist, psychiatrist, clinical social worker). Multi-modal therapies should be considered for patients not responding to single-modality therapy, and combinations should be tailored depending on patient needs, cost, and convenience. To guide patient-specific selection

of therapy, clinicians should evaluate patients and establish or confirm the diagnosis. Detailed recommendations on diagnosis are provided in other guidelines110,179, but evaluation should generally include a focused history, including history and characteristics of pain and potentially contributing factors (e.g., function, psychosocial stressors, sleep) and physical exam, with imaging or other diagnostic testing only if indicated (e.g., if severe or progressive neurologic deficits are present or if serious underlying conditions are suspected).110,179 For complex pain syndromes, pain specialty consultation can be considered to assist with diagnosis as well as management. Diagnosis can help identify disease specific interventions to reverse or ameliorate pain; for example, improving glucose control to prevent progression of diabetic neuropathy; immune-modulating agents for rheumatoid arthritis; physical or occupational therapy to address posture, muscle weakness, or repetitive occupational motions that contribute to musculoskeletal pain; or surgical intervention to relieve mechanical/compressive pain.179 The underlying mechanism for most pain syndromes can be categorized as neuropathic (e.g., diabetic neuropathy, postherpetic neuralgia, fibromyalgia), or nociceptive (e.g., osteoarthritis, muscular back pain). The diagnosis and pathophysiologic mechanism of pain have implications for symptomatic pain treatment with medication. For example, evidence is limited or insufficient for improved pain or function with long-term use of opioids for several chronic pain conditions for which opioids are commonly prescribed, such as low back pain182, headache183, and fibromyalgia184. Although NSAIDs can be used for exacerbations of nociceptive pain, other medications (e.g., tricyclics, selected anticonvulsants, or transdermal lidocaine) generally are recommended for neuropathic pain. In addition, improvement of neuropathic pain can begin weeks or longer after symptomatic treatment is initiated.179 Medications should be used only after assessment and determination that expected benefits outweigh risks given patient-specific factors. For example, clinicians should consider falls risk when selecting and dosing potentially sedating medications such as tricyclics, anticonvulsants, or opioids, and should weigh risks and benefits of use, dose, and duration of NSAIDs when treating older adults as well as patients with hypertension, renal insufficiency, or heart failure, or those with risk for peptic ulcer disease or cardiovascular disease. Some guidelines recommend topical NSAIDs for localized osteoarthritis (e.g., knee osteoarthritis) over oral NSAIDs in patients aged ≥ 75 years to minimize systemic effects.176

Experts agreed that opioids should not be considered first-line or routine therapy for chronic pain (i.e., pain continuing or expected to continue >3 months or past the time of normal

34

tissue healing) outside of active cancer, palliative, and end-of-life care, given small to moderate short-term benefits, uncertain long-term benefits, and potential for serious harms; although evidence on long-term benefits of non-opioid therapies is also limited, these therapies are also associated with short-term benefits, and risks are much lower. This does not mean that patients should be required to sequentially “fail” nonpharmacologic and non-opioid pharmacologic therapy before proceeding to opioid therapy. Rather, expected benefits specific to the clinical context should be weighed against risks before initiating therapy. In some clinical contexts (e.g., headache or fibromyalgia), expected benefits of initiating opioids are unlikely to outweigh risks regardless of previous nonpharmacologic and non-opioid pharmacologic therapies used. In other situations (e.g., serious illness in a patient with poor prognosis for return to previous level of function, contraindications to other therapies, and clinician and patient agreement that the overriding goal is patient comfort), opioids might be appropriate regardless of previous therapies used. In addition, when opioid pain medication is used, it is more likely to be effective if integrated with nonpharmacologic therapy. Nonpharmacologic approaches such as exercise and CBT should be used to reduce pain and improve function in patients with chronic pain. Non-opioid pharmacologic therapy should be used when benefits outweigh risks and should be combined with nonpharmacologic therapy to reduce pain and improve function. If opioids are used, they should be combined with nonpharmacologic therapy and non-opioid pharmacologic therapy, as appropriate, to provide greater benefits to patients in improving pain and function.

2. Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how opioid therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety (recommendation category: A, evidence type: 4).

The clinical evidence review found insufficient evidence to determine long-term benefits of opioid therapy for chronic pain and found an increased risk for serious harms related to long-term opioid therapy that appears to be dose-dependent. In addition, studies on currently available risk assessment instruments were sparse and showed inconsistent results (KQ4). The clinical evidence review for the current guideline considered studies with outcomes examined at ≥1 year that compared opioid use versus non use or placebo. Studies of opioid therapy for chronic pain

that did not have a non-opioid control group have found that although many patients discontinue opioid therapy for chronic non-cancer pain due to adverse effects or insufficient pain relief, there is weak evidence that patients who are able to continue opioid therapy for at least 6 months can experience clinically significant pain relief and insufficient evidence that function or quality of life improves.185 These findings suggest that it is very difficult for clinicians to predict whether benefits of opioids for chronic pain will outweigh risks of ongoing treatment for individual patients. Opioid therapy should not be initiated without consideration of an “exit strategy” to be used if the therapy is unsuccessful. Experts agreed that before opioid therapy is initiated for chronic pain outside of active cancer, palliative, and end-of-life care, clinicians should determine how effectiveness will be evaluated and should establish treatment goals with patients. Because the line between acute pain and initial chronic pain is not always clear, it might be difficult for clinicians to determine when they are initiating opioids for chronic pain rather than treating acute pain. Pain lasting longer than 3 months or past the time of normal tissue healing (which could be substantially shorter than 3 months, depending on the condition) is generally no longer considered acute. However, establishing treatment goals with a patient who has already received opioid therapy for 3 months would defer this discussion well past the point of initiation of opioid therapy for chronic pain. Clinicians often write prescriptions for long-term use in 30-day increments, and opioid prescriptions written for ≥30 days are likely to represent initiation or continuation of long-term opioid therapy. Before writing an opioid prescription for ≥30 days, clinicians should establish treatment goals with patients. Clinicians seeing new patients already receiving opioids should establish treatment goals for continued opioid therapy. Although the clinical evidence review did not find studies evaluating the effectiveness of written agreements or treatment plans (KQ4), clinicians and patients who set a plan in advance will clarify expectations regarding how opioids will be prescribed and monitored, as well as situations in which opioids will be discontinued or doses tapered (e.g., if treatment goals are not met, opioids are no longer needed, or adverse events put the patient at risk) to improve patient safety. Experts thought that goals should include improvement in both pain relief and function (and therefore in quality of life). However, there are some clinical circumstances under which reductions in pain without improvement in physical function might be a more realistic goal (e.g., diseases typically associated with progressive functional impairment or catastrophic injuries such as spinal cord trauma). Experts noted that function can include emotional and social as well as physical dimensions. In addition, experts emphasized that

mood has important interactions with pain and function. Experts agreed that clinicians may use validated instruments such as the three-item “Pain average, interference with Enjoyment of life, and interference with General activity” (PEG) Assessment Scale186 to track patient outcomes. Clinically meaningful improvement has been defined as a 30% improvement in scores for both pain and function.187 Monitoring progress toward patient-centered functional goals (e.g., walking the dog or walking around the block, returning to part-time work, attending family sports or recreational activities) can also contribute to the assessment of functional improvement. Clinicians should use these goals in assessing benefits of opioid therapy for individual patients and in weighing benefits against risks of continued opioid therapy (see Recommendation 7, including recommended intervals for follow-up). Because depression, anxiety, and other psychological co-morbidities often coexist with and can interfere with resolution of pain, clinicians should use validated instruments to assess for these conditions (see Recommendation 8) and ensure that treatment for these conditions is optimized. If patients receiving opioid therapy for chronic pain do not experience meaningful improvements in both pain and function compared with prior to initiation of opioid therapy, clinicians should consider working with patients to taper and discontinue opioids (see Recommendation 7) and should use nonpharmacologic and non-opioid pharmacologic approaches to pain management (see Recommendation 1).

3. Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy (recommendation category: A, evidence type: 3).

The clinical evidence review did not find studies evaluating effectiveness of patient education or opioid treatment plans as risk mitigation strategies (KQ4). However, the contextual evidence review found that many patients lack information about opioids and identified concerns that some clinicians miss opportunities to effectively communicate about safety. Given the substantial evidence gaps on opioids, uncertain benefits of long-term use, and potential for serious harms, patient education and discussion before starting opioid therapy are critical so that patient preferences and values can be understood and used to inform clinical decisions. Experts agreed that essential elements to communicate to patients before starting and periodically during opioid therapy include realistic expected benefits, common and serious harms, and expectations for clinician and patient responsibilities to mitigate risks of opioid therapy.

35

Clinicians should involve patients in decisions about whether to start or continue opioid therapy. Given potentially serious risks of long-term opioid therapy, clinicians should ensure that patients are aware of potential benefits of, harms of, and alternatives to opioids before starting or continuing opioid therapy. Clinicians are encouraged to have open and honest discussions with patients to inform mutual decisions about whether to start or continue opioid therapy. Important considerations include the following:• Be explicit and realistic about expected

benefits of opioids, explaining that while opioids can reduce pain during short-term use, there is no good evidence that opioids improve pain or function with long-term use, and that complete relief of pain is unlikely (clinical evidence review, KQ1).

• Emphasize improvement in function as a primary goal and that function can improve even when pain is still present.

• Advise patients about serious adverse effects of opioids, including potentially fatal respiratory depression and development of a potentially serious lifelong opioid use disorder that can cause distress and inability to fulfill major role obligations.

• Advise patients about common effects of opioids, such as constipation, dry mouth, nausea, vomiting, drowsiness, confusion, tolerance, physical dependence, and withdrawal symptoms when stopping opioids. To prevent constipation associated with opioid use, advise patients to increase hydration and fiber intake and to maintain or increase physical activity. Stool softeners or laxatives might be needed.

• Discuss effects that opioids might have on ability to safely operate a vehicle, particularly when opioids are initiated, when dosages are increased, or when other central nervous system depressants, such as benzodiazepines or alcohol, are used concurrently.

• Discuss increased risks for opioid use disorder, respiratory depression, and death at higher dosages, along with the importance of taking only the amount of opioids prescribed, i.e., not taking more opioids or taking them more often.

• Review increased risks for respiratory depression when opioids are taken with benzodiazepines, other sedatives, alcohol, illicit drugs such as heroin, or other opioids.

• Discuss risks to household members and other individuals if opioids are intentionally or unintentionally shared with others for whom they are not prescribed, including the possibility that others might experience overdose at the same or at lower dosage than prescribed for the patient, and that young children are susceptible to unintentional

ingestion. Discuss storage of opioids in a secure, preferably locked location and options for safe disposal of unused opioids.188

• Discuss the importance of periodic reassessment to ensure that opioids are helping to meet patient goals and to allow opportunities for opioid discontinuation and consideration of additional nonpharmacologic or non-opioid pharmacologic treatment options if opioids are not effective or are harmful.

• Discuss planned use of precautions to reduce risks, including use of prescription drug monitoring program information (see Recommendation 9) and urine drug testing (see Recommendation 10). Consider including discussion of naloxone use for overdose reversal (see Recommendation 8).

• Consider whether cognitive limitations might interfere with management of opioid therapy (for older adults in particular) and, if so, determine whether a caregiver can responsibly co-manage medication therapy. Discuss the importance of reassessing safer medication use with both the patient and caregiver.

Given the possibility that benefits of opioid therapy might diminish or that risks might become more prominent over time, it is important that clinicians review expected benefits and risks of continued opioid therapy with patients periodically, at least every 3 months (see Recommendation 7).

Opioid Selection, Dosage, Duration, Follow-Up, and Discontinuation

4. When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/long-acting (ER/LA) opioids (recommendation category: A, evidence type: 4).

ER/LA opioids include methadone, transdermal fentanyl, and extended-release versions of opioids such as oxycodone, oxymorphone, hydrocodone, and morphine. The clinical evidence review found a fair-quality study showing a higher risk for overdose among patients initiating treatment with ER/LA opioids than among those initiating treatment with immediate-release opioids.77 The clinical evidence review did not find evidence that continuous, time-scheduled use of ER/LA opioids is more effective or safer than intermittent use of immediate-release opioids or that time-scheduled use of ER/LA opioids reduces risks for opioid misuse or addiction (KQ3). In 2014, the FDA modified the labeling for ER/LA opioid pain medications, noting serious risks and recommending that ER/LA opioids be reserved for “management of pain severe

enough to require daily, around-the-clock, long-term opioid treatment” when “alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain” and not used as “as needed” pain relievers.121 FDA has also noted that some ER/LA opioids are only appropriate for opioid-tolerant patients, defined as patients who have received certain dosages of opioids (e.g., 60 mg daily of oral morphine, 30 mg daily of oral oxycodone, or equianalgesic dosages of other opioids) for at least 1 week.189 Time-scheduled opioid use can be associated with greater total average daily opioid dosage compared with intermittent, as-needed opioid use (contextual evidence review). In addition, experts indicated that there was not enough evidence to determine the safety of using immediate-release opioids for breakthrough pain when ER/LA opioids are used for chronic pain outside of active cancer pain, palliative care, or end-of-life care, and that this practice might be associated with dose escalation. Abuse-deterrent technologies have been employed to prevent manipulation intended to defeat extended-release properties of ER/LA opioids and to prevent opioid use by unintended routes of administration, such as injection of oral opioids. As indicated in FDA guidance for industry on evaluation and labeling of abuse-deterrent opioids190, although abuse-deterrent technologies are expected to make manipulation of opioids more difficult or less rewarding, they do not prevent opioid abuse through oral intake, the most common route of opioid abuse, and can still be abused by non-oral routes. The “abuse-deterrent” label does not indicate that there is no risk for abuse. No studies were found in the clinical evidence review assessing the effectiveness of abuse-deterrent technologies as a risk mitigation strategy for deterring or preventing abuse. In addition, abuse-deterrent technologies do not prevent unintentional overdose through oral intake. Experts agreed that recommendations could not be offered at this time related to use of abuse-deterrent formulations. In comparing different ER/LA formulations, the clinical evidence review found inconsistent results for overdose risk with methadone versus other ER/LA opioids used for chronic pain (KQ3). The contextual evidence review found that methadone has been associated with disproportionate numbers of overdose deaths relative to the frequency with which it is prescribed for chronic pain. In addition, methadone is associated with cardiac arrhythmias along with QT prolongation on the electrocardiogram, and it has complicated pharmacokinetics and pharmacodynamics, including a long and variable half-life and peak respiratory depressant effect

36

occurring later and lasting longer than peak analgesic effect. Experts noted that the pharmacodynamics of methadone are subject to more inter-individual variability than other opioids. In regard to other ER/LA opioid formulations, experts noted that the absorption and pharmacodynamics of transdermal fentanyl are complex, with gradually increasing serum concentration during the first part of the 72-hour dosing interval, as well as variable absorption based on factors such as external heat. In addition, the dosing of transdermal fentanyl in mcg/hour, which is not typical for a drug used by outpatients, can be confusing. Experts thought that these complexities might increase the risk for fatal overdose when methadone or transdermal fentanyl is prescribed to a patient who has not used it previously or by clinicians who are not familiar with its effects. Experts agreed that for patients not already receiving opioids, clinicians should not initiate opioid treatment with ER/LA opioids and should not prescribe ER/LA opioids for intermittent use. ER/LA opioids should be reserved for severe, continuous pain and should be considered only for patients who have received immediate-release opioids daily for at least 1 week. When changing to an ER/LA opioid for a patient previously receiving a different immediate-release opioid, clinicians should consult product labeling and reduce total daily dosage to account for incomplete opioid cross tolerance. Clinicians should use additional caution with ER/LA opioids and consider a longer dosing interval when prescribing to patients with renal or hepatic dysfunction because decreased clearance of drugs among these patients can lead to accumulation of drugs to toxic levels and persistence in the body for longer durations. Although there might be situations in which clinicians need to prescribe immediate-release and ER/LA opioids together (e.g., transitioning patients from ER/LA opioids to immediate-release opioids by temporarily using lower dosages of both), in general, avoiding the use of immediate-release opioids in combination with ER/LA opioids is preferable, given potentially increased risk and diminishing returns of such an approach for chronic pain. When an ER/LA opioid is prescribed, using one with predictable pharmacokinetics and pharmacodynamics is preferred to minimize unintentional overdose risk. In particular, unusual characteristics of methadone and of transdermal fentanyl make safe prescribing of these medications for pain especially challenging.• Methadone should not be the first choice

for an ER/LA opioid. Only clinicians who are familiar with methadone’s unique risk profile and who are prepared to educate and closely monitor their patients, including risk assessment for QT prolongation and consideration of electrocardiographic

monitoring, should consider prescribing methadone for pain. A clinical practice guideline that contains further guidance regarding methadone prescribing for pain has been published previously.191

• Because dosing effects of transdermal fentanyl are often misunderstood by both clinicians and patients, only clinicians who are familiar with the dosing and absorption properties of transdermal fentanyl and are prepared to educate their patients about its use should consider prescribing it.

5. When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing opioids at any dosage, should carefully reassess evidence of individual benefits and risks when considering increasing dosage to ≥50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to ≥90 MME/day or carefully justify a decision to titrate dosage to ≥90 MME/day (recommendation category: A, evidence type: 3).

Benefits of high-dose opioids for chronic pain are not established. The clinical evidence review found only one study84 addressing effectiveness of dose titration for outcomes related to pain control, function, and quality of life (KQ3). This randomized trial found no difference in pain or function between a more liberal opioid dose escalation strategy and maintenance of current dosage. (These groups were prescribed average dosages of 52 and 40 MME/day, respectively, at the end of the trial.) At the same time, risks for serious harms related to opioid therapy increase at higher opioid dosage. The clinical evidence review found that higher opioid dosages are associated with increased risks for motor vehicle injury, opioid use disorder, and overdose (KQ2). The clinical and contextual evidence reviews found that opioid overdose risk increases in a dose-response manner, that dosages of 50–<100 MME/day have been found to increase risks for opioid overdose by factors of 1.9 to 4.6 compared with dosages of 1–<20 MME/day, and that dosages ≥100 MME/day are associated with increased risks of overdose 2.0–8.9 times the risk at 1–<20 MME/day. In a national sample of Veterans Health Administration patients with chronic pain who were prescribed opioids, mean prescribed opioid dosage among patients who died from opioid overdose was 98 MME (median 60 MME) compared with mean prescribed opioid dosage of 48 MME (median 25 MME) among patients not experiencing fatal overdose.127

The contextual evidence review found that although there is not a single dosage threshold below which overdose risk is eliminated, holding dosages <50 MME/day would likely

reduce risk among a large proportion of patients who would experience fatal overdose at higher prescribed dosages. Experts agreed that lower dosages of opioids reduce the risk for overdose, but that a single dosage threshold for safe opioid use could not be identified. Experts noted that daily opioid dosages close to or greater than 100 MME/day are associated with significant risks, that dosages <50 MME/day are safer than dosages of 50–100 MME/day, and that dosages <20 MME/day are safer than dosages of 20–50 MME/day. One expert thought that a specific dosage at which the benefit/risk ratio of opioid therapy decreases could not be identified. Most experts agreed that, in general, increasing dosages to 50 or more MME/day increases overdose risk without necessarily adding benefits for pain control or function and that clinicians should carefully reassess evidence of individual benefits and risks when considering increasing opioid dosages to ≥50 MME/day. Most experts also agreed that opioid dosages should not be increased to ≥90 MME/day without careful justification based on diagnosis and on individualized assessment of benefits and risks. When opioids are used for chronic pain outside of active cancer, palliative, and end-of-life care, clinicians should start opioids at the lowest possible effective dosage (the lowest starting dosage on product labeling for patients not already taking opioids and according to product labeling guidance regarding tolerance for patients already taking opioids). Clinicians should use additional caution when initiating opioids for patients aged ≥65 years and for patients with renal or hepatic insufficiency because decreased clearance of drugs in these patients can result in accumulation of drugs to toxic levels. Clinicians should use caution when increasing opioid dosages and increase dosage by the smallest practical amount because overdose risk increases with increases in opioid dosage. Although there is limited evidence to recommend specific intervals for dosage titration, a previous guideline recommended waiting at least five half-lives before increasing dosage and waiting at least a week before increasing dosage of methadone to make sure that full effects of the previous dosage are evident.31 Clinicians should re-evaluate patients after increasing dosage for changes in pain, function, and risk for harm (see Recommendation 7). Before increasing total opioid dosage to ≥50 MME/day, clinicians should reassess whether opioid treatment is meeting the patient’s treatment goals (see Recommendation 2). If a patient’s opioid dosage for all sources of opioids combined reaches or exceeds 50 MME/day, clinicians should implement additional precautions, including increased frequency of follow-up (see Recommendation 7) and considering offering naloxone and overdose prevention education to

37

both patients and the patients’ household members (see Recommendation 8). Clinicians should avoid increasing opioid dosages to ≥90 MME/day or should carefully justify a decision to increase dosage to ≥90 MME/day based on individualized assessment of benefits and risks and weighing factors such as diagnosis, incremental benefits for pain and function relative to harms as dosages approach 90 MME/day, other treatments and effectiveness, and recommendations based on consultation with pain specialists. If patients do not experience improvement in pain and function at ≥90 MME/day, or if there are escalating dosage requirements, clinicians should discuss other approaches to pain management with the patient, consider working with patients to taper opioids to a lower dosage or to taper and discontinue opioids (see Recommendation 7), and consider consulting a pain specialist. Some states require clinicians to implement clinical protocols at specific dosage levels. For example, before increasing long-term opioid therapy dosage to >120 MME/day, clinicians in Washington state must obtain consultation from a pain specialist who agrees that this is indicated and appropriate.30 Clinicians should be aware of rules related to MME thresholds and associated clinical protocols established by their states. Established patients already taking high dosages of opioids, as well as patients transferring from other clinicians, might consider the possibility of opioid dosage reduction to be anxiety-provoking, and tapering opioids can be especially challenging after years on high dosages because of physical and psychological dependence. However, these patients should be offered the opportunity to re-evaluate their continued use of opioids at high dosages in light of recent evidence regarding the association of opioid dosage and overdose risk. Clinicians should explain in a nonjudgmental manner to patients already taking high opioid dosages (≥90 MME/day) that there is now an established body of scientific evidence showing that overdose risk is increased at higher opioid dosages. Clinicians should empathically review benefits and risks of continued high-dosage opioid therapy and should offer to work with the patient to taper opioids to safer dosages. For patients who agree to taper opioids to lower dosages, clinicians should collaborate with the patient on a tapering plan (see Recommendation 7). Experts noted that patients tapering opioids after taking them for years might require very slow opioid tapers as well as pauses in the taper to allow gradual accommodation to lower opioid dosages. Clinicians should remain alert to signs of anxiety, depression, and opioid use disorder (see Recommendations 8 and 12) that might be unmasked by an opioid taper and arrange for management of these co-morbidities. For patients agreeing to taper to lower opioid dosages as well as for those remaining on high opioid dosages, clinicians should establish goals

with the patient for continued opioid therapy (see Recommendation 2), maximize pain treatment with nonpharmacologic and non-opioid pharmacologic treatments as appropriate (see Recommendation 1), and consider consulting a pain specialist as needed to assist with pain management.

6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than seven days will rarely be needed (recommendation category: A, evidence type: 4).

The clinical evidence review found that opioid use for acute pain (i.e., pain with abrupt onset and caused by an injury or other process that is not ongoing) is associated with long-term opioid use, and that a greater amount of early opioid exposure is associated with greater risk for long-term use (KQ5). Several guidelines on opioid prescribing for acute pain from emergency departments192–194 and other settings195,196 have recommended prescribing ≤3 days of opioids in most cases, whereas others have recommended ≤7 days197 or <14 days.30 Because physical dependence on opioids is an expected physiologic response in patients exposed to opioids for more than a few days (contextual evidence review), limiting days of opioids prescribed also should minimize the need to taper opioids to prevent distressing or unpleasant withdrawal symptoms. Experts noted that more than a few days of exposure to opioids significantly increases hazards, that each day of unnecessary opioid use increases likelihood of physical dependence without adding benefit, and that prescriptions with fewer days’ supply will minimize the number of pills available for unintentional or intentional diversion. Experts agreed that when opioids are needed for acute pain, clinicians should prescribe opioids at the lowest effective dose and for no longer than the expected duration of pain severe enough to require opioids to minimize unintentional initiation of long-term opioid use. The lowest effective dose can be determined using product labeling as a starting point with calibration as needed based on the severity of pain and on other clinical factors such as renal or hepatic insufficiency (see Recommendation 8). Experts thought, based on clinical experience regarding anticipated duration of pain severe enough to require an opioid, that in most cases of acute pain not related to surgery or trauma, a ≤3 days’ supply of opioids will be sufficient. For example, in one study of the course of acute

low back pain (not associated with malignancies, infections, spondylarthropathies, fractures, or neurological signs) in a primary care setting, there was a large decrease in pain until the fourth day after treatment with paracetamol, with smaller decreases thereafter.198 Some experts thought that because some types of acute pain might require more than 3 days of opioid treatment, it would be appropriate to recommend a range of ≤3–5 days or ≤3–7 days when opioids are needed. Some experts thought that a range including 7 days was too long given the expected course of severe acute pain for most acute pain syndromes seen in primary care. Acute pain can often be managed without opioids. It is important to evaluate the patient for reversible causes of pain, for underlying etiologies with potentially serious sequelae, and to determine appropriate treatment. When the diagnosis and severity of nontraumatic, nonsurgical acute pain are reasonably assumed to warrant the use of opioids, clinicians should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids, often 3 days or less, unless circumstances clearly warrant additional opioid therapy. More than 7 days will rarely be needed. Opioid treatment for post-surgical pain is outside the scope of this guideline but has been addressed elsewhere.30 Clinicians should not prescribe additional opioids to patients “just in case” pain continues longer than expected. Clinicians should re-evaluate the subset of patients who experience severe acute pain that continues longer than the expected duration to confirm or revise the initial diagnosis and to adjust management accordingly. Given longer half-lives and longer duration of effects (e.g., respiratory depression) with ER/LA opioids such as methadone, fentanyl patches, or extended release versions of opioids such as oxycodone, oxymorphone, or morphine, clinicians should not prescribe ER/LA opioids for the treatment of acute pain.

7. Clinicians should evaluate benefits and harms with patients within 1 to 4 weeks of starting opioid therapy for chronic pain or of dose escalation. Clinicians should evaluate benefits and harms of continued therapy with patients every 3 months or more frequently. If benefits do not outweigh harms of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue opioids (recommendation category: A, evidence type: 4).

Although the clinical evidence review did not find studies evaluating the effectiveness of more frequent monitoring intervals (KQ4), it did find that continuing opioid therapy for 3 months substantially

38

increases risk for opioid use disorder (KQ2); therefore, follow-up earlier than 3 months might be necessary to provide the greatest opportunity to prevent the development of opioid use disorder. In addition, risk for overdose associated with ER/LA opioids might be particularly high during the first 2 weeks of treatment (KQ3). The contextual evidence review found that patients who do not have pain relief with opioids at 1 month are unlikely to experience pain relief with opioids at 6 months. Although evidence is insufficient to determine at what point within the first 3 months of opioid therapy the risks for opioid use disorder increase, reassessment of pain and function within 1 month of initiating opioids provides an opportunity to minimize risks of long-term opioid use by discontinuing opioids among patients not receiving a clear benefit from these medications. Experts noted that risks for opioid overdose are greatest during the first 3–7 days after opioid initiation or increase in dosage, particularly when methadone or transdermal fentanyl are prescribed; that follow-up within 3 days is appropriate when initiating or increasing the dosage of methadone; and that follow-up within 1 week might be appropriate when initiating or increasing the dosage of other ER/LA opioids. Clinicians should evaluate patients to assess benefits and harms of opioids within 1 to 4 weeks of starting long-term opioid therapy or of dose escalation. Clinicians should consider follow-up intervals within the lower end of this range when ER/LA opioids are started or increased or when total daily opioid dosage is ≥50 MME/day. Shorter follow-up intervals (within 3 days) should be strongly considered when starting or increasing the dosage of methadone. At follow up, clinicians should assess benefits in function, pain control, and quality of life using tools such as the three-item “Pain average, interference with Enjoyment of life, and interference with General activity” (PEG) Assessment Scale186 and/or asking patients about progress toward functional goals that have meaning for them (see Recommendation 2). Clinicians should also ask patients about common adverse effects such as constipation and drowsiness (see Recommendation 3), as well as asking about and assessing for effects that might be early warning signs for more serious problems such as overdose (e.g., sedation or slurred speech) or opioid use disorder (e.g., craving, wanting to take opioids in greater quantities or more frequently than prescribed, or difficulty controlling use). Clinicians should ask patients about their preferences for continuing opioids, given their effects on pain and function relative to any adverse effects experienced. Because of potential changes in the balance of benefits and risks of opioid therapy

over time, clinicians should regularly reassess all patients receiving long-term opioid therapy, including patients who are new to the clinician but on long-term opioid therapy, at least every 3 months. At reassessment, clinicians should determine whether opioids continue to meet treatment goals, including sustained improvement in pain and function, whether the patient has experienced common or serious adverse events or early warning signs of serious adverse events, signs of opioid use disorder (e.g., difficulty controlling use, work or family problems related to opioid use), whether benefits of opioids continue to outweigh risks, and whether opioid dosage can be reduced or opioids can be discontinued. Ideally, these reassessments would take place in person and be conducted by the prescribing clinician. In practice contexts where virtual visits are part of standard care (e.g., in remote areas where distance or other issues make follow-up visits challenging), follow-up assessments that allow the clinician to communicate with and observe the patient through video and audio could be conducted, with in person visits occurring at least once per year. Clinicians should re-evaluate patients who are exposed to greater risk of opioid use disorder or overdose (e.g., patients with depression or other mental health conditions, a history of substance use disorder, a history of overdose, taking ≥50 MME/day, or taking other central nervous system depressants with opioids) more frequently than every 3 months. If clinically meaningful improvements in pain and function are not sustained, if patients are taking high-risk regimens (e.g., dosages ≥50 MME/day or opioids combined with benzodiazepines) without evidence of benefit, if patients believe benefits no longer outweigh risks or if they request dosage reduction or discontinuation, or if patients experience overdose or other serious adverse events (e.g., an event leading to hospitalization or disability) or warning signs of serious adverse events, clinicians should work with patients to reduce opioid dosage or to discontinue opioids when possible. Clinicians should maximize pain treatment with nonpharmacologic and non-opioid pharmacologic treatments as appropriate (see Recommendation 1) and consider consulting a pain specialist as needed to assist with pain management.

Considerations for Tapering Opioids Although the clinical evidence review did not find high-quality studies comparing the effectiveness of different tapering protocols for use when opioid dosage is reduced or opioids are discontinued (KQ3), tapers reducing weekly dosage by 10%–50% of the original dosage have been recommended by other clinical

guidelines199, and a rapid taper over 2–3 weeks has been recommended in the case of a severe adverse event such as overdose.30 Experts noted that tapers slower than 10% per week (e.g., 10% per month) also might be appropriate and better tolerated than more rapid tapers, particularly when patients have been taking opioids for longer durations (e.g., for years). Opioid withdrawal during pregnancy has been associated with spontaneous abortion and premature labor. When opioids are reduced or discontinued, a taper slow enough to minimize symptoms and signs of opioid withdrawal (e.g., drug craving, anxiety, insomnia, abdominal pain, vomiting, diarrhea, diaphoresis, mydriasis, tremor, tachycardia, or piloerection) should be used. A decrease of 10% of the original dose per week is a reasonable starting point; experts agreed that tapering plans may be individualized based on patient goals and concerns. Experts noted that at times, tapers might have to be paused and restarted again when the patient is ready and might have to be slowed once patients reach low dosages. Tapers may be considered successful as long as the patient is making progress. Once the smallest available dose is reached, the interval between doses can be extended. Opioids may be stopped when taken less frequently than once a day. More rapid tapers might be needed for patient safety under certain circumstances (e.g., for patients who have experienced overdose on their current dosage). Ultrarapid detoxification under anesthesia is associated with substantial risks, including death, and should not be used.200 Clinicians should access appropriate expertise if considering tapering opioids during pregnancy because of possible risk to the pregnant patient and to the fetus if the patient goes into withdrawal. Patients who are not taking opioids (including patients who are diverting all opioids they obtain) do not require tapers. Clinicians should discuss with patients undergoing tapering the increased risk for overdose on abrupt return to a previously prescribed higher dose. Primary care clinicians should collaborate with mental health providers and with other specialists as needed to optimize non-opioid pain management (see Recommendation 1), as well as psychosocial support for anxiety related to the taper. More detailed guidance on tapering, including management of withdrawal symptoms has been published previously.30,201 If a patient exhibits signs of opioid use disorder, clinicians should offer or arrange for treatment of opioid use disorder (see Recommendation 12) and consider offering naloxone for overdose prevention (see Recommendation 8).

39

Assessing Risk and Addressing Harms of Opioid Use

8. Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (≥50 MME/day), or concurrent benzodiazepine use, are present (recommendation category: A, evidence type: 4).

The clinical evidence review found insufficient evidence to determine how harms of opioids differ depending on patient demographics or patient comorbidities (KQ2). However, based on the contextual evidence review and expert opinion, certain risk factors are likely to increase susceptibility to opioid-associated harms and warrant incorporation of additional strategies into the management plan to mitigate risk. Clinicians should assess these risk factors periodically, with frequency varying by risk factor and patient characteristics. For example, factors that vary more frequently over time, such as alcohol use, require more frequent follow up. In addition, clinicians should consider offering naloxone, re-evaluating patients more frequently (see Recommendation 7), and referring to pain and/or behavioral health specialists when factors that increase risk for harm, such as history of overdose, history of substance use disorder, higher dosages of opioids (≥50 MME/day), and concurrent use of benzodiazepines with opioids, are present.

Patients with Sleep-Disordered Breathing, Including Sleep Apnea Risk factors for sleep-disordered breathing include congestive heart failure, and obesity. Experts noted that careful monitoring and cautious dose titration should be used if opioids are prescribed for patients with mild sleep-disordered breathing. Clinicians should avoid prescribing opioids to patients with moderate or severe sleep-disordered breathing whenever possible to minimize risks for opioid overdose (contextual evidence review).

Pregnant Women Opioids used in pregnancy might be associated with additional risks to both mother and fetus. Some studies have shown an association of opioid use in pregnancy with stillbirth, poor fetal growth, preterm delivery, and birth defects (contextual evidence review). Importantly, in some cases, opioid use during pregnancy leads to neonatal opioid withdrawal

syndrome. Clinicians and patients together should carefully weigh risks and benefits when making decisions about whether to initiate opioid therapy for chronic pain during pregnancy. In addition, before initiating opioid therapy for chronic pain for reproductive age women, clinicians should discuss family planning and how long-term opioid use might affect any future pregnancy. For pregnant women already receiving opioids, clinicians should access appropriate expertise if considering tapering opioids because of possible risk to the pregnant patient and to the fetus if the patient goes into withdrawal (see Recommendation 7). For pregnant women with opioid use disorder, medication-assisted therapy with buprenorphine or methadone has been associated with improved maternal outcomes and should be offered (202) (see Recommendation 12). Clinicians caring for pregnant women receiving opioids for pain or receiving buprenorphine or methadone for opioid use disorder should arrange for delivery at a facility prepared to monitor, evaluate for, and treat neonatal opioid withdrawal syndrome. In instances when travel to such a facility would present an undue burden on the pregnant woman, it is appropriate to deliver locally, monitor and evaluate the newborn for neonatal opioid withdrawal syndrome, and transfer the newborn for additional treatment if needed. Neonatal toxicity and death have been reported in breastfeeding infants whose mothers are taking codeine (contextual evidence review); previous guidelines have recommended that codeine be avoided whenever possible among mothers who are breast feeding and, if used, should be limited to the lowest possible dose and to a 4-day supply (203).

Patients with Renal or Hepatic Insufficiency Clinicians should use additional caution and increased monitoring (see Recommendation 7) to minimize risks of opioids prescribed for patients with renal or hepatic insufficiency, given their decreased ability to process and excrete drugs, susceptibility to accumulation of opioids, and reduced therapeutic window between safe dosages and dosages associated with respiratory depression and overdose (contextual evidence review; see Recommendations 4, 5, and 7).

Patients Aged ≥65 Years Inadequate pain treatment among persons aged ≥65 years has been documented (204). Pain management for older patients can be challenging given increased risks of both non-opioid pharmacologic therapies (see Recommendation 1) and opioid therapy in this population. Given reduced renal function and medication clearance even in the absence of renal disease, patients aged ≥65 years might have increased susceptibility to accumulation of opioids and a smaller therapeutic window between safe

dosages and dosages associated with respiratory depression and overdose (contextual evidence review). Some older adults suffer from cognitive impairment, which can increase risk for medication errors and make opioid-related confusion more dangerous. In addition, older adults are more likely than younger adults to experience co-morbid medical conditions and more likely to receive multiple medications, some of which might interact with opioids (such as benzodiazepines). Clinicians should use additional caution and increased monitoring (see Recommendations 4, 5, and 7) to minimize risks of opioids prescribed for patients aged ≥65 years. Experts suggested that clinicians educate older adults receiving opioids to avoid risky medication-related behaviors such as obtaining controlled medications from multiple prescribers and saving unused medications. Clinicians should also implement interventions to mitigate common risks of opioid therapy among older adults, such as exercise or bowel regimens to prevent constipation, risk assessment for falls, and patient monitoring for cognitive impairment.

Patients with Mental Health Conditions Because psychological distress frequently interferes with improvement of pain and function in patients with chronic pain, using validated instruments such as the Generalized Anxiety Disorder (GAD)-7 and the Patient Health Questionnaire (PHQ)-9 or the PHQ-4 to assess for anxiety, post traumatic stress disorder, and/or depression (205), might help clinicians improve overall pain treatment outcomes. Experts noted that clinicians should use additional caution and increased monitoring (see Recommendation 7) to lessen the increased risk for opioid use disorder among patients with mental health conditions (including depression, anxiety disorders, and PTSD), as well as increased risk for drug overdose among patients with depression. Previous guidelines have noted that opioid therapy should not be initiated during acute psychiatric instability or uncontrolled suicide risk, and that clinicians should consider behavioral health specialist consultation for any patient with a history of suicide attempt or psychiatric disorder.31 In addition, patients with anxiety disorders and other mental health conditions are more likely to receive benzodiazepines, which can exacerbate opioid-induced respiratory depression and increase risk for overdose (see Recommendation 11). Clinicians should ensure that treatment for depression and other mental health conditions is optimized, consulting with behavioral health specialists when needed. Treatment for depression can improve pain symptoms as well as depression and might decrease overdose risk (contextual evidence review). For treatment of chronic pain in patients with depression, clinicians should strongly consider using tricyclic or SNRI

40

antidepressants for analgesic as well as antidepressant effects if these medications are not otherwise contraindicated (see Recommendation 1).

Patients with Substance Use Disorder Illicit drugs and alcohol are listed as contributory factors on a substantial proportion of death certificates for opioid-related overdose deaths (contextual evidence review). Previous guidelines have recommended screening or risk assessment tools to identify patients at higher risk for misuse or abuse of opioids. However, the clinical evidence review found that currently available risk-stratification tools (e.g., Opioid Risk Tool, Screener and Opioid Assessment for Patients with Pain Version 1, SOAPP-R, and Brief Risk Interview) show insufficient accuracy for classification of patients as at low or high risk for abuse or misuse (KQ4). Clinicians should always exercise caution when considering or prescribing opioids for any patient with chronic pain outside of active cancer, palliative, and end-of-life care and should not overestimate the ability of these tools to rule out risks from long-term opioid therapy. Clinicians should ask patients about their drug and alcohol use. Single screening questions can be used.206 For example, the question “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?” (with an answer of one or more considered positive) was found in a primary care setting to be 100% sensitive and 73.5% specific for the detection of a drug use disorder compared with a standardized diagnostic interview.207 Validated screening tools such as the Drug Abuse Screening Test (DAST) (208) and the Alcohol Use Disorders Identification Test (AUDIT) (209) can also be used. Clinicians should use PDMP data (see Recommendation 9) and drug testing (see Recommendation 10) as appropriate to assess for concurrent substance use that might place patients at higher risk for opioid use disorder and overdose. Clinicians should also provide specific counseling on increased risks for overdose when opioids are combined with other drugs or alcohol (see Recommendation 3) and ensure that patients receive effective treatment for substance use disorders when needed (see Recommendation 12). The clinical evidence review found insufficient evidence to determine how harms of opioids differ depending on past or current substance use disorder (KQ2), although a history of substance use disorder was associated with misuse. Similarly, based on contextual evidence, patients with drug or alcohol use disorders are likely to experience greater risks for opioid use disorder and overdose than persons without these conditions. If clinicians consider opioid therapy for chronic pain outside of active cancer,

palliative, and end-of-life care for patients with drug or alcohol use disorders, they should discuss increased risks for opioid use disorder and overdose with patients, carefully consider whether benefits of opioids outweigh increased risks, and incorporate strategies to mitigate risk into the management plan, such as considering offering naloxone (see Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present) and increasing frequency of monitoring (see Recommendation 7) when opioids are prescribed. Because pain management in patients with substance use disorder can be complex, clinicians should consider consulting substance use disorder specialists and pain specialists regarding pain management for persons with active or recent past history of substance abuse. Experts also noted that clinicians should communicate with patients’ substance use disorder treatment providers if opioids are prescribed.

Patients with Prior Nonfatal Overdose Although studies were not identified that directly addressed the risk for overdose among patients with prior nonfatal overdose who are prescribed opioids, based on clinical experience, experts thought that prior nonfatal overdose would substantially increase risk for future nonfatal or fatal opioid overdose. If patients experience nonfatal opioid overdose, clinicians should work with them to reduce opioid dosage and to discontinue opioids when possible (see Recommendation 7). If clinicians continue opioid therapy for chronic pain outside of active cancer, palliative, and end-of-life care in patients with prior opioid overdose, they should discuss increased risks for overdose with patients, carefully consider whether benefits of opioids outweigh substantial risks, and incorporate strategies to mitigate risk into the management plan, such as considering offering naloxone (see Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present) and increasing frequency of monitoring (see Recommendation 7) when opioids are prescribed.

Offering Naloxone to Patients When Factors That Increase Risk for Opioid-Related Harms Are Present Naloxone is an opioid antagonist that can reverse severe respiratory depression; its administration by lay persons, such as friends and family of persons who experience opioid overdose, can save lives. Naloxone precipitates acute withdrawal among patients physically dependent on opioids. Serious adverse effects, such as pulmonary edema, cardiovascular instability, and seizures, have been reported but are rare at doses consistent with labeled use for opioid overdose (210). The contextual evidence

review did not find any studies on effectiveness of prescribing naloxone for overdose prevention among patients prescribed opioids for chronic pain. However, there is evidence for effectiveness of naloxone provision in preventing opioid-related overdose death at the community level through community-based distribution (e.g., through overdose education and naloxone distribution programs in community service agencies) to persons at risk for overdose (mostly due to illicit opiate use), and it is plausible that effectiveness would be observed when naloxone is provided in the clinical setting as well. Experts agreed that it is preferable not to initiate opioid treatment when factors that increase risk for opioid-related harms are present. Opinions diverged about the likelihood of naloxone being useful to patients and the circumstances under which it should be offered. However, most experts agreed that clinicians should consider offering naloxone when prescribing opioids to patients at increased risk for overdose, including patients with a history of overdose, patients with a history of substance use disorder, patients taking benzodiazepines with opioids (see Recommendation 11), patients at risk for returning to a high dose to which they are no longer tolerant (e.g., patients recently released from prison), and patients taking higher dosages of opioids (≥50 MME/day). Practices should provide education on overdose prevention and naloxone use to patients receiving naloxone prescriptions and to members of their households. Experts noted that naloxone co-prescribing can be facilitated by clinics or practices with resources to provide naloxone training and by collaborative practice models with pharmacists. Resources for prescribing naloxone in primary care settings can be found through Prescribe to Prevent at http://prescribetoprevent.org.

9. Clinicians should review the patient’s history of controlled substance prescriptions using state prescription drug monitoring program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months (recommendation category: A, evidence type: 4).

PDMPs are state-based databases that collect information on controlled prescription drugs dispensed by pharmacies in most states and, in select states, by dispensing physicians as well. In addition, some clinicians employed by the federal government, including some clinicians in the Indian

41

Health Care Delivery System, are not licensed in the states where they practice, and do not have access to PDMP data. Certain states require clinicians to review PDMP data prior to writing each opioid prescription (see state level PDMP related policies on the National Alliance for Model State Drug Laws website at http://www.namsdl.org/prescription-monitoring-programs.cfm). The clinical evidence review did not find studies evaluating the effectiveness of PDMPs on outcomes related to overdose, addiction, abuse, or misuse (KQ4). However, even though evidence is limited on the effectiveness of PDMP implementation at the state level on prescribing and mortality outcomes28, the contextual evidence review found that most fatal overdoses were associated with patients receiving opioids from multiple prescribers and/or with patients receiving high total daily opioid dosages; information on both of these risk factors for overdose are available to prescribers in the PDMP. PDMP data also can be helpful when patient medication history is not otherwise available (e.g., for patients from other locales) and when patients transition care to a new clinician. The contextual evidence review also found that PDMP information could be used in a way that is harmful to patients. For example, it has been used to dismiss patients from clinician practices211, which might adversely affect patient safety. The contextual review found variation in state policies that affect timeliness of PDMP data (and therefore benefits of reviewing PDMP data) as well as time and workload for clinicians in accessing PDMP data. In states that permit delegating access to other members of the health care team, workload for prescribers can be reduced. These differences might result in a different balance of benefits to clinician workload in different states. Experts agreed that PDMPs are useful tools that should be consulted when starting a patient on opioid therapy and periodically during long-term opioid therapy. However, experts disagreed on how frequently clinicians should check the PDMP during long-term opioid therapy, given PDMP access issues and the lag time in reporting in some states. Most experts agreed that PDMP data should be reviewed every 3 months or more frequently during long-term opioid therapy. A minority of experts noted that, given the current burden of accessing PDMP data in some states and the lack of evidence surrounding the most effective interval for PDMP review to improve patient outcomes, annual review of PDMP data during long-term opioid therapy would be reasonable when factors that increase risk for opioid-related harms are not present. Clinicians should review PDMP data for opioids and other controlled medications patients might have received from additional prescribers to determine whether a patient is receiving high total opioid dosages or dangerous combinations (e.g., opioids combined with benzodiazepines)

that put him or her at high risk for overdose. Ideally, PDMP data should be reviewed before every opioid prescription. This is recommended in all states with well-functioning PDMPs and where PDMP access policies make this practicable (e.g., clinician and delegate access permitted), but it is not currently possible in states without functional PDMPs or in those that do not permit certain prescribers to access them. As vendors and practices facilitate integration of PDMP information into regular clinical work-flow (e.g., data made available in electronic health records), clinicians’ ease of access in reviewing PDMP data is expected to improve. In addition, improved timeliness of PDMP data will improve their value in identifying patient risks. If patients are found to have high opioid dosages, dangerous combinations of medications, or multiple controlled substance prescriptions written by different clinicians, several actions can be taken to augment clinicians’ abilities to improve patient safety:• Clinicians should discuss information from

the PDMP with their patient and confirm that the patient is aware of the additional prescriptions. Occasionally, PDMP information can be incorrect (e.g., if the wrong name or birth date has been entered, the patient uses a nickname or maiden name, or another person has used the patient’s identity to obtain prescriptions).

• Clinicians should discuss safety concerns, including increased risk for respiratory depression and overdose, with patients found to be receiving opioids from more than one prescriber or receiving medications that increase risk when combined with opioids (e.g., benzodiazepines) and consider offering naloxone (see Recommendation 8).

• Clinicians should avoid prescribing opioids and benzodiazepines concurrently whenever possible. Clinicians should communicate with others managing the patient to discuss the patient’s needs, prioritize patient goals, weigh risks of concurrent benzodiazepine and opioid exposure, and coordinate care (see Recommendation 11).

• Clinicians should calculate the total MME/day for concurrent opioid prescriptions to help assess the patient’s overdose risk (see Recommendation 5). If patients are found to be receiving high total daily dosages of opioids, clinicians should discuss their safety concerns with the patient, consider tapering to a safer dosage (see Recommendations 5 and 7), and consider offering naloxone (see Recommendation 8).

• Clinicians should discuss safety concerns with other clinicians who are prescribing controlled substances for their patient. Ideally clinicians should first discuss concerns with their patient and inform him or

her that they plan to coordinate care with the patient’s other prescribers to improve the patient’s safety.

• Clinicians should consider the possibility of a substance use disorder and discuss concerns with their patient (see Recommendation 12).

• If clinicians suspect their patient might be sharing or selling opioids and not taking them, clinicians should consider urine drug testing to assist in determining whether opioids can be discontinued without causing withdrawal (see Recommendations 7 and 10). A negative drug test for prescribed opioids might indicate the patient is not taking prescribed opioids, although clinicians should consider other possible reasons for this test result (see Recommendation 10).

Experts agreed that clinicians should not dismiss patients from their practice on the basis of PDMP information. Doing so can adversely affect patient safety, could represent patient abandonment, and could result in missed opportunities to provide potentially lifesaving information (e.g., about risks of opioids and overdose prevention) and interventions (e.g., safer prescriptions, non-opioid pain treatment [see Recommendation 1], naloxone [see Recommendation 8], and effective treatment for substance use disorder [see Recommendation 12]).

10. When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit drugs (recommendation category: B, evidence type: 4).

Concurrent use of opioid pain medications with other opioid pain medications, benzodiazepines, or heroin can increase patients’ risk for overdose. Urine drug tests can provide information about drug use that is not reported by the patient. In addition, urine drug tests can assist clinicians in identifying when patients are not taking opioids prescribed for them, which might in some cases indicate diversion or other clinically important issues such as difficulties with adverse effects. Urine drug tests do not provide accurate information about how much or what dose of opioids or other drugs a patient took. The clinical evidence review did not find studies evaluating the effectiveness of urine drug screening for risk mitigation during opioid prescribing for pain (KQ4). The contextual evidence review found that urine drug testing can provide useful information about patients assumed not to be using unreported drugs.

42

Urine drug testing results can be subject to misinterpretation and might sometimes be associated with practices that might harm patients (e.g., stigmatization, inappropriate termination from care). Routine use of urine drug tests with standardized policies at the practice or clinic level might destigmatize their use. Although random drug testing also might destigmatize urine drug testing, experts thought that truly random testing was not feasible in clinical practice. Some clinics obtain a urine specimen at every visit, but only send it for testing on a random schedule. Experts noted that in addition to direct costs of urine drug testing, which often are not covered fully by insurance and can be a burden for patients, clinician time is needed to interpret, confirm, and communicate results. Experts agreed that prior to starting opioids for chronic pain and periodically during opioid therapy, clinicians should use urine drug testing to assess for prescribed opioids as well as other controlled substances and illicit drugs that increase risk for overdose when combined with opioids, including non prescribed opioids, benzodiazepines, and heroin. There was some difference of opinion among experts as to whether this recommendation should apply to all patients, or whether this recommendation should entail individual decision making with different choices for different patients based on values, preferences, and clinical situations. While experts agreed that clinicians should use urine drug testing before initiating opioid therapy for chronic pain, they disagreed on how frequently urine drug testing should be conducted during long-term opioid therapy. Most experts agreed that urine drug testing at least annually for all patients was reasonable. Some experts noted that this interval might be too long in some cases and too short in others, and that the follow-up interval should be left to the discretion of the clinician. Previous guidelines have recommended more frequent urine drug testing in patients thought to be at higher risk for substance use disorder.30 However, experts thought that predicting risk prior to urine drug testing is challenging and that currently available tools do not allow clinicians to reliably identify patients who are at low risk for substance use disorder. In most situations, initial urine drug testing can be performed with a relatively inexpensive immunoassay panel for commonly prescribed opioids and illicit drugs. Patients prescribed less commonly used opioids might require specific testing for those agents. The use of confirmatory testing adds substantial costs and should be based on the need to detect specific opioids that cannot be identified on standard immunoassays or on the presence of unexpected urine drug test results. Clinicians should be familiar with the drugs included in urine drug testing panels used in their practice and should understand how to interpret results for

these drugs. For example, a positive “opiates” immunoassay detects morphine, which might reflect patient use of morphine, codeine, or heroin, but this immunoassay does not detect synthetic opioids (e.g., fentanyl or methadone) and might not detect semisynthetic opioids (e.g., oxycodone). However, many laboratories use an oxycodone immunoassay that detects oxycodone and oxymorphone. In some cases, positive results for specific opioids might reflect metabolites from opioids the patient is taking and might not mean the patient is taking the specific opioid for which the test was positive. For example, hydromorphone is a metabolite of hydrocodone, and oxymorphone is a metabolite of oxycodone. Detailed guidance on interpretation of urine drug test results, including which tests to order and expected results, drug detection time in urine, drug metabolism, and other considerations has been published previously.30 Clinicians should not test for substances for which results would not affect patient management or for which implications for patient management are unclear. For example, experts noted that there might be uncertainty about the clinical implications of a positive urine drug test for tetrahyrdocannabinol (THC). In addition, restricting confirmatory testing to situations and substances for which results can reasonably be expected to affect patient management can reduce costs of urine drug testing, given the substantial costs associated with confirmatory testing methods. Before ordering urine drug testing, clinicians should have a plan for responding to unexpected results. Clinicians should explain to patients that urine drug testing is intended to improve their safety and should also explain expected results (e.g., presence of prescribed medication and absence of drugs, including illicit drugs, not reported by the patient). Clinicians should ask patients about use of prescribed and other drugs and ask whether there might be unexpected results. This will provide an opportunity for patients to provide information about changes in their use of prescribed opioids or other drugs. Clinicians should discuss unexpected results with the local laboratory or toxicologist and with the patient. Discussion with patients prior to specific confirmatory testing can sometimes yield a candid explanation of why a particular substance is present or absent and obviate the need for expensive confirmatory testing on that visit. For example, a patient might explain that the test is negative for prescribed opioids because she felt opioids were no longer helping and discontinued them. If unexpected results are not explained, a confirmatory test using a method selective enough to differentiate specific opioids and metabolites (e.g., gas or liquid chromatography/mass spectrometry) might be warranted to clarify the situation. Clinicians should use unexpected results to improve patient safety (e.g., change in pain management strategy [see Recommendation

1], tapering or discontinuation of opioids [see Recommendation 7], more frequent re-evaluation [see Recommendation 7], offering naloxone [see Recommendation 8], or referral for treatment for substance use disorder [see Recommendation 12], all as appropriate). If tests for prescribed opioids are repeatedly negative, confirming that the patient is not taking the prescribed opioid, clinicians can discontinue the prescription without a taper. Clinicians should not dismiss patients from care based on a urine drug test result because this could constitute patient abandonment and could have adverse consequences for patient safety, potentially including the patient obtaining opioids from alternative sources and the clinician missing opportunities to facilitate treatment for substance use disorder.

11. Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible (recommendation category: A, evidence type: 3).

Benzodiazepines and opioids both cause central nervous system depression and can decrease respiratory drive. Concurrent use is likely to put patients at greater risk for potentially fatal overdose. The clinical evidence review did not address risks of benzodiazepine co-prescription among patients prescribed opioids. However, the contextual evidence review found evidence in epidemiologic series of concurrent benzodiazepine use in large proportions of opioid-related overdose deaths, and a case-cohort study found concurrent benzodiazepine prescription with opioid prescription to be associated with a near quadrupling of risk for overdose death compared with opioid prescription alone.212 Experts agreed that although there are circumstances when it might be appropriate to prescribe opioids to a patient receiving benzodiazepines (e.g., severe acute pain in a patient taking long-term, stable low dose benzodiazepine therapy), clinicians should avoid prescribing opioids and benzodiazepines concurrently whenever possible. In addition, given that other central nervous system depressants (e.g., muscle relaxants, hypnotics) can potentiate central nervous system depression associated with opioids, clinicians should consider whether benefits outweigh risks of concurrent use of these drugs. Clinicians should check the PDMP for concurrent controlled medications prescribed by other clinicians (see Recommendation 9) and should consider involving pharmacists and pain specialists as part of the management team when opioids are co-prescribed with other central nervous system depressants. Because of greater risks of benzodiazepine withdrawal relative to opioid withdrawal, and because tapering opioids can be associated with anxiety, when patients receiving both benzodiazepines and opioids require tapering

43

to reduce risk for fatal respiratory depression, it might be safer and more practical to taper opioids first (see Recommendation 7). Clinicians should taper benzodiazepines gradually if discontinued because abrupt withdrawal can be associated with rebound anxiety, hallucinations, seizures, delirium tremens, and, in rare cases, death (contextual evidence review). A commonly used tapering schedule that has been used safely and with moderate success is a reduction of the benzodiazepine dose by 25% every 1–2 weeks.213,214 CBT increases tapering success rates and might be particularly helpful for patients struggling with a benzodiazepine taper.213 If benzodiazepines prescribed for anxiety are tapered or discontinued, or if patients receiving opioids require treatment for anxiety, evidence-based psychotherapies (e.g., CBT) and/or specific antidepressants or other nonbenzodiazepine medications approved for anxiety should be offered. Experts emphasized that clinicians should communicate with mental health professionals managing the patient to discuss the patient’s needs, prioritize patient goals, weigh risks of concurrent benzodiazepine and opioid exposure, and coordinate care.

12. Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder (recommendation category: A, evidence type: 2).

Opioid use disorder (previously classified as opioid abuse or opioid dependence) is defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) as a problematic pattern of opioid use leading to clinically significant impairment or distress, manifested by at least two defined criteria occurring within a year (http://pcssmat.org/wp-content/uploads/2014/02/5B-DSM-5-Opioid-Use-Disorder-Diagnostic-Criteria.pdf).20

The clinical evidence review found prevalence of opioid dependence (using DSM-IV diagnosis criteria) in primary care settings among patients with chronic pain on opioid therapy to be 3%–26% (KQ2). As found in the contextual evidence review and supported by moderate quality evidence, opioid agonist or partial agonist treatment with methadone maintenance therapy or buprenorphine has been shown to be more effective in preventing relapse among patients with opioid use disorder.151–153 Some studies suggest that using behavioral therapies in combination with these treatments can reduce opioid misuse and increase retention during maintenance therapy and improve compliance after detoxification154,155; behavioral therapies are also recommended by clinical practice guidelines.215 The cited studies

primarily evaluated patients with a history of illicit opioid use, rather than prescription opioid use for chronic pain. Recent studies among patients with prescription opioid dependence (based on DSM-IV criteria) have found maintenance therapy with buprenorphine and buprenorphine-naloxone effective in preventing relapse.216,217 Treatment need in a community is often not met by capacity to provide buprenorphine or methadone maintenance therapy218, and patient cost can be a barrier to buprenorphine treatment because insurance coverage of buprenorphine for opioid use disorder is often limited.219 Oral or long acting injectable formulations of naltrexone can also be used as medication-assisted treatment for opioid use disorder in nonpregnant adults, particularly for highly motivated persons.220,221 Experts agreed that clinicians prescribing opioids should identify treatment resources for opioid use disorder in the community and should work together to ensure sufficient treatment capacity for opioid use disorder at the practice level. If clinicians suspect opioid use disorder based on patient concerns or behaviors or on findings in prescription drug monitoring program data (see Recommendation 9) or from urine drug testing (see Recommendation 10), they should discuss their concern with their patient and provide an opportunity for the patient to disclose related concerns or problems. Clinicians should assess for the presence of opioid use disorder using DSM-5 criteria.20 Alternatively, clinicians can arrange for a substance use disorder treatment specialist to assess for the presence of opioid use disorder. For patients meeting criteria for opioid use disorder, clinicians should offer or arrange for patients to receive evidence-based treatment, usually medication-assisted treatment with buprenorphine or methadone maintenance therapy in combination with behavioral therapies. Oral or long-acting injectable naltrexone, a long-acting opioid antagonist, can also be used in non-pregnant adults. Naltrexone blocks the effects of opioids if they are used but requires adherence to daily oral therapy or monthly injections. For pregnant women with opioid use disorder, medication-assisted therapy with buprenorphine (without naloxone) or methadone has been associated with improved maternal outcomes and should be offered (see Recommendation 8). Clinicians should also consider offering naloxone for overdose prevention to patients with opioid use disorder (see Recommendation 8). For patients with problematic opioid use that does not meet criteria for opioid use disorder, experts noted that clinicians can offer to taper and discontinue opioids (see Recommendation 7). For patients who choose to but are unable to taper, clinicians may reassess for opioid use disorder and offer opioid agonist therapy if criteria are met. Physicians not already certified to provide buprenorphine in an office-based setting

can undergo training to receive a waiver from the Substance Abuse and Mental Health Services Administration (SAMHSA) that allows them to prescribe buprenorphine to treat patients with opioid use disorder. Physicians prescribing opioids in communities without sufficient treatment capacity for opioid use disorder should strongly consider obtaining this waiver. Information about qualifications and the process to obtain a waiver are available from SAMHSA.222 Clinicians do not need a waiver to offer naltrexone for opioid use disorder as part of their practice. Additional guidance has been published previously215 on induction, use, and monitoring of buprenorphine treatment (see Part 5) and naltrexone treatment (see Part 6) for opioid use disorder and on goals, components of, and types of effective psychosocial treatment that are recommended in conjunction with pharmacological treatment of opioid use disorder (see Part 7). Clinicians unable to provide treatment themselves should arrange for patients with opioid use disorder to receive care from a substance use disorder treatment specialist, such as an office-based buprenorphine or naltrexone treatment provider, or from an opioid treatment program certified by SAMHSA to provide supervised medication-assisted treatment for patients with opioid use disorder. Clinicians should assist patients in finding qualified treatment providers and should arrange for patients to follow up with these providers, as well as arranging for ongoing coordination of care. Clinicians should not dismiss patients from their practice because of a substance use disorder because this can adversely affect patient safety and could represent patient abandonment. Identification of substance use disorder represents an opportunity for a clinician to initiate potentially life-saving interventions, and it is important for the clinician to collaborate with the patient regarding their safety to increase the likelihood of successful treatment. In addition, although identification of an opioid use disorder can alter the expected benefits and risks of opioid therapy for pain, patients with co-occurring pain and substance use disorder require ongoing pain management that maximizes benefits relative to risks. Clinicians should continue to use nonpharmacologic and non-opioid pharmacologic pain treatments as appropriate (see Recommendation 1) and consider consulting a pain specialist as needed to provide optimal pain management. Resources to help with arranging for treatment include SAMHSA’s buprenorphine physician locator (http://buprenorphine.samhsa.gov/bwns_locator); SAMHSA’s Opioid Treatment Program Directory (http://dpt2.samhsa.gov/treatment/directory.aspx); SAMHSA’s Provider

44

Clinical Support System for Opioid Therapies (http://pcss-o.org), which offers extensive experience in the treatment of substance use disorders and specifically of opioid use disorder, as well as expertise on the interface of pain and opioid misuse; and SAMHSA’s Provider’s Clinical Support System for Medication-Assisted Treatment (http://pcssmat.org), which offers expert physician mentors to answer questions about assessment for and treatment of substance use disorders.

Conclusions and Future Directions Clinical guidelines represent one strategy for improving prescribing practices and health outcomes. Efforts are required to disseminate the guideline and achieve widespread adoption and implementation of the recommendations in clinical settings. CDC will translate this guideline into user-friendly materials for distribution and use by health systems, medical professional societies, insurers, public health departments, health information technology developers, and clinicians and engage in dissemination efforts. CDC has provided a checklist for prescribing opioids for chronic pain (http://stacks.cdc.gov/view/cdc/38025), additional resources such as fact sheets (http://www.cdc.gov/drugoverdose/prescribing/resources.html), and will provide a mobile application to guide clinicians in implementing the recommendations. CDC will also work with partners to support clinician education on pain management options, opioid therapy, and risk mitigation strategies (e.g., urine drug testing). Activities such as development of clinical decision support in electronic health records to assist clinicians’ treatment decisions at the point of care; identification of mechanisms that insurers and pharmacy benefit plan managers can use to promote safer prescribing within plans; and development of clinical quality improvement measures and initiatives to improve prescribing and patient care within health systems have promise for increasing guideline adoption and improving practice. In addition, policy initiatives that address barriers to implementation of the guidelines, such as increasing accessibility of PDMP data within and across states, e-prescribing, and availability of clinicians who can offer medication-assisted treatment for opioid use disorder, are strategies to consider to enhance implementation of the recommended practices. CDC will work with federal partners and payers to evaluate strategies such as payment reform and health care delivery models that could improve patient health and safety. For example, strategies might include strengthened coverage for nonpharmacologic treatments, appropriate urine drug testing, and medication-assisted treatment; reimbursable time for patient counseling; and payment models that improve access to interdisciplinary, coordinated care. As highlighted in the forthcoming report on the National Pain Strategy, an overarching federal effort that outlines a comprehensive population-level health strategy for addressing pain as a public health problem, clinical guidelines complement

other strategies aimed at preventing illnesses and injuries that lead to pain. A draft of the National Pain Strategy has been published previously.180 These strategies include strengthening the evidence base for pain prevention and treatment strategies, reducing disparities in pain treatment, improving service delivery and reimbursement, supporting professional education and training, and providing public education. It is important that overall improvements be made in developing the workforce to address pain management in general, in addition to opioid prescribing specifically. This guideline also complements other federal efforts focused on addressing the opioid overdose epidemic including prescriber training and education, improving access to treatment for opioid use disorder, safe storage and disposal programs, utilization management mechanisms, naloxone distribution programs, law enforcement and supply reduction efforts, prescription drug monitoring program improvements, and support for community coalitions and state prevention programs. This guideline provides recommendations that are based on the best available evidence that was interpreted and informed by expert opinion. The clinical scientific evidence informing the recommendations is low in quality. To inform future guideline development, more research is necessary to fill in critical evidence gaps. The evidence reviews forming the basis of this guideline clearly illustrate that there is much yet to be learned about the effectiveness, safety, and economic efficiency of long-term opioid therapy. As highlighted by an expert panel in a recent workshop sponsored by the National Institutes of Health on the role of opioid pain medications in the treatment of chronic pain, “evidence is insufficient for every clinical decision that a provider needs to make about the use of opioids for chronic pain”.223 The National Institutes of Health panel recommended that research is needed to improve our understanding of which types of pain, specific diseases, and patients are most likely to be associated with benefit and harm from opioid pain medications; evaluate multidisciplinary pain interventions; estimate cost-benefit; develop and validate tools for identification of patient risk and outcomes; assess the effectiveness and harms of opioid pain medications with alternative study designs; and investigate risk identification and mitigation strategies and their effects on patient and public health outcomes. It is also important to obtain data to inform the cost feasibility and cost-effectiveness of recommended actions, such as use of nonpharmacologic therapy and urine drug testing. Research that contributes to safer and more effective pain treatment can be implemented across public health entities and federal agencies.4 Additional research can inform the development of future guidelines for special populations that could not be adequately addressed in this guideline, such as children and adolescents, where evidence and guidance is needed but currently lacking. CDC is committed to working with partners to identify the highest priority research areas to build the

evidence base. Yet, given that chronic pain is recognized as a significant public health problem, the risks associated with long-term opioid therapy, the availability of effective nonpharmacological and non-opioid pharmacologic treatment options for pain, and the potential for improvement in the quality of health care with the implementation of recommended practices, a guideline for prescribing is warranted with the evidence that is currently available. The balance between the benefits and the risks of long-term opioid therapy for chronic pain based on both clinical and contextual evidence is strong enough to support the issuance of category A recommendations in most cases. CDC will revisit this guideline as new evidence becomes available to determine when evidence gaps have been sufficiently closed to warrant an update of the guideline. Until this research is conducted, clinical practice guidelines will have to be based on the best available evidence and expert opinion. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death. CDC is committed to evaluating the guideline to identify the impact of the recommendations on clinician and patient outcomes, both intended and unintended, and revising the recommendations in future updates when warranted.

AcknowledgmentsMembers of the Core Expert Group; the Core Expert Group facilitator: Don Teater, MD; members of the Stakeholder Review Group; peer reviewers; the Opioid Guideline Workgroup, consultants, and the NCIPC Board of Scientific Counselors; federal partners: Richard Kronick, PhD, Deborah G. Perfetto, PharmD, Agency for Healthcare Research and Quality; Jeffrey A. Kelman, MD, Diane L. McNally, Centers for Medicare & Medicaid Services; Jonathan Woodson, MD, Dave Smith, MD, Jack Smith, MD, Christopher Spevak, MD, Department of Defense; Stephen M. Ostroff, MD, Christopher M. Jones, PharmD, Food and Drug Administration; Jim Macrae, MA, MPP, Alexander F. Ross, ScD, Health Resources and Services Administration; Nora Volkow, MD, David Thomas, PhD, National Institute of DrugAbuse; John Howard, MD, Douglas Trout, MD, National Institute for Occupational Safety and Health; Karen B. DeSalvo, MD, Jennifer Frazier, MPH, Office of the National Coordinator, Michael Botticelli, MEd, Cecelia McNamara Spitznas, PhD, Office of National Drug Control Policy; Kana Enomoto, MA, Jinhee Lee, PharmD, Substance Abuse and Mental Health Services Administration; Robert McDonald, MBA, Jack M. Rosenberg, MD, Veterans Administration; members of the public who provided comment during the webinar; Douglas McDonald, PhD, Brandy Wyant, MPH, Kenneth Carlson, Amy Berninger, MPH, Abt Associates; Thomas Frieden, MD,

45

Anne Schuchat, MD, Ileana Arias, PhD, CDC Office of the Director, Debra Houry, MD, National Center for Injury Prevention and Control, Amy Peeples, MPA, National Center for Injury Prevention and Control, Arlene Greenspan, DrPH, National Center for Injury Prevention and Control, Grant Baldwin, PhD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Rita Noonan, PhD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Julie Gilchrist, MD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Terry Davis, EdD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Wes Sargent, EdD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Brian Manns, PharmD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Lisa Garbarino, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Donovan Newton, MPA, Division of Analysis, Research and Practice Integration, National Center for Injury Prevention and Control, Joann Kang, JD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Noah Aleshire, JD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Jennifer VanderVeur, JD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, LeShaundra Scott, MPH, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Sarah Lewis, MPH, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Helen Kingery, MPH, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Kristen Sanderson, MPH, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Kate Fox, MPP, National Center for Injury Prevention and Control, Leslie Dorigo, MA, National Center for Injury Prevention and Control, Erin Connelly, MPA, National Center for Injury Prevention and Control, Sara Patterson, MA, National Center for Injury Prevention and Control, Mark Biagioni, MPA, National Center for Injury Prevention and Control, and Leonard J. Paulozzi, MD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, CDC.

Corresponding author: Deborah Dowell, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, CDC. E-mail: gdo7@cdc.gov.1Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, CDC, Atlanta, Georgia

References1. Daubresse M, Chang HY, Yu Y, et al. Ambulatory

diagnosis and treatment of nonmalignant pain in the United States, 2000-2010. Med Care 2013;51:870–8. CrossRef PubMed

2. Paulozzi LJ, Mack KA, Hockenberry JM. Vital signs: variation among states in prescribing of opioid pain relievers and benzodiazepines—United States, 2012. MMWR Morb Mortal Wkly Rep 2014;63:563–8. PubMed

3. Levy B, Paulozzi L, Mack KA, Jones CM. Trends in opioid analgesic-prescribing rates by specialty, U.S., 2007–2012. Am J Prev Med 2015;49:409–13. CrossRef PubMed

4. Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington, DC: The National Academies Press; 2011.

5. International Association for the Study of Pain. Classification of chronic pain. Descriptions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain, Subcommittee on Taxonomy. Pain Suppl 1986;3:S1–226. PubMed

6. Hardt J, Jacobsen C, Goldberg J, Nickel R, Buchwald D. Prevalence of chronic pain in a representative sample in the United States. Pain Med 2008;9:803–12. CrossRef PubMed

7. Tsang A, Von Korff M, Lee S, et al. Common chronic pain conditions in developed and developing countries:

gender and age differences and comorbidity with depression-anxiety disorders. J Pain 2008;9:883–91. Corrected in: Demytteneare K. J Pain 2009;10:553. CrossRef PubMed

8. Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain 2015;16:769–80. CrossRef PubMed

9. Furlan A, Chaparro LE, Irvin E, Mailis-Gagnon A. A comparison between enriched and nonenriched enrollment randomized withdrawal trials of opioids for chronic non-cancer pain. Pain Res Manag 2011;16:337–51. PubMed

10. American Pain Society, American Academy of Pain Medicine Opioids Guidelines Panel. Guideline for the use of chronic opioid therapy in chronic non-cancer pain: evidence review. Chicago, IL: American Pain Society; 2009. http://americanpainsociety.org/uploads/education/guidelines/chronic-opioid-therapy-cncp.pdf

11. Anastassopoulos KP, Chow W, Tapia CI, Baik R, Moskowitz B, Kim MS. Reported side effects, bother, satisfaction, and adherence in patients taking hydrocodone for non-cancer pain. J Opioid Manag 2013;9:97–109. CrossRef PubMed

12. Gregorian RS , Gasik A, Kwong WJ, Voeller S, Kavanagh S. Importance of side effects in opioid treatment: a trade-off analysis with patients and physicians. J Pain 2010;11:1095–108.CrossRef PubMed

13. Thielke SM, Turner JA, Shortreed SM, et al. Do patient-perceived pros and cons of opioids predict sustained higher-dose use? Clin J Pain 2014;30:93–101. PubMed

14. Chou R, Deyo R, Devine B, et al. The effectiveness and risks of long-term opioid treatment of chronic pain. Evidence Report/Technology Assessment No. 218. AHRQ Publication No. 14-E005-EF. Rockville, MD: Agency for Healthcare Research and Quality; 2014. http://www.effectivehealthcare.ahrq.gov/ehc/products/557/1971/chronic-pain-opioid-treatment-report-141007.pdf

15. Boudreau D, Von Korff M, Rutter CM, et al. Trends in long-term opioid therapy for chronic non-cancer pain. Pharmacoepidemiol Drug Saf 2009;18:1166–75. CrossRef PubMed

16. CDC. Multiple cause of death data on CDC WONDER. Atlanta, GA: US Department of Health and Human Services, CDC; 2016. http://wonder.cdc.gov/mcd.html

17. CDC, National Center for Health Statistics. Health, United States, 2014: with special feature on adults aged 55–64. Hyattsville, MD: US Department of Health and Human Services, CDC, National Center for Health Statistics; 2015.

18. CDC. Vital signs: overdoses of prescription opioid pain relievers—United States, 1999–2008. MMWR Morb Mortal Wkly Rep 2011;60:1487–92. PubMed

19. Substance Abuse and Mental Health Services Administration. The DAWN report: highlights of the 2011 Drug Abuse Warning Network (DAWN) findings on drug-related emergency department visits. Rockville, MD: US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality; 2013.

20. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

21. Substance Abuse and Mental Health Services Administration. Results from the 2013 National Survey on Drug Use and Health: summary of national findings. Rockville, MD: US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration; 2014.

22. Edlund MJ, Martin BC, Russo JE, DeVries A, Braden JB, Sullivan MD. The role of opioid prescription in incident opioid abuse and dependence among individuals with chronic non-cancer pain: the role of opioid prescription. Clin J Pain 2014;30:557–64. PubMed

23. Zedler B, Xie L, Wang L, et al. Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients. Pain Med 2014;15:1911–29. CrossRefPubMed

24. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 2011;305:1315–21. CrossRef PubMed

25. Kaplovitch E, Gomes T, Camacho X, Dhalla IA, Mamdani MM, Juurlink DN. Sex differences in dose escalation and overdose death during chronic opioid therapy: a population-based cohort study. PLoS One 2015;10:e0134550. CrossRef PubMed

26. Jamison RN, Sheehan KA, Scanlan E, Matthews M, Ross EL. Beliefs and attitudes about opioid prescribing and chronic pain management: survey of primary care providers. J Opioid Manag 2014;10:375–82. CrossRef PubMed

27. Wilson HD, Dansie EJ, Kim MS, Moskovitz BL, Chow W, Turk DC. Clinicians’ attitudes and beliefs about opioids survey (CAOS): instrument development and results of a national physician survey. J Pain 2013;14:613–27. CrossRef PubMed

28. Haegerich TM, Paulozzi LJ, Manns BJ, Jones CM. What we know, and don’t know, about the impact of state policy and systems-level interventions on prescription drug overdose. Drug Alcohol Depend 2014;145:34–47. CrossRef PubMed

29. Chou R, Fanciullo GJ, Fine PG, et al. ; American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. J Pain 2009;10:113–30.e22. CrossRef PubMed

30. Washington State Agency Medical Directors’ Group. AMDG 2015 interagency guideline on prescribing opioids for pain. Olympia, WA: Washington State Agency Medical Directors’ Group; 2015. http://www.agencymeddirectors.wa.gov/guidelines.asp

31. US Department of Veterans Affairs. VA/DoD clinical practice guidelines: management of opioid therapy (OT) for chronic pain. Washington, DC: US Department of Veterans Affairs; 2010.http://www.healthquality.va.gov/guidelines/Pain/cot

32. Nuckols TK, Anderson L, Popescu I, et al. Opioid prescribing: a systematic review and critical appraisal of guidelines for chronic pain. Ann Intern Med 2014;160:38–47. PubMed

33. Liu Y, Logan JE, Paulozzi LJ, Zhang K, Jones CM. Potential misuse and inappropriate prescription practices involving opioid analgesics. Am J Manag Care 2013;19:648–65. PubMed

34. Mack KA, Zhang K, Paulozzi L, Jones C. Prescription practices involving opioid analgesics among Americans with Medicaid, 2010. J Health Care Poor Underserved 2015;26:182–98. CrossRefPubMed

35. Institute of Medicine. Dying in America: improving quality and honoring individual preferences near the end of life. Washington, DC: The National Academies Press; 2015.

36. Mazer-Amirshahi M, Mullins PM, Rasooly IR, van den Anker J, Pines JM. Trends in prescription opioid use in pediatric emergency department patients. Pediatr Emerg Care 2014;30:230–5.CrossRef PubMed

37. DeVries A, Koch T, Wall E, Getchius T, Chi W, Rosenberg A. Opioid use among adolescent patients treated for headache. J Adolesc Health 2014;55:128–33. CrossRef PubMed

38. Veliz P, Epstein-Ngo QM, Meier E, Ross-Durow PL, McCabe SE, Boyd CJ. Painfully obvious: a longitudinal examination of medical use and misuse of opioid medication among adolescent sports participants. J Adolesc Health 2014;54:333–40. CrossRef PubMed

39. McCabe SE, West BT, Boyd CJ. Leftover prescription opioids and nonmedical use among high school seniors: a multi-cohort national study. J Adolesc Health 2013;52:480–5. CrossRefPubMed

40. McCabe SE, West BT, Boyd CJ. Medical use, medical misuse, and nonmedical use of prescription opioids: results from a longitudinal study. Pain 2013;154:708–13. CrossRef PubMed

46

41. Miech R, Johnston L, O’Malley PM, Keyes KM, Heard K. Prescription opioids in adolescence and future opioid misuse. Pediatrics 2015;136:e1169–77. CrossRef PubMed

42. Cerdá M, Santaella J, Marshall BD, Kim JH, Martins SS. Nonmedical prescription opioid use in childhood and early adolescence predicts transitions to heroin use in young adulthood: a national study. J Pediatr 2015;167:605–12.e2. CrossRef PubMed

43. Cantrill SV, Brown MD, Carlisle RJ, et al. ; American College of Emergency Physicians Opioid Guideline Writing Panel. Clinical policy: critical issues in the prescribing of opioids for adult patients in the emergency department. Ann Emerg Med 2012;60:499–525. CrossRef PubMed

44. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2012;116:248–73. CrossRef PubMed

45. Pennsylvania Department of Health, Department of Drug and Alcohol Programs. Pennsylvania guidelines on the use of opioids in dental practice. Harrisburg, PA: Pennsylvania Department of Drug and Alcohol Programs; 2015. http://www.ddap.pa.gov/Document%20Library/Prescriber_Guidelines_Dental.pdf

46. National Heart Lung and Blood Institute. Evidence-based management of sickle cell disease. Expert Panel report. Washington, DC: National Institutes of Health; 2014.

47. Ahmed F. Advisory Committee on Immunization Practices handbook for developing evidence-based recommendations. Version 1.2. Atlanta, GA: US Department of Health and Human Services, CDC; 2013. http://www.cdc.gov/vaccines/acip/recs/GRADE/about-grade.html#resources

48. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6. CrossRef PubMed

49. Guyatt GH, Oxman AD, Vist GE, et al. ; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924–6.CrossRef PubMed

50. Andrews JC, Schünemann HJ, Oxman AD, et al. GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation’s direction and strength. J Clin Epidemiol 2013;66:726–35. CrossRef PubMed

51. Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol 2011;64:380–2.CrossRef PubMed

52. Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med 2015;162:276–86. CrossRef PubMed

53. Agency for Healthcare Research and Quality. Methods guide for effectiveness and comparative effectiveness reviews. Effective Health Care Program. AHRQ Publication No. 10(13)-EHC063-EF. Rockville, MD: US Department of Health and Human Services, Agency for Healthcare Research and Quality; 2013. http://www.effectivehealthcare.ahrq.gov

54. Graham E. The effectiveness and risks of long-term opioid treatment of chronic pain. PROSPERO: international prospective register of systematic reviews. York, UK: University of York; 2014.http://www.crd.yor k.ac.uk/PROSPERO/display_record.asp?ID=CRD42014007016

55. Banta-Green CJ, Merrill JO, Doyle SR, Boudreau DM, Calsyn DA. Opioid use behaviors, mental health and pain—development of a typology of chronic pain patients. Drug Alcohol Depend 2009;104:34–42. CrossRef PubMed

56. Boscarino JA, Rukstalis M, Hoffman SN, et al. Risk factors for drug dependence among outpatients on opioid therapy in a large US health-care system. Addiction 2010;105:1776–82.CrossRef PubMed

57. Compton PA, Wu SM, Schieffer B, Pham Q, Naliboff BD. Introduction of a self-report version of the Prescription Drug Use Questionnaire and relationship to medication agreement noncompliance. J Pain Symptom Manage 2008;36:383–95. CrossRef PubMed

58. Cowan DT, Wilson-Barnett J, Griffiths P, Allan LG. A survey of chronic non-cancer pain patients prescribed opioid analgesics. Pain Med 2003;4:340–51. CrossRef PubMed

59. Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DD. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain 2007;8:573–82. CrossRef PubMed

60. Højsted J, Nielsen PR, Guldstrand SK, Frich L, Sjøgren P. Classification and identification of opioid addiction in chronic pain patients. Eur J Pain 2010;14:1014–20. CrossRef PubMed

61. Portenoy RK, Farrar JT, Backonja MM, et al. Long-term use of controlled-release oxycodone for non-cancer pain: results of a 3-year registry study. Clin J Pain 2007;23:287–99. CrossRefPubMed

62. Reid MC, Engles-Horton LL, Weber MB, Kerns RD, Rogers EL, O’Connor PG. Use of opioid medications for chronic non-cancer pain syndromes in primary care. J Gen Intern Med 2002;17:173–9. CrossRef PubMed

63. Saffier K, Colombo C, Brown D, Mundt MP, Fleming MF. Addiction Severity Index in a chronic pain sample receiving opioid therapy. J Subst Abuse Treat 2007;33:303–11. CrossRef PubMed

64. Schneider JP, Kirsh KL. Defining clinical issues around tolerance, hyperalgesia, and addiction: a quantitative and qualitative outcome study of long-term opioid dosing in a chronic pain practice. J Opioid Manag 2010;6:385–95. CrossRef PubMed

65. Wasan AD, Butler SF, Budman SH, et al. Does report of craving opioid medication predict aberrant drug behavior among chronic pain patients? Clin J Pain 2009;25:193–8. CrossRefPubMed

66. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med 2010;152:85–92. CrossRef PubMed

67. Gomes T, Mamdani MM, Dhalla IA, Paterson JM, Juurlink DN. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med 2011;171:686–91. CrossRefPubMed

68. Saunders KW, Dunn KM, Merrill JO, et al. Relationship of opioid use and dosage levels to fractures in older chronic pain patients. J Gen Intern Med 2010;25:310–5. CrossRef PubMed

69. Li L, Setoguchi S, Cabral H, Jick S. Opioid use for non-cancer pain and risk of fracture in adults: a nested case-control study using the general practice research database. Am J Epidemiol 2013;178:559–69. CrossRef PubMed

70. Carman WJ, Su S, Cook SF, Wurzelmann JI, McAfee A. Coronary heart disease outcomes among chronic opioid and cyclooxygenase-2 users compared with a general population cohort. Pharmacoepidemiol Drug Saf 2011;20:754–62. CrossRef PubMed

71. Li L, Setoguchi S, Cabral H, Jick S. Opioid use for non-cancer pain and risk of myocardial infarction amongst adults. J Intern Med 2013;273:511–26. CrossRef PubMed

72. Deyo RA, Smith DH, Johnson ES, et al. Prescription opioids for back pain and use of medications for erectile dysfunction. Spine (Phila Pa 1976) 2013;38:909–15. CrossRef PubMed

73. Rubinstein A, Carpenter DM. Elucidating risk factors for androgen deficiency associated with daily opioid use. Am J Med 2014;127:1195–201. CrossRef PubMed

74. Gomes T, Redelmeier DA, Juurlink DN, Dhalla IA, Camacho X, Mamdani MM. Opioid dose and risk of road trauma in Canada: a population-based study. JA-MA Intern Med 2013;173:196–201.CrossRef PubMed

75. Salzman RT, Roberts MS, Wild J, Fabian C, Reder RF, Goldenheim PD. Can a controlled-release oral dose form of oxycodone be used as readily as an immediate-release form for the purpose of titrating to stable pain

control? J Pain Symptom Manage 1999;18:271–9. CrossRef PubMed

76. Jamison RN, Raymond SA, Slawsby EA, Nedeljkovic SS, Katz NP. Opioid therapy for chronic non-cancer back pain. A randomized prospective study. Spine (Phila Pa 1976) 1998;23:2591–600.CrossRef PubMed

77. Miller M, Barber CW, Leatherman S, et al. Prescription opioid duration of action and the risk of unintentional overdose among patients receiving opioid therapy. JAMA Intern Med 2015;175:608–15. CrossRef PubMed

78. Allan L, Richarz U, Simpson K, Slappendel R. Transdermal fentanyl versus sustained release oral morphine in strong-opioid naïve patients with chronic low back pain. Spine (Phila Pa 1976) 2005;30:2484–90. CrossRef PubMed

79. Wild JE, Grond S, Kuperwasser B, et al. Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract 2010;10:416–27. CrossRef PubMed

80. Mitra F, Chowdhury S, Shelley M, Williams G. A feasibility study of transder-mal buprenorphine versus transdermal fentanyl in the long-term management of persistent non-cancer pain. Pain Med 2013;14:75–83. CrossRef PubMed

81. Krebs EE, Becker WC, Zerzan J, Bair MJ, McCoy K, Hui S. Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain. Pain 2011;152:1789–95. CrossRef PubMed

82. Hartung DM, Middleton L, Haxby DG, Koder M, Ketchum KL, Chou R. Rates of adverse events of long-acting opioids in a state Medicaid program. Ann Pharmacother 2007;41:921–8.CrossRef PubMed

83. Ray WA, Chung CP, Murray KT, Cooper WO, Hall K, Stein CM. Out-of-hospital mortality among patients receiving methadone for non-cancer pain. JAMA Intern Med 2015;175:420–7.CrossRef PubMed

84. Naliboff BD, Wu SM, Schieffer B, et al. A randomized trial of 2 prescription strategies for opioid treatment of chronic nonmalignant pain. J Pain 2011;12:288–96. CrossRef PubMed

85. Cowan DT, Wilson-Barnett J, Griffiths P, Vaughan DJ, Gondhia A, Allan LG. A randomized, double-blind, placebo-controlled, crossover pilot study to assess the effects of long-term opioid drug consumption and subsequent abstinence in chronic non-cancer pain patients receiving controlled-release morphine. Pain Med 2005;6:113–21. CrossRef PubMed

86. Ralphs JA, Williams AC, Richardson PH, Pither CE, Nicholas MK. Opiate reduction in chronic pain patients: a comparison of patient-controlled reduction and staff controlled cocktail methods. Pain 1994;56:279–88. CrossRef PubMed

87. Tennant FS , Rawson RA. Outpatient treatment of prescription opioid dependence: comparison of two methods. Arch Intern Med 1982;142:1845–7. CrossRef PubMed

88. Akbik H, Butler SF, Budman SH, Fernandez K, Katz NP, Jamison RN. Validation and clinical application of the Screener and Opioid Assessment for Patients with Pain (SOAPP). J Pain Symptom Manage 2006;32:287–93. CrossRef PubMed

89. Jones T, Moore T, Levy JL, et al. A comparison of various risk screening methods in predicting discharge from opioid treatment. Clin J Pain 2012;28:93–100. CrossRef PubMed

90. Moore TM, Jones T, Browder JH, Daffron S, Passik SD. A comparison of common screening methods for predicting aberrant drug-related behavior among patients receiving opioids for chronic pain management. Pain Med 2009;10:1426–33. CrossRef PubMed

91. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the Opioid Risk Tool. Pain Med 2005;6:432–42. CrossRef PubMed

47

92. Jones T, Lookatch S, Grant P, McIntyre J, Moore T. Further validation of an opioid risk assessment tool: the Brief Risk Interview. J Opioid Manag 2014;10:353–64. CrossRef PubMed

93. Jones T, Moore T. Preliminary data on a new opioid risk assessment measure: the Brief Risk Interview. J Opioid Manag 2013;9:19–27. CrossRef PubMed

94. Alam A, Gomes T, Zheng H, Mamdani MM, Juurlink DN, Bell CM. Long-term analgesic use after low-risk surgery: a retrospective cohort study. Arch Intern Med 2012;172:425–30. CrossRefPubMed

95. Webster BS, Verma SK, Gatchel RJ. Relationship between early opioid prescribing for acute occupational low back pain and disability duration, medical costs, subsequent surgery and late opioid use. Spine (Phila Pa 1976) 2007;32:2127–32. CrossRef PubMed

96. Ganann R, Ciliska D, Thomas H. Expediting systematic reviews: methods and implications of rapid reviews. Implement Sci 2010;5:56. CrossRef PubMed

97. Williams AC, Eccleston C, Morley S. Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev 2012;11:CD007407. PubMed

98. Hayden JA, van Tulder MW, Malmivaara A, Koes BW. Exercise therapy for treatment of non-specific low back pain. Cochrane Database Syst Rev 2005;3:CD000335. PubMed

99. Fransen M, McConnell S, Harmer AR, Van der Esch M, Simic M, Bennell KL. Exercise for osteoarthritis of the knee. Cochrane Database Syst Rev 2015;1:CD004376. PubMed

100. Fransen M, McConnell S, Hernandez-Molina G, Reichenbach S. Exercise for osteoarthritis of the hip. Cochrane Database Syst Rev 2014;4:CD007912 . CrossRef PubMed

101. Busch AJ, Barber KA, Overend TJ, Peloso PM, Schachter CL. Exercise for treating fibromyalgia syndrome. Cochrane Database Syst Rev 2007;4:CD003786. PubMed

102. Lee C, Crawford C, Swann S; Active Self-Care Therapies for Pain (PACT) Working Group. Multimodal, integrative therapies for the self-management of chronic pain symptoms. Pain Med 2014;15(Suppl 1):S76–85. CrossRef PubMed

103. Kamper SJ, Apeldoorn AT, Chiarotto A, et al. Multidisciplinary biopsychosocial rehabilitation for chronic low back pain: Cochrane systematic review and meta-analysis. BMJ 2015;350:h444.CrossRef

104. Zhang W, Doherty M, Arden N, et al. ; EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2005;64:669–81. CrossRef PubMed

105. Zhang W, Doherty M, Leeb BF, et al. EULAR evidence based recommendations for the management of hand osteoarthritis: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007;66:377–88. CrossRef PubMed

106. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:137–62. CrossRef PubMed

107. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis Cartilage 2007;15:981–1000. CrossRef PubMed

108. Jordan KM, Arden NK, Doherty M, et al. ; Standing Committee for International Clinical Studies Including Therapeutic Trials ESCISIT. EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis

2003;62:1145–55. CrossRef PubMed109. American Geriatrics Society Panel on Pharmacological

Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc 2009;57:1331–46. CrossRef PubMed

110. Chou R, Qaseem A, Snow V, et al. ; Clinical Efficacy Assessment Subcommittee of the American College of Physicians; American College of Physicians; American Pain Society Low Back Pain Guidelines Panel. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007;147:478–91. CrossRef PubMed

111. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011;342:c7086. CrossRef PubMed

112. Food and Drug Administration. FDA drug safety communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2015. http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm

113. O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med 2009;122(Suppl):S22–32. CrossRef PubMed

114. Attal N, Cruccu G, Baron R, et al. ; European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:1113–e88. CrossRef PubMed

115. Moulin DE, Clark AJ, Gilron I, et al. ; Canadian Pain Society. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 2007;12:13–21. PubMed

116. Bril V, England J, Franklin GM, et al. ; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;76:1758–65. Corrected in: Neurology 2011;77:603. CrossRef PubMed

117. Wallen M, Gillies D. Intra-articular steroids and splints/rest for children with juvenile idiopathic arthritis and adults with rheumatoid arthritis. Cochrane Database Syst Rev 2006:(1):CD002824. PubMed

118. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006;2:CD005328.PubMed

119. Buchbinder R, Green S, Youd JM. Corticosteroid injections for shoulder pain. Cochrane Database Syst Rev 2003;1:CD004016. PubMed

120. Food and Drug Administration. Epidural corticosteroid injection: drug safety communication. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2014. http://www.fda.gov/Safety/MedWatch/Safety Infor mat ion/SafetyAlertsforHumanMedicalProducts/ucm394530.htm

121. Goal of label changes: better prescribing, safer use of opioids. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2013.http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm367660.htm

122. Von Korff M, Merrill JO, Rutter CM, Sullivan M, Campbell CI, Weisner C. Time-scheduled vs. pain-contingent opioid dosing in chronic opioid therapy. Pain 2011;152:1256–62. CrossRefPubMed

123. Paulozzi L, Mack KA, Jones CM. Vital signs: risk for overdose from methadone used for pain relief—United States, 1999–2010. MMWR Morb Mortal Wkly Rep 2012;61:493–7. PubMed

124. Gwira Baumblatt JA, Wiedeman C, Dunn JR, Schaffner W, Paulozzi LJ, Jones TF. High-risk use by patients prescribed opioids for pain and its role in overdose deaths. JAMA Intern Med 2014;174:796–801. CrossRef PubMed

125. Paulozzi LJ, Kilbourne EM, Shah NG, et al. A history of being prescribed controlled substances and risk of drug overdose death. Pain Med 2012;13:87–95. CrossRef PubMed

126. Liang Y, Turner BJ. Assessing risk for drug overdose in a national cohort: role for both daily and total opioid dose? J Pain 2015;16:318–25. CrossRef PubMed

127. Bohnert ASB, Logan JE, Ganoczy D, Dowell D. A detailed exploration into the association of prescribed opioid dosage and prescription opioid overdose deaths among patients with chronic pain. Med Care 2016. Epub ahead of print. http://journals.lww.com/lww-medical-care/Abstract/publishahead/A_Detailed_Exploration_Into_the_Association_of.98952.aspx

128. Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S. Cohort study of the impact of high-dose opioid analgesics on overdose mortality. Pain Med 2015. Epub ahead of print.https://uncch.pure.elsevier.com/en/publications/cohor t-study-of-the-impact-of-high-dose-opioid-analgesics-on-over

129. Jones CM, McAninch JK. Emergency department visits and overdose deaths from combined use of opioids and benzodiazepines. Am J Prev Med 2015;49:493–501. CrossRef PubMed

130. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003;349:1943–53. CrossRef PubMed

131. Kalso E, Simpson KH, Slappendel R, Dejonckheere J, Richarz U. Predicting long-term response to strong opioids in patients with low back pain: findings from a randomized, controlled trial of transdermal fentanyl and morphine. BMC Med 2007;5:39. CrossRef PubMed

132. Yue HJ, Guilleminault C. Opioid medication and sleep-disordered breathing. Med Clin North Am 2010;94:435–46. CrossRef PubMed

133. Webster LR, Choi Y, Desai H, Webster L, Grant BJB. Sleep-disordered breathing and chronic opioid therapy. Pain Med 2008;9:425–32. CrossRef PubMed

134. Goodman LS, Limberd LE. Goodman and Gilman’s the pharmacologic basis of therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996.

135. Rowe JW, Andres R, Tobin JD, Norris AH, Shock NW. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol 1976;31:155–63. CrossRefPubMed

136. Rolita L, Spegman A, Tang X, Cronstein BN. Greater number of narcotic analgesic prescriptions for osteoarthritis is associated with falls and fractures in elderly adults. J Am Geriatr Soc 2013;61:335–40. CrossRef PubMed

137. Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with the use of morphine and opiates. J Intern Med 2006;260:76–87. CrossRef PubMed

138. Spector W, Shaffer T, Potter DE, Correa-de-Araujo R, Rhona Limcangco M. Risk factors associated with the occurrence of fractures in U.S. nursing homes: resident and facility characteristics and prescription medications. J Am Geriatr Soc 2007;55:327–33. CrossRef PubMed

139. Yazdy MM, Mitchell AA, Tinker SC, Parker SE, Werler MM. Periconceptional use of opioids and the risk of neural tube defects. Obstet Gynecol 2013;122:838–44. CrossRef PubMed

140. Broussard CS, Rasmussen SA, Reefhuis J, et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011;204:314 e1–11. PubMed

141. Whiteman VE, Salemi JL, Mogos MF, Cain MA, Aliyu MH, Salihu HM. Maternal opioid drug use during pregnancy and its impact on perinatal morbidity, mortality, and the costs of medical care in the United States. J Pregnancy 2014;906723. CrossRef PubMed

48

142. Hadi I, da Silva O, Natale R, Boyd D, Morley-Forster PK. Opioids in the parturient with chronic nonmalignant pain: a retrospective review. J Opioid Manag 2006;2:31–4. PubMed

143. Edlund MJ, Steffick D, Hudson T, Harris KM, Sullivan M. Risk factors for clinically recognized opioid abuse and dependence among veterans using opioids for chronic non-cancer pain. Pain 2007;129:355–62. CrossRef PubMed

144. Howe CQ, Sullivan MD. The missing ‘P’ in pain management: how the current opioid epidemic highlights the need for psychiatric services in chronic pain care. Gen Hosp Psychiatry 2014;36:99–104. CrossRef PubMed

145. Turner BJ, Liang Y. Drug Overdose in a retrospective cohort with non-cancer pain treated with opioids, antidepressants, and/or sedative-hypnotics: interactions with mental health disorders. J Gen Intern Med 2015;30:1081–96; Epub ahead of print. . CrossRef PubMed

146. Paulozzi L. CDC grand rounds: prescription drug overdoses—a U.S. epidemic. MMWR Morb Mortal Wkly Rep 2012;61:10–3. PubMed

147. Walley AY, Xuan Z, Hackman HH, et al. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ 2013;346:f174. CrossRef PubMed

148. Coffin P, Banta-Green C. The dueling obligations of opioid stewardship. Ann Intern Med 2014;160:207–8. CrossRef PubMed

149. Twillman RK, Kirch R, Gilson A. Efforts to control prescription drug abuse: Why clinicians should be concerned and take action as essential advocates for rational policy. CA Cancer J Clin 2014;64:369–76. CrossRef PubMed

150. Cicero TJ, Ellis MS, Surratt HL. Effect of abuse-deterrent formulation of Oxy-Contin. N Engl J Med 2012;367:187–9. CrossRef PubMed

151. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2014;2:CD002207 .CrossRef PubMed

152. Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev 2009;3:CD002209 .CrossRef PubMed

153. Fullerton CA, Kim M, Thomas CP, et al. Medication-assisted treatment with methadone: assessing the evidence. Psychiatr Serv 2014;65:146–57. CrossRef PubMed

154. Amato L, Minozzi S, Davoli M, Vecchi S. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. Cochrane Database Syst Rev 2011;9:CD005031 . CrossRef PubMed

155. Connock M, Juarez-Garcia A, Jowett S, et al. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technol Assess 2007;11:1–171. CrossRef PubMed

156. Keller CE, Ashrafioun L, Neumann AM, Van Klein J, Fox CH, Blondell RD. Practices, perceptions, and concerns of primary care physicians about opioid dependence associated with the treatment of chronic pain. Subst Abus 2012;33:103–13. CrossRef PubMed

157. Payne M, Gething M, Moore AA, Reid MC. Primary care providers’ perspectives on psychoactive medication disorders in older adults. Am J Geriatr Pharmacother 2011;9:164–72. CrossRefPubMed

158. Hagemeier NE, Gray JA, Pack RP. Prescription drug abuse: a comparison of prescriber and pharmacist perspectives. Subst Use Misuse 2013;48:761–8. CrossRef PubMed

159. Hooten WM, Bruce BK. Beliefs and attitudes about prescribing opioids among healthcare providers seeking continuing medical education. J Opioid Manag 2011;7:417–24. PubMed

160. Hwang CS, Turner LW, Kruszewski SP, Kolodny A, Alexander GC. Prescription drug abuse: a national survey of primary care physicians. JAMA Intern Med 2015;175:302–4. CrossRefPubMed

161. Green TC, Mann MR, Bowman SE, et al. How does use of a prescription monitoring program change medical practice? Pain Med 2012;13:1314–23. CrossRef PubMed

162. Ringwalt C, Garrettson M, Alexandridis A. The effects of North Carolina’s prescription drug monitoring program on the prescribing behaviors of the state’s providers. J Prim Prev 2015;36:131–7. CrossRef PubMed

163. Pergolizzi J, Pappagallo M, Stauffer J, et al. ; Integrated Drug Compliance Study Group (IDCSG). The role of urine drug testing for patients on opioid therapy. Pain Pract 2010;10:497–507.CrossRef PubMed

164. Starrels JL, Wu B, Peyser D, et al. It made my life a little easier: primary care providers’ beliefs and attitudes about using opioid treatment agreements. J Opioid Manag 2014;10:95–102.CrossRef PubMed

165. Smith RJ, Kilaru AS, Perrone J, et al. How, why, and for whom do emergency medicine providers use prescription drug monitoring programs? Pain Med 2015;16:1122–31. CrossRefPubMed

166. Bair MJ, Krebs EE. Why is urine drug testing not used more often in practice? Pain Pract 2010;10:493–6. CrossRef PubMed

167. Mangione MP, Crowley-Matoka M. Improving pain management communication: how patients understand the terms “opioid” and “narcotic”. J Gen Intern Med 2008;23:1336–8. CrossRefPubMed

168. Moore SK, Guarino H, Acosta MC, et al. Patients as collaborators: using focus groups and feedback sessions to develop an interactive, web-based self-management intervention for chronic pain. Pain Med 2013;14:1730–40. CrossRef PubMed

169. Simmonds MJ, Finley EP, Vale S, Pugh MJ, Turner BJ. A qualitative study of veterans on long-term opioid analgesics: barriers and facilitators to multimodality pain management. Pain Med 2015;16:726–32. CrossRef PubMed

170. Hansen RN, Oster G, Edelsberg J, Woody GE, Sullivan SD. Economic costs of nonmedical use of prescription opioids. Clin J Pain 2011;27:194–202. CrossRef PubMed

171. Birnbaum HG, White AG, Schiller M, Waldman T, Cleveland JM, Roland CL. Societal costs of prescription opioid abuse, dependence, and misuse in the United States. Pain Med 2011;12:657–67.CrossRef PubMed

172. Inocencio TJ, Carroll NV, Read EJ, Holdford DA. The economic burden of opioid-related poisoning in the United States. Pain Med 2013;14:1534–47. CrossRef PubMed

173. Stagnitti MN. Trends in prescribed outpatient opioid use and expenses in the U.S. civilian noninstitutionalized population, 2002–2012. Statistical Brief No. 478. Rockville, MD: Agency for Healthcare Research and Quality; 2015.

174. Gore M, Tai K-S, Sadosky A, Leslie D, Stacey BR. Use and costs of prescription medications and alternative treatments in patients with osteoarthritis and chronic low back pain in community-based settings. Pain Pract 2012;12:550–60. CrossRef PubMed

175. Laffer A, Murphy R, Winegarden W, et al. An economic analysis of the costs and benefits associated with regular urine drug testing for chronic pain patients in the United States. Nashville, TN: Laffer Associates; 2011.

176. Hochberg MC, Altman RD, April KT, et al. ; American College of Rheumatology. American College of

Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012;64:465–74. CrossRef PubMed

177. Sullivan MD, Edlund MJ, Zhang L, Unützer J, Wells KB. Association between mental health disorders, problem drug use, and regular prescription opioid use. Arch Intern Med 2006;166:2087–93. CrossRef PubMed

178. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA 2013;309:657–9. CrossRef PubMed

179. Hooten WM, Timming R, Belgrade M, et al. Assessment and management of chronic pain. Bloomington, MN: Institute for Clinical Systems Improvement; 2013.https://www.icsi.org/_asset/bw798b/ChronicPain.pdf

180. The Interagency Pain Research Coordinating Committee. Draft of the National Pain Strategy: a comprehensive population health level strategy for pain. Bethesda, MD: National Institutes of Health; 2015. http://iprcc.nih.gov/National_Pain_Strategy/NPS_Main.htm

181. Mannion AF, Müntener M, Taimela S, Dvorak J. A randomized clinical trial of three active therapies for chronic low back pain. Spine (Phila Pa 1976) 1999;24:2435–48. CrossRef PubMed

182. Chaparro LE, Furlan AD, Deshpande A, Mailis-Gagnon A, Atlas S, Turk DC. Opioids compared with placebo or other treatments for chronic low back pain: an update of the Cochrane Review. Spine (Phila Pa 1976) 2014;39:556–63. CrossRef PubMed

183. Loder E, Weizenbaum E, Frishberg B, Silberstein S; American Headache Society Choosing Wisely Task Force. Choosing wisely in headache medicine: the American Headache Society’s list of five things physicians and patients should question. Headache 2013;53:1651–9. CrossRef PubMed

184. Gaskell H, Moore RA, Derry S, Stannard C. Oxycodone for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2014;6:CD010692 . CrossRef PubMed

185. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic non-cancer pain. Cochrane Database Syst Rev 2010:1:CD006605 . CrossRef PubMed

186. Krebs EE, Lorenz KA, Bair MJ, et al. Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference. J Gen Intern Med 2009;24:733–8. CrossRefPubMed

187. Ostelo RW, Deyo RA, Stratford P, et al. Interpreting change scores for pain and functional status in low back pain: towards international consensus regarding minimal important change. Spine (Phila Pa 1976) 2008;33:90–4. CrossRef PubMed

188. Food and Drug Administration. Disposal of unused medicines: what you should know. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2015.http://www.fda.gov/Dr ugs/ResourcesForYou/C o n s u m e r s / B u y i n g U s i n g M e d i c i n e S a f e l y /E n s u r i n g S a f e U s e o f M e d i c i n e /SafeDisposalofMedicines/ucm186187.htm#Flush_List

189. Food and Drug Administration. FDA blueprint for prescriber education for extended-release and long-acting opioid analgesics. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2014.

190. Food and Drug Administration. Abuse-deterrent opioids: evaluation and labeling guidance for industry. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research; 2015.

49

191. Chou R, Cruciani RA, Fiellin DA, et al. ; American Pain Society; Heart Rhythm Society. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain 2014;15:321–37. CrossRef PubMed

192. Chu J, Farmer B, Ginsburg B, Hernandez S, Kenny J, Majlesi N. New York City emergency department discharge opioid prescribing guidelines. New York, NY: New York City Department of Health and Mental Hygiene; 2013. http://www.nyc.gov/html/doh/html/hcp/drug-opioid-guidelines.shtml

193. Cheng D, Majlesi N. Clinical practice statement: emergency department opioid prescribing guidelines for the treatment of non-cancer related pain. Milwaukee, WI: American Academy of Emergency Medicine; 2013.American College of Emergency Physicians. Maryland emergency department and acute care facility guidelines for prescribing opioids. Baltimore, MD: Maryland Chapter, American College of Emergency Physicians; 2014. http://www.mdacep.org/MD%20ACEP%20Pamphlet%20FINAL_April%202014.pdf

194. Paone D, Dowell D, Heller D. Preventing misuse of prescription opioid drugs. City Health Information 2011;30:23–30.

195. Thorson D, Biewen P, Bonte B, et al. Acute pain assessment and opioid prescribing protocol. Bloomington, MN: Institute for Clinical Systems Improvement; 2014.https://www.icsi.org/_asset/dyp5wm/Opioids.pdf

196. Cantrill SV, Brown MD, Carlisle RJ, et al. ; American College of Emergency Physicians Opioid Guideline Writing Panel. Clinical policy: critical issues in the prescribing of opioids for adult patients in the emergency department. Ann Emerg Med 2012;60:499–525. CrossRef PubMed

197. Coste J, Delecoeuillerie G, Cohen de Lara A, Le Parc JM, Paolaggi JB. Clinical course and prognostic factors in acute low back pain: an inception cohort study in primary care practice. BMJ 1994;308:577–80. CrossRef PubMed

198. CDC. Common elements in guidelines for prescribing opioids for chronic pain. Atlanta, GA: US Department of Health and Human Services, CDC; 2015.http://www.cdc.gov/drugoverdose/prescribing/common-elements.html

199. Berlin D, Farmer BM, Rao RB, et al. . Deaths and severe adverse events associated with anesthesia-assisted rapid opioid detoxification—New York City, 2012. MMWR Morb Mortal Wkly Rep 2013;62:777–80. PubMed

200. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic non-cancer pain: Evidence and recommendations for everyday practice. Mayo Clin Proc 2015;90:828–42.CrossRef PubMed

201. ACOG Committee on Health Care for Underserved Women; American Society of Addiction Medicine. ACOG Committee Opinion No. 524: Opioid abuse, dependence, and addiction in pregnancy. Obstet Gynecol 2012;119:1070–6. CrossRef PubMed

202. National Opioid Use Guideline Group. Canadian guideline for safe and effective use of opioids for chronic non-cancer pain; 2010.http://nationalpaincentre.mcmaster.ca/opioid/documents.html

203. Bernabei R, Gambassi G, Lapane K, et al. Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology. JAMA 1998;279:1877–82. CrossRef PubMed

204. Kroenke K, Spitzer RL, Williams JBBL, Löwe B. The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: a systematic review. Gen Hosp Psychiatry 2010;32:345–59. CrossRef PubMed

205. Saitz R, Cheng DM, Allensworth-Davies D, Winter MR, Smith PC. The ability of single screening questions for unhealthy alcohol and other drug use to identify substance dependence in primary care. J Stud Alcohol Drugs 2014;75:153–7. CrossRef PubMed

206. Smith PC, Schmidt SM, Allensworth-Davies D, Saitz R. A single-question screening test for drug use in primary care. Arch Intern Med 2010;170:1155–60. CrossRef PubMed

207. Yudko E, Lozhkina O, Fouts A. A comprehensive review of the psychometric properties of the Drug Abuse Screening Test. J Subst Abuse Treat 2007;32:189–98. CrossRef PubMed

208. Reinert DF, Allen JP. The alcohol use disorders identification test: an update of research findings. Alcohol Clin Exp Res 2007;31:185–99. CrossRef PubMed

209. Enteen L, Bauer J, McLean R, et al. Overdose prevention and naloxone prescription for opioid users in San Francisco. J Urban Health 2010;87:931–41. CrossRef PubMed

210. Irvine JM, Hallvik SE, Hildebran C, Marino M, Beran T, Deyo RA. Who uses a prescription drug monitoring program and how? Insights from a statewide survey of Oregon clinicians. J Pain 2014;15:747–55. CrossRef PubMed

211. Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ 2015;350:h2698. CrossRef PubMed

212. Paquin AM, Zimmerman K, Rudolph JL. Risk versus risk: a review of benzodiazepine reduction in older adults. Expert Opin Drug Saf 2014;13:919–34. CrossRef PubMed

213. Schweizer E, Case WG, Rickels K. Benzodiazepine dependence and withdrawal in elderly patients. Am J Psychiatry 1989;146:529–31. CrossRef PubMed

214. American Society of Addiction Medicine. The ASAM national practice guideline for the use of medications in the treatment of addiction involving opioid use. Chevy Chase, MD: American Society of Addiction Medicine; 2015. http://www.asam.org/docs/default-source/practice-support/guidelines-and-consensus-docs/national-practice-guideline.pdf?sfvrsn=22

215. Fiellin DA, Schottenfeld RS, Cutter CJ, Moore BA, Barry DT, O’Connor PG. Primary care-based buprenorphine taper vs maintenance therapy for prescription opioid dependence: a randomized clinical trial. JAMA Intern Med 2014;174:1947–54. CrossRef PubMed

216. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry 2011;68:1238–46. CrossRef PubMed

217. Jones CM, Campopiano M, Baldwin G, McCance-Katz E. National and state treatment need and capacity for opioid agonist medication-assisted treatment. Am J Public Health 2015;105:e55–63. CrossRef PubMed

218. Mark TL, Lubran R, McCance-Katz EF, Chalk M, Richardson J. Medicaid coverage of medications to treat alcohol and opioid dependence. J Subst Abuse Treat 2015;55:1–5. CrossRefPubMed

219. Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database Syst Rev 2006:1:CD001333. PubMed

220. Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomized trial. Lancet 2011;377:1506–13. CrossRef PubMed

221. Substance Abuse and Mental Health Services Administration. Physician waiver qualifications.

Rockville, MD: US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration; 2015. http://www.samhsa.gov/medication-assisted-treatment/buprenorphine-waivermanagement

222. Reuben DB, Alvanzo AAH, Ashikaga T, et al. National Institutes of Health Pathways to Prevention Workshop: the role of opioids in the treatment of chronic pain. Ann Intern Med 2015;162:295–300. CrossRef PubMed

50

Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic

painOutcome Studies Limitations Inconsistency Imprecision Type of evidence Other factors Estimates of effect/

findings

Effectiveness and comparative effectiveness (KQ1)

Effectiveness of long-term opioid therapy versus placebo or no opioid therapy for long-term (≥1 year) outcomes

Pain, function, and quality of life

None —† — — Insufficient — No evidence

Harms and adverse events (KQ2)

Risks of opioids versus placebo or no opioids on opioid abuse, addiction, and related outcomes; overdose; and other harms

Abuse or addiction

1 cohort study (n = 568,640)

Serious limitations Unknown (1 study)

No imprecision 3 None identified One retrospective cohort study found long-term use of prescribed opioids associated with an increased risk of abuse or dependence diagnosis versus no opioid use (adjusted OR ranged from 14.9 to 122.5, depending on dose).

Abuse or addiction

10 uncontrolled studies (n = 3,780)

Very serious limitations

Very serious inconsistency

No imprecision 4 None identified In primary care settings, prevalence of opioid abuse ranged from 0.6% to 8% and prevalence of dependence from 3% to 26%. In pain clinic settings, prevalence of misuse ranged from 8% to 16% and addiction from 2% to 14%. Prevalence of aberrant drug-related behaviors ranged from 6% to 37%.

Overdose 1 cohort study (n = 9,940)

Serious limitations Unknown (1 study)

Serious imprecision

3 None identified Current opioid use associated with increased risk of any overdose events (adjusted HR 5.2, 95% CI = 2.1–12) and serious overdose events (adjusted HR 8.4, 95% CI = 2.5–28) versus current nonuse.

Fractures 1 cohort study (n = 2,341) and 1 case–control study (n = 21,739 case patients)

Serious limitations No inconsistency No imprecision 3 None identified Opioid use associated with increased risk of fracture in 1 cohort study (adjusted HR 1.28, 95% CI = 0.99–1.64) and 1 case-control study (adjusted OR 1.27, 95% CI = 1.21–1.33).

Myocardial infarction

1 cohort study (n = 426,124) and 1 case–control study (n = 11,693 case patients)

No limitations No inconsistency No imprecision 3 None identified Current opioid use associated with increased risk of myocardial infarction versus nonuse (adjusted OR 1.28, 95% CI = 1.19–1.37 and incidence rate ratio 2.66, 95% CI = 2.30–3.08).

51

Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain (continued)

Endocrinologic harms

1 cross-sectional study (n = 11,327)

Serious limitations

Unknown (1 study)

No imprecision 3 None identified

Long-term opioid use associated with increased risk for use of medications for erectile dysfunction or testosterone replacement versus nonuse (adjusted OR 1.5, 95% CI = 1.1–1.9).

Outcome Studies Limitations Inconsistency Imprecision Type of evidence

Other factors

Estimates of effect/findings

How do harms vary depending on the opioid dose used?

Abuse or addiction

1 cohort study (n = 568,640)

Serious limitations

Unknown (1 study)

No imprecision 3 None identified

One retrospective cohort study found higher doses of long-term opioid therapy associated with increased risk of opioid abuse or dependence than lower doses. Compared to no opioid prescription, the adjusted odds ratios were 15 (95% CI = 10–21) for 1 to 36 MME/day, 29 (95 % CI = 20–41) for 36 to120 MME/day, and 122 (95 % CI = 73–205) for ≥120 MME/day.

Overdose 1 cohort study (n = 9,940) and 1 case–control study (n = 593 case patients in primary analysis)

Serious limitations

No inconsistency

No imprecision 3 Magnitude of effect, dose response relationship

Versus 1 to <20 MME/day, one cohort study found an adjusted HR for an overdose event of 1.44 (95% CI = 0.57–3.62) for 20 to <50 MME/day that increased to 8.87 (95% CI = 3.99–19.72) at ≥100 MME/day; one case-control study found an adjusted OR for an opioid-related death of 1.32 (95% CI = 0.94–1.84) for 20 to 49 MME/day that increased to 2.88 (95% CI = 1.79–4.63) at ≥200 MME/day.

Fractures 1 cohort study (n = 2,341)

Serious limitations

Unknown (1 study)

Serious imprecision

3 None identified

Risk of fracture increased from an adjusted HR of 1.20 (95% CI = 0.92–1.56) at 1 to <20 MME/day to 2.00 (95% CI = 1.24–3.24) at ≥50 MME/day; the trend was of borderline statistical significance.

52

Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain (continued)

Myocardial infarction

1 cohort study (n = 426,124)

Serious limitations

Unknown (1 study)

No imprecision 3 None identified

Relative to a cumulative dose of 0 to 1,350 MME during a 90-day period, the incidence rate ratio for myocardial infarction for 1350 to <2700 MME was 1.21 (95% CI = 1.02–1.45), for 2,700 to <8,100 MME was 1.42 (95% CI = 1.21–1.67), for 8,100 to <18,000 MME was 1.89 (95% CI = 1.54–2.33), and for ≥8,000 MME was 1.73 (95% CI = 1.32–2.26).

Motor vehicle crash injuries

1 case–control study (n = 5,300 case patients)

No limitations

Unknown (1 study)

No imprecision 3 None identified

No association between opioid dose and risk of motor vehicle crash injuries even though opioid dosages ≥20 MME/day were associated with increased odds of road trauma among drivers.

Endocrinologic harms

1 cross-sectional study (n = 11,327) New for update: 1 additional cross-sectional study (n=1,585)

Serious limitations

Consistent No imprecision 3 None identified

Relative to 0 to <20 MME/day, the adjusted OR for ≥120 MME/day for use of medications for erectile dysfunction or testosterone replacement was 1.6 (95% CI = 1.0–2.4). One new cross-sectional study found higher-dose long-term opioid therapy associated with increased risk of androgen deficiency among men receiving immediate-release opioids (adjusted OR per 10 MME/day 1.16, 95% CI = 1.09–1.23), but the dose response was very weak among men receiving ER/LA opioids.

Outcome Studies Limitations Inconsistency Imprecision Type of evidence

Other factors

Estimates of effect/findings

Dosing strategies (KQ3)

Comparative effectiveness of different methods for initiating opioid therapy and titrating doses

Pain 3 randomized trials (n = 93)

Serious limitations

Serious inconsistency

Very serious imprecision

4 None identified

Trials on effects of titration with immediate-release versus ER/LA opioids reported inconsistent results and had additional differences be-tween treatment arms in dosing protocols (titrated versus fixed dosing) and doses of opioids used.

53

Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain (continued)

Overdose New for update: 1 cohort study (n = 840,606)

Serious limitations

Unknown (1 study)

No imprecision 4 None identified

One new cross-sectional study found initiation of therapy with an ER/LA opioid associated with increased risk of overdose versus initiation with an immediate-release opioid (adjusted HR 2.33, 95% CI = 1.26–4.32).

Comparative effectiveness of different ER/LA opioids

Pain and function

3 randomized trials (n= 1,850)

Serious limitations

No inconsistency

No imprecision 3 None identified

No differences

Outcome Studies Limitations Inconsistency Imprecision Type of evidence

Other factors

Estimates of effect/findings

All-cause mortality

1 cohort study (n = 108,492) New for update: 1 cohort study (n = 38,756)

Serious limitations

Serious inconsistency

No imprecision 4 None identified

One cohort study found methadone to be associated with lower all-cause mortality risk than sustained-release morphine in a propensity-adjusted analysis (adjusted HR 0.56, 95% CI = 0.51–0.62) and one cohort study among Tennessee Medicaid patients found methadone to be associated with higher risk of all-cause mortality than sustained-release morphine (adjusted HR 1.46, 95% CI = 1.17–1.73).

Abuse and related outcomes

1 cohort study (n = 5,684)

Serious limitations

Unknown (1 study)

Serious imprecision

4 None identified

One cohort study found some differences between ER/LA opioids in rates of adverse outcomes related to abuse, but outcomes were nonspecific for opioid-related adverse events, precluding reliable conclusions.

ER/LA versus immediate-release opioids

Endocrinologic harms

New for update: 1 cross-sectional study (n = 1,585)

Serious limitations

Unknown (1 study)

No imprecision 4 None identified

One cross-sectional study found ER/LA opioids associated with increased risk of androgen deficiency versus immediate-release opioids (adjusted OR 3.39, 95% CI = 2.39–4.77).

Dose escalation versus dose maintenance or use of dose thresholds

Pain, function, or withdrawal due to opioid misuse

1 randomized trial (n = 140)

Serious limitations

Unknown (1 study)

Very serious imprecision

3 None identified

No difference between more liberal dose escalation versus maintenance of current doses in pain, function, or risk of withdrawal due to opioid misuse, but there was limited separation in opioid doses between groups (52 versus 40 MME/day at the end of the trial).

54

Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain (continued)

Outcome Studies Limitations Inconsistency Imprecision Type of evidence

Other factors Estimates of effect/findings

Immediate-release versus ER/LA opioids; immediate-release plus ER/LA opioids versus ER/LA opioids alone; scheduled and continuous versus as-needed dosing of opioids; or opioid rotation versus maintenance of current therapy

Pain, function, quality of life, and outcomes related to abuse

None — — — Insufficient — No evidence

Effects of decreasing or tapering opioid doses versus continuation of opioid therapy

Pain and function

1 randomized trial (n = 10)

Very serious limitations

Unknown (1 study)

Very serious imprecision

4 None identified

Abrupt cessation of morphine was associated with increased pain and decreased function compared with continuation of morphine.

Comparative effectiveness of different tapering protocols and strategies

Opioid abstinence

2 nonrandomized trials (n = 150)

Very serious limitations

No inconsistency

Very serious imprecision

4 None identified

No clear differences between different methods for opioid discontinuation or tapering in likelihood of opioid abstinence after 3–6 months

Risk assessment and risk mitigation strategies (KQ4)

Diagnostic accuracy of instruments for predicting risk for opioid overdose, addiction, abuse, or misuse among patients with chronic pain being considered for long-term opioid therapy

Opioid risk tool 3 studies of diagnostic accuracy (n = 496) New for update:2 studies of diagnostic accuracy (n = 320)

Serious limitations

Very serious inconsistency

Serious imprecision

4 None identified

Based on a cutoff score of ≥4 (or unspecified), five studies (two fair quality, three poor quality) reported sensitivity that ranged from 0.20 to 0.99 and specificity that ranged from 0.16 to 0.88.

Screener and Opioid Assessment for Patients with Pain, Version 1

2 studies of diagnostic accuracy (n = 203)

Very serious limitations

No inconsistency

Serious imprecision

3 None identified

Based on a cutoff score of ≥8, sensitivity was 0.68 and specificity was 0.38 in one study, for a positive likelihood ratio of 1.11 and a negative likelihood ratio of 0.83. Based on a cutoff score of >6, sensitivity was 0.73 in one study.

Screener and Opioid Assessment for Patients with Pain-Revised

New for update: 2 studies of diagnostic accuracy (n = 320)

Very serious limitations

No inconsistency

Serious imprecision

3 None identified

Based on a cutoff score of >3 or unspecified, sensitivity was 0.25 and 0.53 and specificity was 0.62 and 0.73 in two studies, for likelihood ratios close to 1.

55

Table 1. Grading of Recommendations Assessment, Development and Evaluation (GRADE) clinical evidence review ratings of the evidence for the key clinical questions regarding effectiveness and risks of long-term opioid therapy for chronic pain (continued)

Brief Risk Interview

New for update: 2 studies of diagnostic accuracy (n = 320)

Very serius limitations

No inconsistency

Serious imprecision

3 None identified

Based on a “high risk” assessment, sensitivity was 0.73 and 0.83 and specificity was 0.43 and 0.88 in two studies, for positive likelihood ratios of 1.28 and 7.18 and negative likelihood ratios of 0.63 and 0.19.

Outcome Studies Limitations Inconsistency Imprecision Type of evidence

Other factors

Estimates of effect/findings

Effectiveness of risk prediction instruments on outcomes related to overdose, addiction, abuse, or misuse in patients with chronic pain

Outcomes related to abuse

None — — — Insufficient — No evidence

Effectiveness of risk mitigation strategies, including opioid management plans, patient education, urine drug screening, use of prescription drug monitoring program data, use of monitoring instruments, more frequent monitoring intervals, pill counts, and use of abuse-deterrent formulations, on outcomes related to overdose, addiction, abuse, or misuse

Outcomes related to abuse

None — — — Insufficient — No evidence

Effectiveness of risk prediction instruments on outcomes related to overdose, addiction, abuse, or misuse in patients with chronic pain

Outcomes related to abuse

None – – – Insufficient – No evidence

Effectiveness of risk mitigation strategies, including opioid management plans, patient education, urine drug screening, use of prescription drug monitoring program data, use of monitoring instruments, more frequent monitoring intervals, pill counts, and use of abuse-deterrent formulations, on outcomes related to overdose, addiction, abuse, or misuse

Outcomes related to abuse

None – – – Insufficient – No evidence

Comparative effectiveness of treatment strategies for managing patients with addiction to prescription opioids

Outcomes related to abuse

None – – – Insufficient – No evidence

Effects of opioid therapy for acute pain on long-term use (KQ5)

Long-term opioid use

New for update:2 cohort studies(n = 399,852)

Serious limitations

No inconsistency

No imprecision 3 None identified

One study found use of opioids within 7 days of low-risk surgery associated with increased likelihood of opioid use at 1 year (adjusted OR 1.44, 95% CI = 1.39–1.50), and one study found use of opioids within 15 days of onset of low back pain among workers with a compensation claim associated with increased risk of late opioid use (adjusted OR 2.08, 95% CI = 1.55–2.78 for 1 to 140 MME/day and OR 6.14, 95% CI = 4.92–7.66 for ≥450 MME/day).

Abbreviations: CI = confidence interval; ER/LA = extended release/long-acting; HR = hazard ratio; MME = morphine milligram equivalents; OR = odds ratio.*Ratings were made per GRADE quality assessment criteria; “no limitations” indicates that limitations assessed through the GRADE method were not identified.†Not applicable as no evidence was available for rating.

56

Table 2. Morphine Milligram Equivalent (Mme) Doses For Commonly Prescribed Opioids

Opioid Conversion factor*

Codeine 0.15

Fentanyl transdermal (in mcg/hr) 2.4

Hydrocodone 1

Hydromorphone 4

Methadone

1–20 mg/day 4

21–40 mg/day 8

41–60 mg/day 10

≥61–80 mg/day 12

Morphine 1

Oxycodone 1.5

Oxymorphone 3

Tapentadol† 0.4

Source: Adapted from Von Korff M, Saunders K, Ray GT, et al. Clin J Pain 2008;24:521–7 and Washington State Interagency Guideline on Prescribing Opioids for Pain (http://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf).*Multiply the dose for each opioid by the conversion factor to determine the dose in MMEs. For example, tablets containing hydrocodone 5 mg and acetaminophen 300 mg taken four times a day would contain a total of 20 mg of hydrocodone daily, equivalent to 20 MME daily; extended-release tablets containing oxycodone 10mg and taken twice a day would contain a total of 20mg of oxycodone daily, equivalent to 30 MME daily. The following cautions should be noted: 1) All doses are in mg/day except for fentanyl, which is mcg/hr. 2) Equianal-gesic dose conversions are only estimates and cannot account for individual variability in genetics and pharmacokinetics. 3) Do not use the calculated dose in MMEs to determine the doses to use when converting opioid to another; when converting opioids the new opioid is typically dosed at substantially lower than the calculated MME dose to avoid accidental overdose due to incomplete cross-tolerance and individual variability in opioid pharmacokinetics. 4) Use particular caution with methadone dose conversions because the conversion factor increases at higher doses. 5) Use particular caution with fentanyl since it is dosed in mcg/hr instead of mg/day, and its absorption is affected by heat and other factors.†Tapentadol is a mu receptor agonist and norepinephrine reuptake inhibitor. MMEs are based on degree of mu-receptor agonist activity, but it is unknown if this drug is associated with overdose in the same dose-dependent manner as observed with medications that are solely mu receptor agonists.

Steering Committee and Core Expert Group Members

Steering Committee: Deborah Dowell, MD, Tamara M. Haegerich, PhD; Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, CDC; Roger Chou, MD; on detail to CDC under contract

Core Expert Group Members: Pam Archer, MPH, Oklahoma State Department of Health; Jane Ballantyne, MD; University of Washington (retired); Amy Bohnert, PhD; University of Michigan; Bonnie Burman, ScD; Ohio Department on Aging; Roger Chou, MD; on detail to CDC under contract; Phillip Coffin, MD, San Francisco Department of Public Health; Gary Franklin, MD, MPH; Washington State Department of Labor and Industries/University of Washington; Erin Krebs, MDH; Minneapolis VA Health Care System/University of Minnesota; Mitchel Mutter, MD, Tennessee Department of Health; Lewis Nelson, MD; New York University School of Medicine; Trupti Patel, MD, Arizona Department of Health Services; Christina A. Porucznik, PhD, University of Utah; Robert “Chuck” Rich, MD, FAAFP, American Academy of Family Physicians; Joanna Starrels, MD, Albert Einstein College of Medicine of Yeshiva University; Michael Steinman, MD, Society of General Internal Medicine; Thomas Tape, MD, American College of Physicians; Judith Turner, PhD, University of Washington.

Stakeholder Review GroupJohn Markman, MD, American Academy of Neurology; Bob Twillman, PhD, American Academy of Pain Management; Edward C. Covington, MD, American Academy of Pain Medicine; Roger F. Suchyta, MD, FAAP, American Academy of Pediatrics; Kavitha V. Neerukonda, JD, American Academy of Physical Medicine and Rehabilitation; Mark Fleury, PhD, American Cancer Society Cancer Action Network; Penney Cowan, American Chronic Pain Association; David Juurlink, BPharm, MD, PhD, American College of Medical Toxicology; Gerald “Jerry” F. Joseph, Jr, MD, American College of Obstericians and Gynecologists; Bruce Ferrell, MD, AGSF, M. Carrington Reid, MD, PhD, American Geriatrics Society; Ashley Thompson, American Hospital Association; Barry D. Dickinson, PhD, American Medical Association; Gregory Terman MD, PhD, American Pain Society; Beth Haynes, MPPA, American Society of Addiction Medicine; Asokumar Buvanendran, MD, American Society of Anesthesiologists; Robert M. Plovnick; MD, American Society of Hematology; Sanford M. Silverman, MD, American Society of Interventional Pain Physicians; Andrew Kolodny, MD, Physicians for Responsible Opioid Prescribing.

57

Opioid Guideline WorkgroupChair: Christina Porucznik, PhD, MSPHWorkgroup Members: Anne Burns, RPh; Penney Cowan; Chinazo Cunningham, MD, MS; Katherine Galluzzi, DO; Traci Green, PhD, MSC; Mitchell Katz, MD; Erin Krebs, MD, MPH; Gregory Terman, MD, PhD; Mark Wallace, MD. Workgroup Consultants: Roger Chou, MD; Edward Covington, MD; Diana Eppolito; Michael Greene, MD; Steven Stanos, DO.

Peer ReviewersJeanmarie Perrone, MD, University of Pennsylvania; Matthew Bair, MD, Indiana University School of Medicine;, David Tauben, MD, University of WashingtonNCIPC Board of Scientific CounselorsChair: Stephen Hargarten, MD, MPH; Members: John Allegrante, PhD; Joan Marie Duwve, MD, Samuel Forjuoh, MD, MPH, DrPH, FGCP; Gerard Gioia, PhD; Deborah Gorman-Smith, PhD; Traci Green, PhD; Sherry Lynne Hamby, PhD; Robert Johnson, MD; Angela Mickalide, PhD, MCHES; Sherry Molock, PhD; Christina Porucznik, PhD, MSPH; Jay Silverman, PhD; Maria Testa, PhD; Shelly Timmons, MD, PhD, FACS, FAANS; Ex Officio Members: Melissa Brodowski, PhD; Dawn Castillo, MPH; Wilson Compton, MD, MPE; Elizabeth Edgerton, MD, MPH; Thomas Feucht, PhD; Meredith Fox, PhD; Holly Hedegaard, MD, MSPH; John Howard, MD; Lyndon Joseph, PhD; Jinhee Lee, PharmD; Iris Mabry-Hernandez, MD, MPH; Valeri Maholmes, PhD; Angela Moore Parmley, PhD; Thomas Schroeder, MS.

Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.

References to non-CDC sites on the Internet are provided as a service to MMWR readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of pages found at these sites. URL addresses listed in MMWR were current as of the date of publication.

All HTML versions of MMWR articles are generated from final proofs through an automated process. This conversion might result in character translation or format errors in the HTML version. Users are referred to the electronic PDF version (http://www.cdc.gov/mmwr) and/or the original MMWR paper copy for printable versions of official text, figures, and tables. An original paper copy of this issue can be obtained from the Superintendent of Documents, U.S. Government Printing Office (GPO), Washington, DC 20402-9371; telephone: (202) 512-1800. Contact GPO for current prices

58

16. What percentage of patients presenting to physician offices with non-cancer pain symptoms or pain-related diagnoses currently receive an opioid prescription in the US?A. 5%B. 10%C. 15%D. 20%

17. The CDC guidelines (and others) define chronic pain as pain lasting more than ___________ or past the time of normal tissue healing. A. 4 weeksB. 1 monthC. 3 monthsD. 6 months

18. Although the terms “abuse,” “dependence,” and “addiction,” have been used in the past to describe a problematic pattern of opioid use leading to clinically significant impairment or distress, which term is now generally favored?A. Substance use disorderB. Opioid use disorderC. Dysfunctional opioid toleranceD. Opioid-induced dysthymia

19. Which statement best summarizes the CDC finding about opioids for chronic pain?A. Opioid analgesics should be confined to use in

patients with neuropathic, as opposed to nociceptive, pain syndromes

B. Chronic non-cancer pain can be effectively treated with immediate-release opioid agents, but should not be treated with long-acting or extended-release formulations

C. No evidence shows a long-term benefit of opioids in pain and function versus no opioids although extensive evidence shows the potential harms of opioids

D. Evidence supports the use of opioid analgesics for long-term non-cancer chronic pain except in patients with pre-existing substance use disorders

20. How soon after starting a patient on opioid therapy should a clinician evaluate the risks and benefits of the treatment?A. Within 1-4 weeksB. Within 1-4 monthsC. After 6 monthsD. After a year

21. What is one suggestion for a way to augment opioid treatment in order to help improve a patient’s pain and function?A. Use an every-other-day dosing pattern for the opioid,

alternating with an NSAID analgesicB. Rotate the route of administration every 6 weeksC. Add a long-acting opioid to a prescription for an

immediate-release opioid D. Try concurrent nonpharmacologic approaches such

as exercise or cognitive behavioral therapy

22. Which statement accurately describes a challenge clinicians face when considering initiating treatment with an opioid?A. It is difficult to predict whether an individual patient

will experience constipation as a side effect of an opioid

B. It is very difficult to predict whether benefits of opioids for chronic pain will outweigh risks for individual patients

C. Patients are generally reluctant to sign provider/patient agreements about treatment with opioids

D. Few guidelines exist to help clinicians decide which patients are appropriate for opioids

23. Which of the following is not a key point for clinicians to discuss with patients when an opioid is prescribed?A. Insurance may not cover some forms of opioidsB. No good evidence shows that opioids improve pain or

function with long-term useC. Function can improve even when pain is still presentD. Opioids pose many risks including overdose or life-

long opioid use disorder

CDC OPIOID PRESCRIBING GUIDELINES FOR CHRONIC PAINSelf-Assessment

Choose the best possible answer for each question and mark your answers on the Self-Assessment answer sheet at the end of this book. There is a required score of 70% or better to receive a Certificate of completion.

59

24. Why should ER/LA opioids be avoided when starting opioid therapy for chronic pain?A. They tend to be more expensive than immediate-

release opioidsB. They are not as effective as immediate-release

opioidsC. There is a higher risk of overdose among patients

starting treatment with ER/LA opioidsD. ER/LA opioids are more difficult for patients to self-

administer

25. At which level of opioid dosing should a clinician carefully reassess the evidence of benefits and risks for the patient?A. ≥ 50 MMEDB. ≥ 60 MMEDC. ≥ 80 MMEDD. ≥ 90 MMED

26. Most experts agree that opioid dosages should not be increased to _______ without careful justification based on diagnosis and on an individualized assessment of benefits and risks.A. ≥ 50 MMEDB. ≥ 60 MMEDC. ≥ 80 MMEDD. ≥ 90 MMED

27. In general, the amount of opioids prescribed for acute pain should be limited to a ____ day supply:A. 1B. 3C. 7D. 10

28. Long-acting (LA) and extended-release (ER) formulations of opioids should typically not be used for treating which kind of pain?A. Cancer painB. Acute painC. End-of-life painD. Nociceptive pain

29. What is the initial suggested rate of taper for weaning patients safely off of an opioid?A. Decrease of 5% of original dose/weekB. Decrease of 10% of original dose/weekC. Decrease of 15% of original dose/weekD. Decrease of 20% of original dose/week

30. What do the CDC guidelines suggest regarding the prescription of opioids to pregnant women?A. Clinicians and patients should carefully weigh risks

and benefits when deciding whether to start an opioidB. Completely avoid prescribing opioids to this

populationC. Prescribe ER/LA opioids rather than short-acting

opioids to avoid spike exposure to fetusD. Prescribe opioids as needed for maternal pain, but

monitor infant after delivery for possible neonatal abstinence syndrome

31. For the treatment of chronic pain in patients with depression, which two classes of antidepressants are recommended?A. Atypicals and dopamine-agonist antidepressantsB. SSRIs and SNRIsC. MAOIs and tricyclicsD. SNRIs and tricyclics

32. The DAST and AUDIT tools are examples of which kind of assessment?A. Quantifying patients’ pain perceptionsB. Assessing patient risk of opioid misuse or abuseC. Evaluating risk of physical adverse reactions to

opioidsD. Determining a reason for opioid pain medications

33. Which of the following is not a possible reason for prescribing naloxone to a patient who has been prescribed an opioid analgesic?A. The patient is taking a higher dose of an opioid (>50

MMED) B. The patient has recently been released from prison C. The patient has history of substance use disorderD. The patient has a concurrent prescription for an SSRI

antidepressant

34. How frequently should PDMP data be reviewed for patients on long-term opioid therapy? A. Every 4 weeksB. Every monthC. Every 3 months or more frequentlyD. Every 6 months or more frequently

60

35. Which of the following is not a potential benefit of urine drug testing?A. Can provide information about drug use that is not

reported by the patientB. Provides objective evidence of abstinence from

drugs of abuseC. Can help identify patients who are not taking opioids

prescribed for themD. Can provide accurate information about how much or

what dose of opioids a patient may be using

61

This course is designed for all physicians (MD/DO) and other healthcare professionals caring for people who are nearing the end of life.

This monograph summarizes the major dimensions of EOL care that clinicians are likely to encounter as they attempt to care for patients in their final phase of life. The activity will discuss methods for proactively addressing many of the barriers to effective EOL, including incorporating patient-centered treatment goals, clinician communication skills and the management of pain and other physical symptoms near the end of life.

InforMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

InforMed designates this enduring material for maximum of 2 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Completion of this course will better enable the course participant to:1. Explain the difference between palliative care and hospice care as these terms are understood in the US.2. Discuss the process for formulating patient-centered goals for end-of-life care, including culturally sensitive

communication skills. 3. Describe Strategies for communicating with patients and family members, including the concept of reflective

listening. 4. Identify ways to assess pain in a patient with reduced or absent consciousness.5. Recognize 2 advantages and 2 disadvantages of opioid pain medications in the context of end-of-life pain

management.6. Discuss ways to help manage mood or emotional dysfunctions in patients at the end of life.7. Explain ways to effectively provide nutrition and hydration.

TARGET AUDIENCE

COURSE OBJECTIVE

ACCREDITATION STATEMENT:

DESIGNATION STATEMENT:

LEARNING OBJECTIVE

HOW TO RECEIVE CREDIT:

MAXIMUM CREDITS: FORMAT:COURSE DATES:

Read the course materials

Complete the self-assessment questions at the end. A score of 70% is required.

Return your customer information/answer sheet, evaluation,and payment to Informed by mail, phone, fax or complete online at course website under NETPASS.

Enduring Material (Self Study)

Release Date: 10/2016Exp. Date: 10/2019

2 AMA PRA Category 1 CreditsTM

CARING FOR PATIENTS AT THE END OF LIFE

62

Paul J. Christo, MDDirector, Multidisciplinary Pain Fellowship ProgramAssociate Professor of Anesthesiology and Critical Care MedicineThe Johns Hopkins University School of Medicine

Stephen BraunMedical WriterBraun Medical Media

Elizabeth ThomasMSN, WHNP-BC, NP-C

Special Designation:

This course satisfies Two (2) CME credit hours on Pain Management and the Appropriate

Treatment of the Terminally Ill

The Medical Board of California requires most physicians and surgeons to complete a one-time mandatory 12 hours of CME in the subjects of pain management and the treatment of

terminally ill & dying patients

In accordance with the ACCME Standards for Commercial Support of CME, Informed implemented mechanisms, prior to the planning and implementation of this CME activity, to identify and resolve conflicts of interest for all individuals in a position to control content of this CME activity.

DISCLAIMER* 2018. All rights reserved. These materials, except those in the public domain, may not be reproduced without permission from InforMed. This publication is designed to provide general information prepared by professionals in regard to the subject matter covered. It is provided with the understanding that InforMed, Inc. is not engaged in rendering legal, medical or other professional services. Although prepared by professionals, this publication should not be utilized as a substitute for professional services in specific situations. If legal advice, medical advice or other expert assistance is required, the service of a professional should be sought.

FACULTY:

ACTIVITY PLANNER:

DISCLOSURE OF INTEREST:

FACULTY/PLANNING COMMITTEE DISCLOSURE:The following faculty and/or planning committee members have indicated they have no relationship(s) with industry to disclose relative to the content of this CME activity:• Stephen Braun• Elizabeth ThomasThe following faculty and/or planning committee members have indicated that they have relationship(s) with industry to disclose• Paul J. Christo, MD has received honoraria from Grunenthal, Quest

Diagnostics, Revo Pharma, Daiichi Sankyo, Collegium Pharma, and Insys Therapeutic

STAFF & CONTENT REVIEWERS:Informed staff and all content validation reviewers involved with this activity have reported no relevant financial relationships with commercial interests.

COURSE SATISFIES

2Pain Management

and Terminally Ill Patients

63

Trends in End-of-Life CareIn the past century, life expectancy in the United States has increased by approximately 30 years.2 As a consequence, most people alive today will die at an older age than in previous years, and most will die after a period of chronic illness and physical decline.3 At the same time, studies document serious defects in the care provided to dying people, including under treatment of pain, over-use of technological means of prolonging life, and communication difficulties between patients, family members, and health care providers.4 Pain management at the end of life (EOL) has become a particularly challenging issue because of widespread problems with diversion and abuse of opioids in certain patient populations, which continue to be the mainstay analgesics in the terminal phase of many illnesses. Although the education of health professionals who provide care to people nearing the end of life has improved substantially in the past two decades, serious problems remain.5 Knowledge gains have not necessarily been transferred to clinicians caring for people with advanced serious illness who are nearing the end of life. In addition, the number of hospice and palliative care specialists is small, which means the need for palliative care also must be met through primary care and through the other clinical specialties that entail care for significant numbers of people nearing the end of life.5

This monograph summarizes the major dimensions of EOL care that clinicians are likely to encounter as they attempt to

care for, and comfort, patients in their final phase of life.

Palliative Care vs. Hospice CareIn the United States, a distinction is made between “palliative care” and “hospice care.”6 Both aim to relieve pain and other distressing symptoms and attempt, in a holistic manner, to improve a patient’s overall functioning and quality of life. A guiding principle of both is that dying is a normal process and that the goal of care is to neither hasten nor postpone death. This effort involves caring for the physical, psychological, emotional, cultural, and spiritual components of dying, both for the patient and their loved ones. The emphasis to avoid the over-use of technological life support systems arises from studies showing that terminally ill patients who were put on a mechanical ventilator, given electrical defibrillation or chest compressions, or admitted, near death, to intensive care had a substantially worse quality of life in their last week than those who received no such interventions.7 The use of technological life support is also associated with poorer quality of life for the close caregivers of patients who received it. In one study of the issue. In the US, the term “hospice care” is reserved for people who are not expected to live more than 6 months if a disease runs its normal course.6 “Palliative care” is a broader term and encompasses care of patients who have complicated or advanced diseases that may, or may not, be life-threatening. Palliative care may be provided at any phase of a disease process, whereas

hospice care is provided only in the terminal phase. This monograph focuses exclusively on end-of-life care and, hence, will use the terms “hospice care” and “end-of-life care” synonymously while avoiding the use of “palliative care” (even though most of the principles and practices described here apply equally to palliative care efforts).

End-of-Life Care Teams Patient circumstances dictate who provides end-of-life care, however this care will likely involve interdisciplinary care teams. These teams, while different in composition depending on the patient circumstances, have similar goals: to provide access, treat symptoms, support decision making, and adhere to patient and family goals, while engaging patients and family members in collaborative care. The National Quality Forum and the National Consensus Project for Quality Palliative Care have outlined the essential structural elements of a palliative care team:8

• An interdisciplinary team of clinical staff (physician, nurse, social worker, spiritual counselor, pharmacist, aide, volunteers). The team may also include trained facilitators for advance care planning discussions

• A staff trained, credentialed, and/or certified in palliative care

• Staffing ratios are determined by the nature and size of population to be served

• Access and responsiveness twenty-four hours per day, seven days per week

Table 1. Palliative vs. Hospice Care

Palliative Care Hospice CareLocation Frequently at health care venues, such as

hospitals or nursing homes, but also in offices and patient homes

Frequently in-home, but can be at a hospital, extended care facility, or designated hospice care venue

Timing At any point in care End-of-life, with a life expectancy of six months or less

Payment Likely covered by regular insurance, with treatment billed per episode

Varies by policy but coverage can include all costs

64

Settings for EOL CarePalliative and hospice care centers have increased substantially in numbers in the United States in recent years. The Center to Advance Palliative Care reported that in 2007 more than 1,240 hospitals had palliative care programs, while the National Hospice and Palliative Care Organization reported that there were more than 4,500 hospice programs.8 Delivery modes of palliative and hospice care include: Hospice Care: these services can be provided in the home, nursing home, residential facility, or on an inpatient unit.Institutional Palliative Care: Programs in the hospital or nursing home. This can involve a consultation team, a fixed-bed unit, or a swing-bed unit.Outpatient Palliative Care: Programs in ambulatory care settings or home.Community Palliative Care: Home-based programs employing community consultative teams.

Barriers to Good EOL CareBarriers to effective EOL care may arise from:• A failure to recognize the importance

of end-of-life care by the public or health care providers

• Delayed introduction of end-of-life care, resulting in ineffective delivery

• Exaggerated fear of adverse effects, particularly for pain management medications, by patients or providers.

• Provider discomfort with communicating bad news or poor prognosis

• Lack of provider skill in assisting patients and families to negotiate clear goals of care and treatment priorities

• Lack of provider understanding regarding patients’ rights to decline or withdraw treatment

• Personal fears, fantasies, worries, and lack of confidence among providers

Less frequently, legal and institutional barriers may arise, including restrictive legislation on symptom or pain control medications. Proactively addressing these issues may increase patient access to effective care. For example, failure to discuss the benefits and disadvantages of hospice care before it is needed may not give the patient

the time to make a considered decision when hospice care becomes a viable option. Further, implementation of established end-of-life care delivery models may help minimize many of these barriers. Employing effective patient-provider communication tools can help address many of these barriers. Finally, provider knowledge of legal and institutional regulations may also help minimize many end-of-life palliative care barriers.

Essential ComponentsThe National Consensus Project and National Quality Forum designates eight essential components of palliative care:8

1. Structure and processes of care2. Physical aspects of care3. Psychosocial and psychiatric aspects

of care4. Social aspects of care5. Spiritual, religious, and existential

aspects of care6. Cultural aspects of care7. Care of the imminently dying patient8. Ethical and legal aspects of care The physical, psychological, social, and spiritual components address all aspects of patient and family suffering, which extends beyond just managing physical pain. The remaining components focus on efficient, effective, appropriate, and sensitive delivery of care. These components are the foundation for the goals of end-of-life care, which include: • Respecting the goals, desires, and

choices of the patient and his or her loved ones

• Addressing the physical, emotional, social, and spiritual needs of the patient

• Supporting the needs of the patient’s family members

• Providing access to needed health care providers and appropriate care settings

Clinician Communication SkillsEffective patient-provider communication is achieved in part through active listening, facilitation, and empathetic comments.9 These skills lead to an engaged, dynamic relationship between patients, their families, and health care providers. This partnership

should be grounded in mutuality, which includes the sharing of information, creation of consensus, and shared decision making.10

Reflective listening An effective communication strategy in any patient-physician relationship is reflective listening. This means listening carefully and non-judgmentally to what your patient is saying, then reflecting it back in a slightly modified or re-framed manner.11 This lets the clinician confirm the accuracy of their understanding of the patient and gives the patient both the indication that they are being heard (an all-too-rare experience for many patients with chronic illness) and a chance to correct mistaken beliefs or perceptions that could affect their care. Using a reflective listening strategy can take practice. If a patient says something at odds with the evidence, for example, or uses threatening or hostile language, one’s natural reaction is to immediately defend oneself, rebut the charges, or deny the underlying assumptions. This can quickly create confrontation or a power-struggle that can be difficult to reverse. In these situations it’s important to pause before speaking, and then to consciously try to simply re-state what the patient just said. For example, a patient may say, “Doctor, those pills you gave me don’t work—I told you before that I need something stronger.” A directly confrontational response will probably be ineffective. A better response would be something like “You seem to be irritated with me because you don’t think the medications I prescribed are working for you.” In summary, reflective listening techniques provide several advantages:11 • They are less likely to evoke or

exacerbate patient defensiveness• They encourage the patient to keep

talking and reveal more about their true feelings

• They communicate respect and caring, and encourage a therapeutic alliance

• They open an opportunity for the patient to clarify exactly what he or she means

65

Delivering Bad NewsRelating bad news to patients is an unavoidable component of providing care. However, determining that life-sustaining treatment options have failed and communicating this to the patient and his or her family is difficult. Remember that awareness of imminent death is a one of the features of a “good death” in Western culture. Delivering the news of imminent death allows providers and patients to reset care goals and focus on maximizing quality of life. Providers can follow a few general rules for breaking bad news to their patients:12 Create an appropriate environment

• Comfortable, quiet room with seating for all

• Determine who should attend (i.e., patient, family, health care team)

• Turn off mobile devices and check personal appearance

• Review medical record and talk with consultants

Conduct of the meeting• Open the meeting

• Greeting and introductions• Attend to patient’s comfort• Determine what patient and family

know• Summarize the patient’s illness

• Discuss bad news• Speak slowly, deliberately, and clearly• Provide information in small chunks;

check patient’s understanding• Use nontechnical language• Allow the patient and family to talk

early and often; provide information at their pace

• Acknowledge, validate, and reflect emotion

• Communicate compassion, kindness, and caring

• Develop a follow-up plan• Negotiate plan for follow-up meeting• Refer patient and family to social

support (i.e., chaplain, support group)

• Summarize plan and expectations for follow-up team

• Document the conference• Who attended, what was discussed,

and what is the plan• Engage in self-reflection• Recognize and acknowledge your

own feelings• Accept your emotions• Share thoughts and feelings with a

colleague or in a journal

Case Study Exercise 1Spend 5 minutes reviewing the case below and considering the questions that follow.

Janet is an 83-year-old woman with amyotrophic lateral sclerosis (ALS). Her speech has become very slurred, she is having difficulty chewing and swallowing, and has lost 40 pounds over the course of the past 18 months. She has never liked what she calls the “medical establishment,” takes no prescription drugs, and prefers natural and alternative methods of dealing with health issues. Her neurologist and her three grown children are all concerned about her weight loss and growing frailty and have suggested she have a percutaneous endoscopic gastrostomy (PEG) tube placed so she can get more adequate nutrition and hydration. Janet, however, is not cooperating. She has delayed making a decision and appears unwilling to discuss the matter with anybody. She is now sitting in your office, with one of her sons present, and has just replied angrily to your statement that further delays in getting a feeding tube will hasten her death. “What if I don’t see the point in continuing to live, doctor?” she says, struggling to enunciate the words. “Has it crossed your mind that I might not enjoy living under these horrible conditions?”

Question 1: What would be a possible response to Janet’s outburst that would employ the technique of reflective listening?

_______________________________

_______________________________

_______________________________Question 2: How could you work with Janet to establish a set of care goals that would be appropriate for either course of action (i.e., having, or not having, the PEG placed)?

_______________________________

_______________________________

_______________________________Question 3: If Janet refuses the PEG, what steps could you take to make her final weeks more comfortable?

_______________________________

_______________________________

_______________________________

Talking with Family MembersAlthough the needs of a patient must necessarily be a clinician’s priority, the needs and concerns of family members must also be addressed.13 Family members or loved ones often need counseling, education, and other support because they are often centrally involved in caring for the patient. But the death of a loved one is consequential at the least and, more often, is overtly traumatic. Family members often remember vividly the last days of their loved one’s life, especially whether or not the loved one appeared to be comfortable.14 These perceptions may profoundly influence not only their own emotional state and the course of their grieving process, but also how they approach their own death.15 In addition, grief can exert well-documented impacts on physical and mental health, raising the risk for depression, sleep disorders, increased use of alcohol and other drugs, and suicide.16 The following are some suggested strategies for communicating with bereaved loved ones or family members.1,15

• Use the name of the deceased when talking to the bereaved

• Talk about the deceased, and, if appropriate, say it was a honor to know him or her and that you will miss him or her

• Ask the bereaved if they have any questions about the final illness or treatment at the end of life

• Ask how the bereaved is feeling since the death of the deceased, or how the deceased’s death is affecting them

• Say “I can’t imagine what you’re going through” (even if you have experienced the death of a loved one yourself)

• Say, “I wish things were different.” • Don’t ask, “What do you want when

you are dying?” Ask, “If time becomes short, what is most important to you? What are your worries?

66

“It’s the meaning behind the information that people are looking for more than the facts. The best way to convey meaning is to tell people what the information means to you yourself. And there are three words to do that: “I am worried.” They were such simple words, but it wasn’t hard to sense how much they communicated. I had given her the facts. But by including the fact that I was worried, I’d not only told her about the seriousness of the situation, I’d told her that I was on her side—I was pulling for her. The words also told her that, although I feared something serious, there remained uncertainties—possibilities for hope within the parameters nature had imposed.”--Atul Gawande, MD

Culturally Sensitive Communication Communicating effectively with both patients and their loved ones requires an awareness of some of the cultural differences that can create unexpected barriers or misunderstandings. End-of-life discussions are particularly challenging because of their emotional and interpersonal intensity. Many physicians are unfamiliar with common cultural variations regarding physician-patient communication, medical decision making, and attitudes about formal documents such as code status guidelines and advance directives.17

Although cultural differences certainly exist, generalizations about specific cultures are not always applicable to specific patients because there is wide variation in the ways that individuals adhere or adopt the stereotypical beliefs, values, or attitudes of a particular culture. In fact, research suggests that when compared with whites of European descent, ethnic minorities exhibit greater variability in their cultural beliefs and preferences.18 Clinicians should be aware that different cultures may place different emphasis—or disagree completely—with principles of medical conduct that they take for granted. For example, in the United States, legal documents such as advance directives and durable powers of attorney are strategies to prolong autonomy in situations in which patients can no longer represent themselves. Other cultures, however, de-emphasize autonomy, perceiving it as isolating rather than empowering. These non-Western cultures believe that communities and families, not individuals alone, are affected by life-threatening illnesses and the accompanying medical decisions.19 Cultures valuing non-malfeasance (doing no harm) may try to protect patients from the emotional and physical harm caused by directly addressing death and end-of-

life care. Many Asian and Native American cultures value beneficence (physicians’ obligation to promote patient welfare) by encouraging patient hope, even in the face of terminal illness. Patient or family member preferences for nondisclosure of medical information and family-centered decision making may also be surprising to American-trained physicians. Physicians may improve their rapport with ethnically diverse patients simply by showing interest in their cultural heritage (Table 2).

Table 2. Questions Related to Cultural Differences in End-of-Life Care

“Some people want to know everything about their medical condition, and others do not. What is your preference?”“Do you prefer to make medical decisions about future tests or treatments for yourself, or would you prefer that someone else make them for you?”To patients who request that the physician discuss their condition with family members: “Would you be more comfortable if I spoke with your (brother, son, daughter) alone, or would you like to be present?” If the patient chooses not to be present: “If you change your mind at any point and would like more information, please let me know. I will answer any questions you haveWhen discussing medical issues with family members, particularly through a translator, it is often helpful to confirm their understanding: “I want to be sure that I am explaining your mother’s treatment options accurately. Could you explain to me your understanding about your mother’s condition and the treatment that we are recommending?”

“Is there anything that would be helpful for me to know about your family or religious views about serious illness and treatment?”“Sometimes people are uncomfortable discussing these issues with a doctor who is of a different race or cultural background. Are you comfortable with me treating you? Will you please let me know if there is anything about your background that would be helpful for me to know in working with you or your (mother, father, sister, brother)?”Source: Searight HR, Gafford J. Cultural Diversity at the End of Life: Issues and Guidelines for Family Physicians. Am Fam Physician. 2005;71(3):515-22.

By using patient-centered questions, and by including interpreters as necessary, physicians can develop a richer understanding of patients’ health care preferences and be in a better position to provide effective, culturally sensitive end-of-life care.

Patient-Centered Treatment GoalsDefining clear patient-centered goals of care is a first step to developing an optimal care strategy at the end of life. These goals should be guided by four core ethical values that apply broadly, but are particularly important at the end of life:20

1. Autonomy of the patient2. Beneficence (the physician’s obligation

to promote patient welfare)3. Justice 4. Non-malfeasance (avoiding harm) These four values are embodied in the question at the core of any consideration of an end-of-life intervention: do the expected benefits outweigh the expected burdens from the patient’s perspective?21 This question applies as much to minor interventions such as phlebotomy as to more complex interventions such as chemotherapy or surgery.

67

Answering this question, of course, requires a clinician to understand what a particular patient would consider a “benefit” or a “burden” and what the patient’s goals are. The question also can seldom be answered with absolute certainty since the outcomes, particularly of complex interventions, are inherently difficult to predict. In developing plans of care, therefore, clinicians must engage with the patient (or designated surrogate) to carefully consider the patient’s values, beliefs, and priorities.

Table 3: Possible Patient-Centered Goals of Care

Longer life

Symptom relief

Time at home

Ability to travel

Mental clarity

Physical mobility

Ability to interact with loved ones

Minimizing burdens on loves ones

Personal/Spiritual growth

“Dignity” (though meanings will vary)Source: Forrow L, Smith HS. Pain Management in End of Life: Palliative Care. In Principles & Practice of Pain Medicine, 2nd Ed. Warfield CA and Bajwa ZH Eds. 2004. McGraw-Hill, New York, NY.

A 7-step process designed to help both patients and providers discuss patient goals has been developed by Marvin Stone, MD of Baylor Medical School:22

1. Create the right setting. Find out where patients and their families would prefer to discuss care options.

2. Determine what the patient and family know. Do not make assumptions about the patient’s or family’s understanding of the disease.

3. Explore what they are expecting or

hoping for. This includes both general and specific expectations.

4. Suggest realistic goals. Show empathy and use patient-friendly language.

5. Respond empathetically. Always try and cultivate empathy.

6. Make a plan and follow through. This is a key component to ensure that the patient’s goals are met.

7. Review and revise periodically, as appropriate. These goals may evolve with the patients, so it is important for providers to repeatedly discuss the patient’s goals these during the course of care.

Not all patients will have similar decision making processes or styles. Patients may be passive, avoidant, panicked, or rational. They may delay decisions or defer to providers. Very ill patients may prefer that decisions be made by others. Further, many decisions at the end-of-life may be technical and complicated, and patients may not understand the details of a process or be capable of adequately assessing the consequences of their decisions under these circumstances. Thus, it is imperative that the provider fully explain the consequences and potential outcomes for specific decisions, helping the patient and his or her family choose care options that best conform to their goals and desires. Many of the goal-defining processes are similar when interacting with either family or patients. There remains an emphasis on building trust and presenting decision options in a clear and accurate format.

Pain ManagementAlthough pain relief is often considered—and may sometimes be—an end unto itself,

it is particularly important for clinicians to recognize that, at the end of life, pain management and control of symptoms may be more appropriately viewed as means of achieving the more primary goal of improving or maintaining a patient’s overall quality of life. The meaning of “quality of life” varies, not just from patient to patient, but even between the phases of an illness experienced by a single patient. A focus on quality of life is important because sometimes a patient may have priorities that compete with, or supersede, the relief of pain. For example, the end of life can be an extremely important and meaningful time.23 For some patients, mental alertness sufficient to allow maximal interactions with loved ones may be more important than physical comfort. Optimal pain management, in such cases, may mean lower doses of an analgesic and the experience, by the patient, of higher levels of pain. The point is that, at the end of life, decisions about pain relief must be more than usually balanced with a mindful consideration of the patient’s own values and desires. The types of pain syndromes arising at the end of life include most of the acute and chronic pain syndromes clinicians confront in other patients, and many of the same diagnostic and therapeutic strategies and skills are the same or similar. But pain management at the end of life does raise some unique clinical and ethical issues and, hence, these issues are appropriate for a focused consideration. In addition, the prospect of severe, unrelieved pain at the end of life ranks very high among patient fears. Indeed, as shown in Figure 1, many people consider the experience of severe pain to be worse than death, which underscores the importance of a thorough clinical understanding this issue.24

Figure 1: Percent of sampled adults who rated the hypothetical state of severe pain as worse than death.

68

Managing pain and other symptoms at the end of life is just one component of a wider effort to relieve suffering and help a patient cope with the emotional and psychological aspects of dying. Nonetheless, a failure to manage pain and other symptoms may make it impossible for the patient to attend to these important dimensions. Uncontrolled pain can push all other priorities aside and sap a person’s energy and motivation to focus on potentially positive goals or meaningful experiences. A patient’s perception that his or her pain cannot be controlled may also contribute to a broader feeling that he or she has lost control over their lives in general, which can precipitate a downward spiral of depression and/or hopelessness. Effective pain control, on the other hand, not only directly reduces suffering but may allow a patient the energy and positive attitude needed to engage with the emotional and psychological aspects of dying.

Assessing Pain at the End of LifeThe end of life is often characterized by a reduced level of consciousness or complete lack of consciousness. This can make assessments of pain very challenging. If a patient is not alert enough to communicate, then nonverbal signs or cues must be used to determine if the patient is experiencing pain and to what degree an analgesic approach is effective. In general, even ambiguous signs of discomfort should usually be treated, although caution must be exercised in interpreting such signs.21 Patients who are actively dying may groan or grunt in ways that suggest they are in pain, although such sounds may, in fact, be the normal expressions attendant to the last moments or hours of life. Signs of discomfort that are accompanied by more rapid breathing or heart rate should be taken more seriously. Likewise, if physical stimulation of the patient (i.e., during bathing) causes signs of discomfort, increased analgesia may be warranted. Prolonged rapid breathing (> 20/min.) may be uncomfortable because of muscle fatigue and it may therefore be reasonable, even in the absence of other evidence of discomfort, to titrate a pain medication with a target respiratory rate of 15 to 20/minute.21

Opioids Opioid formulations are available in such variety in the US that, typically, a pain regimen can be tailored to each patient.25 Because there is great variability in how individual patients respond to particular opioid agents, no specific agent is superior to another as first-line therapy. Although morphine was previously considered the ‘‘gold standard,’’ it is now recognized that the most appropriate agent is the opioid that works for an individual patient.26 Morphine and other opioids are available in a wide range of formulations and routes of administration, including oral, transmucosal, transdermal, parenteral, and rectal delivery. Both rectal and transdermal routes can be especially valuable at the end of life when the oral route is precluded because of reduced or absent consciousness, difficulty swallowing, or to reduce the chances of nausea and vomiting.27 When selecting an opioid, clinicians should also consider cost, since expensive agents can place undue burden on patients and families. Some opioids may not be appropriate in the end-of-life setting. For example, meperidine is not recommended in cancer pain management due to the neurotoxic effects of its metabolites.28 In addition, mixed agonist-antagonist opioid analgesics, including butorphanol, nalbuphine, and pentazocine, are not recommended in cancer pain management because they are more likely to cause psychotomimetic effects and they can precipitate the abstinence syndrome if given to a patient who is physically dependent on a pure opioid agonist.28

Opioid-related side effects must be considered in advance of treatment and steps must be taken to minimize these effects to the extent possible, since adverse effects contribute significantly to analgesic nonadherence. This is particularly true for constipation and sedation. Tolerance rarely develops to constipation and therefore it must be prevented and, if unsuccessful, treated aggressively. A prophylactic bowel regimen that includes a laxative and stool softener, such as senna and docusate, should be used, although a recent study suggested that senna alone was just as effective.29 Bulking agents, such as

psyllium, are ineffective and may exacerbate gastrointestinal distress unless the patient can drink significant amounts of fluids. Methylnaltrexone, an opioid antagonist that works on receptors in the GI system and is given subcutaneously, can be used as a rescue when constipation is clearly related to opioid therapy.30

Sedation is often attributed to opioid therapy given at the end of life, although many other drugs used at this time may be sedating, including benzodiazepines, antiemetics, and other agents. Tolerance to opioid-induced sedation may develop within a few days of regular use; however, in some cases this may persist and opioid rotation may be warranted. A psychostimulant, such as methylphenidate or dextroamphetamine, might be added to offset sedative effects, typically starting at a dose of 5 to 10 mg once or twice daily. One study found that with proper timing, the administration of methylphenidate did not disrupt sleep.31

Nausea and vomiting are relatively common in opioid-naive individuals. Around-the-clock antiemetic therapy instituted at the beginning of opioid therapy may prevent this adverse effect.26 The antiemetic can be weaned in most cases after 2 to 3 days. The itching that can occur early in the course of opioid treatment may be at least partially alleviated with antihistamines. Opioid rotation to a more synthetic agent or an agent with a different route of administration, such as oxymorphone or transdermal fentanyl has also been reported to be helpful. The potential adverse effect of respiratory depression may lead to clinician under-prescribing of opioids or the reluctance by patients to take the medication.26 Despite this fear, studies have revealed no correlation between opioid dose, timing of opioid administration, and time of death.32,33

69

Case Study Exercise 2Spend 5 minutes reviewing the case below and considering the questions that follow.

Samuel is a 94-year-old man in the late stages of metastatic prostate cancer. The cancer was initially treated 16 years earlier with a radical prostatectomy and adjuvant radiation therapy, but it has recurred with infiltration to his pelvic bones. He has been under home hospice care for the past month. His pain is being treated with transdermal fentanyl which has reduced the nausea he was experiencing with oral ER/LA oxycodone. Now, however, he says he often feels “fuzzy” and “out of it” to the point that he can’t remember conversations he has had with his wife or daughter. On a visit by the hospice nurse, Ralph complains about this, saying “I want to be able to say goodbye to people, and thank them, but I just feel like a goddamned zombie half the time.”

Question 1: How might Ralph’s competing desires for pain relief and mental clarity be addressed?

_______________________________

_______________________________

_______________________________Question 2: Are there any alternative pharmacological or non-pharmacological analgesic options that might be appropriate for Ralph?

_______________________________

_______________________________

_______________________________Question 3: What other types of health care professionals might be called on to help Ralph achieve the kinds of end-of-life communication he desires?

_______________________________

_______________________________

_______________________________

Non-steroidal Anti-inflammatory (NSAID) Analgesics and AcetaminophenNSAIDs or acetaminophen may be useful in the treatment of pain conditions mediated by inflammation, including those caused by cancer, such as bone metastases.26 NSAIDs typically cause less nausea than opioids, though this is most true with low doses. NSAIDS also do not cause constipation, sedation, or adverse effects on mental functioning. NSAIDs may, therefore, be useful for the control of moderate to severe pain, usually as an adjunct to opioid analgesic therapy.34 The addition of an NSAIDs to an opioid may allow a reduction in the opioid dose, although such combinations must be used with care. Typically, the non-opioid co-analgesic agent, such as acetaminophen or an NSAID, has a ceiling dose above which efficacy will plateau as risk for adverse effects increases. Thus, combining these products, either as separately-administered agents or in combination products, are typically used for patients who are not expected to need substantial dose escalations.11 Using a combination product when dose escalation is required risks increasing adverse effects from the non-opioid co-analgesic, even if an increase of the opioid dose is appropriate. In such cases, using a pure opioid may be preferable. (Single-agent formulations are available for many types of opioids, such as morphine, oxycodone, and hydromorphone.) The FDA has limited to 325 mg the amount of acetaminophen allowed in prescription opioid combination products in an attempt to limit liver damage and other ill effects primarily due to excessive doses of combined products.35

Contraindications for NSAIDs include decreased renal function (relatively common at the end of life) and liver failure. Platelet dysfunction or other potential bleeding disorders, common due to cancer or its treatment, are also contraindications to non-selective NSAIDS because of their inhibitory effects on platelet aggregation, with resultant prolonged bleeding time.36 Proton pump inhibitors or misoprostol may be considered to prevent GI bleeding.37

Attention has recently been focused on the potential limited efficacy of

acetaminophen in older patients. Although it has been considered a viable co-analgesic with opioids, and to be first-line therapy in elderly patients with musculoskeletal pains or pain associated with osteoarthritis, the relative limited efficacy and significant adverse effects of this agent, particularly hepatic and renal toxicity, have raised concerns.38 Additionally, acetaminophen must be used cautiously in those receiving cancer chemotherapy because there are case reports of interactions between anticancer agents and acetaminophen leading to hepatic toxicity.39 Reduced doses of 2000 mg/day or the avoidance of acetaminophen is recommended in the face of renal insufficiency or liver failure, and particularly in individuals with a history of significant alcohol use.40

Adjuvant AnalgesicsAlthough opioid medications are a mainstay of pain management at the end-of-life, many other classes of medications have proven effective and, in some cases, preferable to opioids. Some exert a direct analgesic effect mediated by non-opioid receptors centrally or peripherally. Other adjuvant “analgesics” have no direct analgesic qualities but may provide pain relief indirectly by affecting organs or body systems involved in painful sensations. Some antidepressant agents appear to exert analgesic properties and may be particularly helpful for neuropathic pain conditions. Tricyclic antidepressants inhibit reuptake of norepinephrine and serotonin, which appears to exert analgesic effects, either directly or indirectly. These agents have been shown to provide clinically relevant effects in a review of analgesic studies conducted in neuropathic pain conditions, primarily diabetic neuropathy and other non-cancer conditions.41 One consensus panel listed this pharmacologic category as one of several first-line therapies for neuropathic pain.42 Potential side effects include cardiac arrhythmias, conduction abnormalities, narrow-angle glaucoma, and clinically significant prostatic hyperplasia. On the other hand, the sleep-enhancing and mood-elevating effects of these antidepressants may benefit some patients.

70

Table 4. Adjuvant Analgesics for End-of-Life Pain Management

Drug Class Agent Route of Administration

Potential adverse effects Indications

Antidepressants Nortriptyline Oral Anticholinergic effects Neuropathic pain

Desipramine Oral Cardiac arrhythmia

Venlafaxine Oral Nausea, dizziness

Duloxetine Oral Nausea

Anti-epilepsy drugs Gabapentin Oral Dizziness Neuropathic pain

Pregabalin Oral Dizziness

Clonazepam Oral Sedation

Corticosteroids Dexamethasone Oral/IV/Sq “Steroid psychosis” Neuropathic pain, cerebral edema, spinal cord compression, bone pain, visceral pain

Lidocaine Lidocaine patch Topical Erythema (rare) Neuropathic pain

Lidocaine infusion IV/sq Perioral numbness, cardiac changes Intractable neuropathic pain

NMDA antagonists Ketamine Oral/iv Hallucinations Unrelieved neuropathic pain; need to reduce opioid dose

Bisphosphonates Pamidronate IV Pain flare, osteonecrosis Osteolytic bone pain

Zoledronic acid IV

Cannabinoids THC (Marinol®) Oral Dizziness, nausea, tachycardia, euphoria

Nausea, loss of appetite, spasticity, neuropathic pain‡Nabilone (Cesamet®) Oral

THC and CBD (cannabidiol) (Sativex®)§

Oromucosal spray

§ Currently available in: United Kingdom, Canada, Spain, Germany, Denmark, and New Zealand

‡ As evidenced in some clinical trials; not an FDA-approved indication

Sources: Paice JA, Ferrell B. CA Cancer J Clin. 2011;61-157-182.; Marinol Full Prescribing Information

Although little evidence supports an analgesic effect for SSRIs, some newer antidepressants, such as the serotonin-norepinephrine reuptake inhibitors have been shown to be effective in relieving neuropathic pain, including venlafaxine and duloxetine.43 These have the added advantage of alleviating hot flashes, a common and disturbing symptom, particularly in breast cancer patients undergoing hormonal therapy. Care must be taken in such situation, however, because duloxetine reduces the bioavailability of tamoxifen, potentially reducing its therapeutic efficacy.44 The anti-epilepsy drugs gabapentin and pregabalin have undergone extensive testing in many non-cancer neuropathy syndromes, and a recent review concluded that these drugs have a clinically meaningful effect.41 The most common adverse effects reported by patients are dizziness; some patients also develop fluid retention. Although the data for the efficacy of other anticonvulsants are not as conclusive as those for gabapentin

and pregabalin, existing reports suggest potential efficacy. As with most adjuvant analgesics, antiepileptic agents are commonly used in combination with opioid therapy, particularly when pain is moderate to severe. A review of cancer trials found that adjuvant analgesics added to opioids provide additional relief, usually within 4 to 8 days, with the strongest evidence for gabapentin.45 Corticosteroids can play a valuable role in treating end-of-life pain related to neuropathic pain syndromes, pain associated with stretching of the liver capsule due to metastases, for treating bone pain (due to their anti-inflammatory effects) as well as for relieving malignant intestinal obstruction.46 Dexamethasone produces the least amount of mineralocorticoid effect and is available in a variety of delivery forms, including oral, intravenous, subcutaneous, and epidural.26 Local anesthetics may be useful in preventing procedural pain and in relieving neuropathic pain. Local anesthetics can be given topically, intravenously,

subcutaneously, or spinally. Both gel and patch versions of lidocaine have been shown to reduce the pain of postherpetic neuralgia and cancer-related neuropathic pain.47 Intravenous or subcutaneous lidocaine at 1 to 5 mg/kg administered over 1 hour, followed by a continuous infusion of 1 to 2 mg/kg/hour, has been reported to reduce intractable neuropathic pain in patients in inpatient palliative care and home hospice settings.48 NMDA antagonists (dextromethorphan, amantadine, and ketamine) are believed to exert their analgesic effects by blocking receptors for glutamate and other excitatory amino acids at the level of the spinal cord. Ketamine is the most commonly-used agent, and can be administered intravenously, intramuscularly, subcutaneously, intranasally, sublingually, rectally, and topically. A general recommendation is to reduce the opioid dose by approximately 25% to 50% when starting ketamine to avoid sedation.26

71

Psychotomimetic reactions consisting of hallucinations, vivid imagery delirium, confusion, and irrational behavior have been reported to occur in approximately 12% of individuals receiving the drug systemically.27 Adverse effects, including hallucinations and unpleasant cognitive sensations, responded to diazepam at a dose of 1 mg intravenously.27 In recent years there has been a resurgence of interest in the use of cannabinoids for the relief of pain and the end of life. Like opioids, cannabinoids produce their pharmacological effects via actions at specific receptors in the body that are designed for endogenously produced compounds with normal regulatory, homeostatic properties.49 Unlike opioids, however, there has never been a documented case of death from cannabis overdose—indeed, cannabis has no known lethal dose.50

The CB1 and CB2 receptors have been shown to mediate the analgesic effects of cannabinoids.51 This has allowed for the development of more selective agents that may provide analgesia while minimizing cognitive or perceptual side effects. Two oral cannabinoid preparations are FDA-approved and available in the US (dronabinol and nabilone), and an oromucosal preparation is available in Canada (sativex) and several European countries. These routes of administration avoid the potential hazards and dosing uncertainties involved with inhaled or edible forms of cannabis. A review of the existing literature evaluating the role of cannabinoids currently approved for human use suggests that these agents are moderately effective for neuropathic pain with adverse effects that are less than or comparable to existing analgesics.52 Cannabinoids have been shown to exert no appreciable effects on opioid plasma levels and may even augment the efficacy of oxycodone and morphine in patients suffering from a variety of chronic pain conditions, potentially allowing a reduction in the opioid doses used in such patients.53 The authors of a review of the role of cannabinoids in hospice and palliative care concluded: “Many patients in a palliative care setting who are currently on long-term opioids for chronic pain could potentially be treated with either cannabis

alone or in combination with a lower dose of opioids. From a pharmacological perspective, cannabinoids are considerably safer than opioids and have broad applicability in palliative care.”49

Managing Pain in Intensive Care UnitsSeveral studies show that most US adults wish to die at home.54 And yet more than half of deaths occur in hospitals, most with ICU care.55 When curative approaches are not expected to be successful, a transition to primary comfort-focused care and the withdrawal of ineffective or burdensome therapies is often necessary. Although guidelines and detailed strategies have been developed for analgesic therapy during the removal of life-sustaining interventions, communication about what to expect and how things may proceed remain paramount to negotiating this care transition.56 Some patients and families may be able to have meaningful interactions at the end of life, and thus brief interruption of sedatives and analgesics may be reasonable. Rarely are dying ICU patients able to self-report information about their pain.56 Thus it is incumbent on the critical care health professionals, perhaps with the assistance of the patient’s family members, to assess pain without self-report input from the patient. Two pain assessment

instruments have been validated for use in the ICU setting: the Behavioral Pain Scale57

and the Critical-Care Pain Observation Tool.58 Both tools describe specific observations that the patient’s ICU care providers (including family members or loved ones)

can make that, when present, could indicate the patient is experiencing pain such as grimacing, rigidity, wincing, shutting of eyes, clenching of fists, verbalization, and moaning.59

Reports by family members or other people close to a patient should not be overlooked. In the Study to Understand Prognosis and Preference for Outcomes and Risks of Treatment (SUPPORT) study, surrogates for patients who could not communicate verbally had a 73.5% accuracy rate in estimating presence or absence of the patient’s pain.60

Complementary and Alternative TherapiesA wide range of complementary and alternative therapies (CAT) are commonly used in end-of-life care (Figure 2).61 More than half of providers that offered CAT offered massage, supportive group therapy, music and pet therapy, and guided imagery and relaxation.62

Figure 2. Percentage of patients reporting using specific CAM therapies during study period

Source: Corbin L. The use of complementary and alternative medicine therapies by patients with advanced cancer and pain in a hospice setting: a multi-centered, descriptive study. J Palliat Med. 12(1):7–8. 2009.

72

CAT interventions are aimed at reducing pain, inducing relaxation, and enhancing a sense of control over the pain or the underlying disease. Breathing exercises, relaxation, imagery, hypnosis, and other behavioral therapies are among the modalities shown to be potentially helpful to patients.26 Physical modalities such as massage, use of heat or cold, acupuncture, acupressure, and other physical methods may be provided in consultation with physical or occupational therapy. These treatments can enhance patients’ sense of control as well as greatly reduce the family caregivers’ sense of helplessness when they are engaged in pain relief. A 2008 study found that both massage and “simple touch” induced statistically significant improvements in pain, quality of life, and physical and emotional symptom distress over time without increasing analgesic medication use.63

Psychosocial interventions for end-of-life pain may include cancer pain education, hypnosis and imagery based methods, and coping skills training.64 Educational programs are one of the most common interventions to address cancer pain barriers, and current studies provide high-quality evidence that pain education is feasible, cost-effective, and practical in end-of-life settings.64 Coping skills training may be beneficial for patients and family caregivers dealing with chronic cancer pain, although the dose and components of a coping skills training regimen remain uncertain. Other integrative and behavioral approaches found to be helpful for managing end-of-life pain are massage therapy and acupuncture.65

Managing Mood or Emotional Disorders at EOLAs with the assessment of pain and other physical symptoms at the end of life, guidelines recommend that psychological status be assessed and managed based upon the best available evidence.8 Several common screening questions may be useful for determining the patient’s psychological status. Providers should ask patients if they are confused or have hallucinations. Providers should assess patient mood, including sadness and anxiety. Particular

attention should be paid to the patient’s coping strategies. Patients should be asked whether they have had recent episodes of depression, anxiety, or substance abuse. Providers should follow up with questions about what treatments have been helpful. Stressors, such as financial considerations and types of physical and emotional pain, should be identified. Common psychiatric disorders in dying patients include depression, anxiety, and delirium. Depression is both under-diagnosed and undertreated in this population. Because end-of-life patients may have neurovegatative symptoms, such as decreased appetite, sleep disturbance, and fatigue resulting from their underlying disease or its treatment, it may be difficult to use these symptoms to diagnose depression. Instead, emotional symptoms such as hopelessness, helplessness, worthlessness, despondence, and suicidal ideation may be better indicators of depression in this population. However, differentiating depression from grief can be a major clinical challenge in end-of-life palliative care. Directly asking patients about depressed mood can be useful for the diagnosis of depression, although some patients may not wish to verbalize their depression. Providers can also use social withdrawal, irritability, insomnia, and anxiety as indicators of depression. It is important to note that some medications that may be used in the end-of-life setting, such as interferon, corticosteroids, cycloserine, and tamoxifen, may be associated with the development of depression. Prophylactic use of antidepressants may be warranted for some patients. As many antidepressant medications are well tolerated, providers should employ a low threshold for treatment initiation. Not surprisingly, anxiety is frequent among dying patients. Providers should attempt to determine if patient anxiety was preexisting or whether it developed as a consequence of patient circumstances. Ongoing exploration of fears and support are major components of anxiety treatment. Withdrawal of opioids or other medications can lead to anxiety. Patients with elevated anxiety may be prescribed anxiolytic mediations, such as benzodiazepines, and

engage in behavioral treatments, such as meditation. Patients with mild or moderate anxiety may be managed with supportive psychotherapeutic interventions.

Nutrition and Hydration at the End of LifeThe provision of nutrition and hydration can become a clinical challenge at the end of life and can be directly related to the use of analgesics, particularly in decisions about the preferred route of analgesic administration. As with decisions about analgesia itself, the fundamental question regarding various alternatives for nutrition or hydration is whether the potential benefits outweigh the burdens from the patient’s perspective. The patient’s own expression of interest should be the primary guide. If a dying patient shows interest in either food or fluids, they should never be withheld unless providing them clearly causes greater suffering (i.e., in patients for whom oral feeding causes significant discomfort).21 In most cases, patients either do not show an active interest in food or are satisfied with very small amounts of specific foods (such as sweet custards or ice cream) which are well-tolerated. The forced administration of nutrients, either parenterally or through a nasogastric or gastrostomy tube, has little or no benefit to most patients in the last days or weeks of life, and the placement or continuation of an intravenous line or enteral feeding tube can be burdensome. Enteral feeding tubes used during the terminal phase of illness are often more useful as a means of administering medications than nutrients. Concerns about adequate hydration are frequently misplaced. Relative dehydration can be beneficial during the terminal phase for the following reasons:21

• By decreasing urine output urinary incontinence or difficulties of using a bedpan or commode are reduced

• Reduced gastrointestinal secretions may reduce nausea and vomiting

• Pain may be improved by a reduction in tumor edema

• Reduction in oropharyngeal and pulmonary secretions may lead to reduced airway congestion and diminished pooling of secretions the patient cannot clear on his or her own

73

Delirium/confusionDelirium is an acute, reversible, mental disorder characterized by a reduced ability to maintain attention to external stimuli, disorganized thinking, and an altered level of consciousness. Delirium is a major cause of morbidity in patients with cancer or with advanced heart, renal, hepatic, or pulmonary disease.66 Physicians who are not psychiatrists are rarely trained to recognize the early stages of delirium, especially hypoactive delirium, which may be mistaken for depression. Reorientation, providing eyeglasses and hearing aids, and maintaining or reestablishing a normal wake-sleep cycle have helped prevent delirium in elderly hospitalized patients and are likely to help younger at-risk patients. If delirium occurs, discontinue the likely inciting agents (or, if opioids are suspected, change to a different opioid), and treat with standing, not “as needed,” antipsychotic agents such as haloperidol or olanzapine. Benzodiazepines may be added to the antipsychotics for very agitated patients, but they should not be used alone to control the agitation. They do not resolve the mental status changes and may have the paradoxical effect of worsening the delirium.

ConstipationMethylnaltrexone is a mu receptor antagonist that acts at the level of the gut opioid receptors and has very limited ability to cross the blood-brain barrier. Given subcutaneously, methylnaltrexone effectively and efficiently reverses opioid-induced constipation in almost 50% of patients who have constipation that has been persistently refractory to the usual bowel stimulants without reversing opioid-induced pain relief.66 Methylnaltrexone has been shown to remain effective during 12 weeks of open label studies.67 Naloxegol (movantik) is another peripheral mu opioid antagonist used for opioid induced constipation, but is more typically used in patients being treated for non-cancer pain.

NauseaChemotherapy-induced nausea and vomiting can be treated with antiemetic regimensincluding dexamethasone along with a variety

of agents that block different receptors in the fourth ventricle’s chemoreceptor trigger zone, including the 5-hydroxytryptamine-3 receptor (e.g., ondansetron, palonosetron), and the neurokinin-1 receptor (e.g., aprepitant, casoprepitant). Patients take antiemetic agents the day before chemotherapy, and up to five days after. Data suggest encapsulated ginger given in this fashion may boost the antiemetic effect (of which medicines?).68 Other agents that also block receptors in the fourth ventricle may be added; these include nabilone and marinol, which block the endocannabinoid receptors, and metoclopramide, prochlorperazine, chlorpromazine, haloperidol, and olanzapine, which block the dopamine-2 receptor.

Caring for a Person Near Death: Tips for Family Caregivers69

• Continue to talk to the person and say the things you need or want to say. Remember that the person may be able to hear, even when not able to respond

• Allow the person to sleep as much as he or she wishes

• Reposition the person if it makes him or her more comfortable

• Moisten the person’s mouth with a damp cloth

• If the person has a fever or is hot, apply a cool cloth to the forehead

• Give medications as ordered to decrease symptoms such as anxiety, restlessness, agitation or moist breathing

• Keep a light on in the room, it may be comforting

• Play the person’s favorite music softly • Encourage visitors to identify

themselves when talking to the person • Keep things calm in the environment • Open a window or use a fan in the

room if the person is having trouble breathing

• Continue to touch and stay close to your loved one

Ethical ConsiderationsA potential barrier to good pain management at the end of life is the misconception on the part of providers, family members, or both, that an escalation

of pain medications or other palliative therapies will unethically hasten or cause death. Although ethical and legal consensus upholds the appropriateness of withdrawing unwanted or unhelpful therapies to avoid the prolongation of the dying process and the administration of medications with the intent of relieving suffering, such concerns may mitigate optimal administration of therapies.20 When providers administer pain medications and other palliative therapies to a dying patient, the intent should explicitly be on relief of symptoms, and communication with the family must stress this goal, even if the possibility exists that such treatments could hasten death.56

The doctrine of double effect draws a clear distinction between the aggressive palliation of pain with the intent to relieve suffering and the active and purposeful hastening of death. The doctrine asserts that the alleviation of pain is ethically justifiable as long as the caregiver’s primary intent is alleviating suffering.21 (The doctrine of double effect holds that an act that might have a good or bad effect is ethical if the nature of the act is morally good or neutral and the intent of the act is good even if there is potential for bad effect.)21 Health-care providers should communicate this strategy with patient and families and document the rationale for any dose escalation used for the alleviation of pain. Contrary to fears among patient and their families, research suggests that aggressive pain management at the end of life does not necessarily shorten life. In fact, pain management may be life-prolonging by decreasing the systemic effects of uncontrolled pain that can compromise vital organ function.70 If a patient experiences intense pain, discomfort or other undesirable states at the end of life despite the best efforts of pain management providers, palliative sedation (also known as terminal, continuous, controlled, or deep-sleep sedation) is an option.56 Palliative sedation is the intentional sedation of a patient suffering uncontrollable refractory symptoms in the last days of life to the point of almost, or complete, unconsciousness and maintaining sedation until death—but not intentionally causing death.71

74

Although palliative sedation may bring intolerable suffering to an end and allow people to die peacefully, it nonetheless can be challenging to put into practice and has been criticized as “slow euthanasia.”72

Acknowledging the inherently complex and subjective nature of decisions about palliative sedation, guidelines have nonetheless been developed to help guide responsible use of this alternative. Many guidelines state that palliative sedation should only be considered when:73,74 • The patient is terminally ill• Death is expected within hours or days• The patient is suffering acute symptoms

unresponsive to therapy• Consent is obtained from the patient or

his/her proxy• The withdrawal of food and water is

discussed• Families are informed that the patient

will likely not regain consciousness and will die

• Causing death is not the intention even though it may not be possible to achieve adequate symptom control except at the risk of shortening the patient’s life

The degree to which palliative sedation is used, and the manner in which it is used, must, in the end, be a matter of clinical judgment on the part of individual physicians.

ConclusionsExpert pain management in the terminal phase of life requires that clinicians employ the full range of their therapeutic skills in order to holistically care for the physical, psychological, and emotional needs of their patients and their loved ones. This is a time when diagnostic skills and medical knowledge may be less important that emotional intelligence and communication skills. It may also entail a shift away from previous goals of aggressive treatment with advanced medical technology, and toward a realistic assessment of what such technology can actually provide a patient in terms of comfort, dignity, and peace of mind at the end of life. Pain management—a critical component of EOL care, may become highly dynamic. Ongoing comprehensive

pain assessment may be needed to detect changes in pain such as the development of painful bone metastasis, resolution of treatable causes such as infections, or worsened neuropathic or visceral pain due to tumor growth. Careful refinement of pain management regimens is often required at the end of life and may include changes in the route of analgesics if patients can no longer take oral medications, the need to rotate opioids, or the addition of agents such as steroids or psychostimulants. Clinicians should seek expert consultation from pain services or palliative care teams for complex cases or when pain appears to be refractory to all efforts. Early referral to hospice care may allow time for a carefully planned pain regimen to ensure comfort at the end of life. The other symptoms that can accompany the end of life, such as dyspnea, agitation, delirium, and anxiety, each need to be carefully assessed and treated with coordinated interventions. Fortunately, a wide array of analgesics, interventional strategies, adjuvant medications, varied routes of administration, and complementary and alternative therapies exist that, if used cooperatively and effectively, can greatly improve the chances that patients and their families will experience death without trauma, suffering, or unrelieved pain.

ResourcesAmerican Academy of Hospice and Palliative Medicineaahpm.org

American Cancer Societycancer.org or

American Pain Societyampainsoc.org

American Society for Pain Management Nursingaspmn.org

City of Hope Pain & Palliative Care Resource Centerprc.coh.org

Hospice and Palliative Nurses Associationhpna.org

References1. Atul Gawande. Being Mortal. New York, NY: Penquin Books; 2014.2. Centers for Disease Control and Prevention. Ten great public health achievements — United States, 1900-1999. MMWR Morb Mortal Wkly Rep. 1999;48(12):241-243.3. Lunney JR, Lynn J, Foley DJ, Lipson S, Guralnik JM. Patterns of functional decline at the end of life. JAMA. 2003;289(18):2387-2392.4. Rao JK, Abraham LA, Anderson LA. Novel approach, using end-of-life issues, for identifying items for public health surveillance. Prev Chronic Dis. 2009;6(2):A57.5. Institute of Medicine. Dying in America: Improving quality and honoring individual preferences near the end of life. Washington, DC: The National Academies Press; 2015.6. United Hospital Fund. Family Caregiver’s Guide to Hospice and Palliative Care. Next Step in Care series. 2010.7. Wright AA, Zhang B, Ray A, et al. Associations between end-of-life discussions, patient mental health, medical care near death, and caregiver bereavement adjustment. JAMA. 2008;300(14):1665-1673.8. National Consensus Project for Quality Palliative Care. Clinical Practice Guidelines for Quality Palliative Care, 2nd Edition. 2009.9. Ngo-Metzger Q, August KJ, Srinivasan M, Liao S, Meyskens FL, Jr. End-of-Life care: guidelines for patient-centered communication. Am Fam Physician. 2008;77(2):167-174.10. Quill TE. Perspectives on care at the close of life. Initiating end-of-life discussions with seriously ill patients: addressing the “elephant in the room”. JAMA. 2000;284(19):2502-2507.11. Fishman SM. Responsible Opioid Prescribing: A Clinician’s Guide, 2nd Ed. Washington, DC: Waterford Life Sciences; 2012.12. Ambuel B, Mazzone MF. Breaking bad news and discussing death. Prim Care. 2001;28(2):249-267.13. Balaban RB. A physician’s guide to talking about end-of-life care. J Gen Intern Med. 2000;15(3):195-200.14. Billings JA. The end-of-life family meeting in intensive care part I: Indications, outcomes, and family needs. J Palliat Med. 2011;14(9):1042-1050.15. Prigerson HG, Jacobs SC. Perspectives on care at the close of life. Caring for bereaved patients: “all the doctors just suddenly go”. JAMA. 2001;286(11):1369-1376.16. Stroebe MS, Hansson RO, Stroebe W, Schut H. Introduction: concepts and issues in contemporary research on bereavement. In: Stroebe MS, Hansson RO, Stroebe W, Schut H, eds. Handbook of Bereavement Research:

75

Consequences, Coping and Care. Washington DC: American Psychological Association; 2001.17. Searight HR, Gafford J. Cultural diversity at the end of life: issues and guidelines for family physicians. Am Fam Physician. 2005;71(3):515-522.18. Blackhall LJ, Murphy ST, Frank G, Michel V, Azen S. Ethnicity and attitudes toward patient autonomy. JAMA. 1995;274(10):820-825.19. Candib LM. Truth telling and advance planning at the end of life: problems with autonomy in a multicultural world. Fam Syst Health. 2002;20:213-228.20. Beauchamp TL, Childress JF. Principles of biomedical ethics, 5th Ed. Oxford, UK: Oxford University Press; 2001.21. Forrow L, Smith HS. Pain Management in End of Life: Palliative Care. In: Warfield CA, Bajawa ZH, eds. Principles & Practice of Pain Medicine, 2nd Ed. New York, NY: McGraw-Hill; 2004.22. Stone MJ. Goals of care at the end of life. Proc (Bayl Univ Med Cent). 2001;14(2):134-137.23. Byock I. Dying Well: The Prospect for Growth at the End of Life. New York, NY: Riverhead Books; 1997.24. Patrick DL, Pearlman RA, Starks HE, Cain KC, Cole WG, Uhlmann RF. Validation of preferences for life-sustaining treatment: implications for advance care planning. Ann Intern Med. 1997;127(7):509-517.25. Abrahm JL. A Physician’s Guide to Pain and Symptom Management in Cancer Patients. Baltimore, MD: Johns Hopkins University Press; 2005.26. Paice JA, Ferrell B. The management of cancer pain. CA Cancer J Clin. 2011;61(3):157-182.27. Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic effect of intravenous ketamine in cancer patients on morphine therapy: a randomized, controlled, double-blind, crossover, double-dose study. J Pain Symptom Manage. 2000;20(4):246-252.28. Kaiko RF, Foley KM, Grabinski PY, et al. Central nervous system excitatory effects of meperidine in cancer patients. Ann Neurol. 1983;13(2):180-185.29. Hawley PH, Byeon JJ. A comparison of sennosides-based bowel protocols with and without docusate in hospitalized patients with cancer. J Palliat Med. 2008;11(4):575-581.30. Portenoy RK, Thomas J, Moehl Boatwright ML, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. J Pain Symptom

Manage. 2008;35(5):458-468.31. Bruera E, Driver L, Barnes EA, et al. Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. J Clin Oncol. 2003;21(23):4439-4443.32. Morita T, Tsunoda J, Inoue S, Chihara S. Effects of high dose opioids and sedatives on survival in terminally ill cancer patients. J Pain Symptom Manage. 2001;21(4):282-289.33. Sykes N, Thorns A. The use of opioids and sedatives at the end of life. Lancet Oncol. 2003;4(5):312-318.34. McNicol E, Strassels SA, Goudas L, Lau J, Carr DB. NSAIDS or paracetamol, alone or combined with opioids, for cancer pain. Cochrane Database Syst Rev. 2005(1):CD005180.35. Harris G. FDA Plans New Limits on Prescription Painkillers. New York Times. January 13 2011.36. Rainsford KD. Anti-inflammatory drugs in the 21st century. Subcell Biochem. 2007;42:3-27.37. Schlansky B, Hwang JH. Prevention of nonsteroidal anti-inflammatory drug-induced gastropathy. J Gastroenterol. 2009;44 Suppl 19:44-52.38. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older P. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57(8):1331-1346.39. Ridruejo E, Cacchione R, Villamil AG, Marciano S, Gadano AC, Mando OG. Imatinib-induced fatal acute liver failure. World J Gastroenterol. 2007;13(48):6608-6111.40. Swarm R, Abernethy AP, Anghelescu DL, et al. Adult cancer pain. J Natl Compr Canc Netw. 2010;8(9):1046-1086.41. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150(3):573-581.42. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132(3):237-251.43. Durand JP, Goldwasser F. Dramatic recovery of paclitaxel-disabling neurosensory toxicity following treatment with venlafaxine. Anticancer Drugs. 2002;13(7):777-780.44. Goetz MP, Knox SK, Suman VJ, et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen. Breast Cancer Res Treat. 2007;101(1):113-121.45. Bennett MI. Effectiveness of antiepileptic or antidepressant drugs when added to opioids for cancer pain: systematic review. Palliat Med. 2011;25(5):553-559.46. Wooldridge JE, Anderson CM, Perry MC. Corticosteroids in advanced cancer.

Oncology (Williston Park). 2001;15(2):225-234; discussion 234-226.47. Fleming JA, O’Connor BD. Use of lidocaine patches for neuropathic pain in a comprehensive cancer centre. Pain Res Manag. 2009;14(5):381-388.48. Ferrini R, Paice JA. How to initiate and monitor infusional lidocaine for severe and/or neuropathic pain. J Support Oncol. 2004;2(1):90-94.49. Carter GT, Flanagan AM, Earleywine M, Abrams DI, Aggarwal SK, Grinspoon L. Cannabis in palliative medicine: improving care and reducing opioid-related morbidity. Am J Hosp Palliat Care. 2011;28(5):297-303.50. Aggarwal SK, Kyashna-Tocha M, Carter GT. Dosing medical marijuana: rational guidelines on trial in Washington State. MedGenMed. 2007;9(3):52.51. Rahn EJ, Zvonok AM, Thakur GA, Khanolkar AD, Makriyannis A, Hohmann AG. Selective activation of cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic agent paclitaxel in rats. J Pharmacol Exp Ther. 2008;327(2):584-591.52. Ashton JC, Milligan ED. Cannabinoids for the treatment of neuropathic pain: clinical evidence. Curr Opin Investig Drugs. 2008;9(1):65-75.53. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011;90(6):844-851.54. Weitzen S, Teno JM, Fennell M, Mor V. Factors associated with site of death: a national study of where people die. Med Care. 2003;41(2):323-335.55. Angus DC, Barnato AE, Linde-Zwirble WT, et al. Use of intensive care at the end of life in the United States: an epidemiologic study. Crit Care Med. 2004;32(3):638-643.56. Mularski RA, Puntillo K, Varkey B, et al. Pain management within the palliative and end-of-life care experience in the ICU. Chest. 2009;135(5):1360-1369.57. Payen JF, Bru O, Bosson JL, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med. 2001;29(12):2258-2263.58. Gelinas C, Fillion L, Puntillo KA, Viens C, Fortier M. Validation of the critical-care pain observation tool in adult patients. Am J Crit Care. 2006;15(4):420-427.59. Puntillo KA, Morris AB, Thompson CL, Stanik-Hutt J, White CA, Wild LR. Pain behaviors observed during six common procedures: results from Thunder Project II. Crit Care Med. 2004;32(2):421-427.

76

60. Desbiens NA, Mueller-Rizner N. How well do surrogates assess the pain of seriously ill patients? Crit Care Med. 2000;28(5):1347-1352.61. Corbin LW, Mellis BK, Beaty BL, Kutner JS. The use of complementary and alternative medicine therapies by patients with advanced cancer and pain in a hospice setting: a multicentered, descriptive study. J Palliat Med. 2009;12(1):7-8.62. Bercovitz A, Sengupta M, Jones A, Harris-Kojetin LD. Complementary and alternative therapies in hopsice: the national home and hospice care survey: United States, 2007. Hyattsville, MD: National Center for Health Statistics;2010.63. Kutner JS, Smith MC, Corbin L, et al. Massage therapy versus simple touch to improve pain and mood in patients with advanced cancer: a randomized trial. Ann Intern Med. 2008;149(6):369-379.64. Keefe FJ, Abernethy AP, L CC. Psychological approaches to understanding and treating disease-related pain. Annu Rev Psychol. 2005;56:601-630.65. Cassileth BR, Keefe FJ. Integrative and behavioral approaches to the treatment of cancer-related neuropathic pain. Oncologist. 2010;15 Suppl 2:19-23.66. Abrahm JL. Advances in palliative medicine and end-of-life care. Annu Rev Med. 2011;62:187-199.67. Chamberlain BH, Cross K, Winston JL, et al. Methylnaltrexone treatment of opioid-induced constipation in patients with advanced illness. J Pain Symptom Manage. 2009;38(5):683-690.68. Zick SM, Ruffin MT, Lee J, et al. Phase II trial of encapsulated ginger as a treatment for chemotherapy-induced nausea and vomiting. Support Care Cancer. 2009;17(5):563-572.69. Hospice & Palliative Nurses Association. Final Days: Patient/Family Teaching Sheet. 2012.70. Edwards MJ. Opioids and benzodiazepines appear paradoxically to delay inevitable death after ventilator withdrawal. J Palliat Care. 2005;21(4):299-302.71. Bruce A, Boston P. Relieving existential suffering through palliative sedation: discussion of an uneasy practice. J Adv Nurs. 2011;67(12):2732-2740.72. Battin MP. Terminal sedation: pulling the sheet over our eyes. Hastings Cent Rep. 2008;38(5):27-30.73. Peppin JF. Intractable symptoms and palliative sedation at the end of life. Christ Bioeth. 2003;9(2-3):343-355.74. Verkerk M, van Wijlick E, Legemaate J, de Graeff A. A national guideline for palliative

sedation in the Netherlands. J Pain Symptom Manage. 2007;34(6):666-670.

77

NOTES

78

36. In the United States, what term is generally used for care of people who are not expected to live more than 6 months? A. Palliative careB. Hospice careC. Nursing home careD. Terminal care

37. Which statement is most true about pain relief at the end of life?A. Pain relief is the primary treatment goal at the end

of lifeB. The goal of treatment should be zero pain for the

patientC. Patients typically ask for maximum pain reliefD. Pain relief may often be the means to the larger

end of improving or maintaining a patient’s overall quality of life

38. In crafting goals of treatment, the values, beliefs, and priorities of which person should be primary?A. The physician B. The primary care giverC. The patientD. Nursing staff

39. If a patient is not alert enough to communicate, what should be used to determine if he or she is experiencing pain?A. Physician clinical opinionB. Non-verbal signs and cuesC. Advance directivesD. Current dose of analgesic

40. Which of the following questions is an example of the technique of reflective listening?A. “You seem to be irritated with me because you

don’t think the medication I prescribed are working for you.”

B. “I don’t think you should be irritated with me, I’m only trying to help.”

C. “The medication I prescribed for you are going to help control your pain more effectively.”

D. “Why don’t you like the medication I prescribed to you?”

41. Which of the following is a possible way to reduce the potential for GI bleeding with NSAIDs?A. Limit the total daily NSAID dose to 4000 mgB. Advise the patient to avoid spicy foodsC. Use a combination opioid/NSAID productD. Add a proton pump inhibitor

42. In the absence of other indicators, which of the following would be the least effective indicator of depression in a patient with terminal cancer?A. DespondenceB. HopelessnessC. GriefD. Fatigue

43. What condition of a patient may be beneficial during the terminal phase of an illness?A. HyperglycemiaB. HypoglycemiaC. Relative dehydrationD. Bradycardia

44. Which of the following is an example of how a clinician can show support for a bereaved relative or loved one? A. Silently put an arm around the bereaved personB. Use the name of the deceased in conversation and,

if appropriate, say it was an honor to know him or her

C. Leave interactions with bereaved relatives to nursing staff

D. Offer the name and contact information of an on-staff spiritual advisor or religious representative

45. What is an example of a culturally-specific value that might surprise an American-trained physician?A. Believing that end-of-life decisions are family

decisions, not those of the individual aloneB. Belief that information about a patient’s prognosis

should not be disclosed to the patient him- or herself

C. Belief that a physician should continue to encourage a patient’s hope of recovery even when the likelihood of such recovery is near zero

D. All of the above

CARING FOR PATIENTS AT THE END OF LIFESelf-Assessment

Choose the best possible answer for each question and mark your answers on the Self-Assessment answer sheet at the end of this book. There is a required score of 70% or better to receive a Certificate of completion.

79

This course is designed for all physicians (MD/DO), physician assistants, and nurse practitioners.

The purpose of this course is to educate prescribers about Risk Evaluation and Mitigation Strategies (REMS) in accordance with the FDA Blueprint for Prescriber Education related to extended release (ER) and long-acting (LA) opioid analgesics. This course is designed in accordance with the FDA’s Blueprint for Prescriber Education for Extended-Release and Long-Acting (ER/LA) Opioid Analgesics.

InforMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

InforMed designates this enduring material for maximum of 3 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Completion of this course will better enable the course participant to:1. Describe how to assess patients for treatment with ER/LA opioid analgesics. 2. Recognize how to initiate therapy, modify dose, and discontinue use of ER/LA opioid analgesics. 3. Explain how to manage ongoing therapy with ER/LA opioid analgesics. 4. Discuss how to counsel patients and caregivers about the safe use of ER/LA opioid analgesics, including

proper storage and disposal. 5. Identify general and product-specific drug information concerning ER/LA opioid analgesics. 6. Describe the two major competing responsibilities of clinicians related to the prescription of opioid pain

medications.7. List 3 advantages of creating written patient/provider opioid agreements.8. Explain the value of function-based treatment goals as opposed to pain-relief goals.9. List 2 ways to potentially address unpleasant or intolerable opioid side effects.

TARGET AUDIENCE

COURSE OBJECTIVE

ACCREDITATION STATEMENT:

DESIGNATION STATEMENT:

LEARNING OBJECTIVE

HOW TO RECEIVE CREDIT:

MAXIMUM CREDITS: FORMAT:COURSE DATES:

Read the course materials

Complete the self-assessment questions at the end. A score of 70% is required.

Return your customer information/answer sheet, evaluation,and payment to Informed by mail, phone, fax or complete online at course website under NETPASS.

Enduring Material (Self Study)

Release Date: 12/2016Exp. Date: 12/2019

3 AMA PRA Category 1 CreditsTM

Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics

80

Paul J. Christo, MDDirector, Multidisciplinary Pain Fellowship ProgramAssociate Professor of Anesthesiology and Critical Care MedicineThe Johns Hopkins University School of Medicine

Melissa B. Weimer, DO, MCRAssistant Professor of MedicineDivision of General & Internal Medicine & GeriatricsOregon Health & Science University

Stephen BraunMedical WriterBraun Medical Media

Elizabeth ThomasMSN, WHNP-BC, NP-C

SPECIAL DESIGNATION

This course satisfies (3) three AMA PRA Category 1 CreditsTM in pain management,

opioid use and addiction.

The Alaska Board of Medicine requires all licensees with with a valid DEA

certificate of registration to complete (2) two AMA PRA Category 1 CreditsTM in pain management, opioid use and

addiction.

In accordance with the ACCME Standards for Commercial Support of CME, Informed implemented mechanisms, prior to the planning and implementation of this CME activity, to identify and resolve conflicts of interest for all individuals in a position to control content of this CME activity.

FACULTY/PLANNING COMMITTEE DISCLOSURE:The following faculty and/or planning committee members have indicated they have no relationship(s) with industry to disclose relative to the content of this CME activity:• Melissa B. Weimer, DO, MCR• Elizabeth Thomas, MSN, WHNP-BC, NP-C• Stephen Braun

The following faculty and/or planning committee members have indicated that they have relationship(s) with industry to disclose: • Paul J. Christo, MD has received honoraria from Grunenthal,

Quest Diagnostics, Revo Pharma, Daiichi Sankyo, Collegium Pharma, and Insys Therapeutics

STAFF AND CONTENT REVIEWERS:Informed staff and all content validation reviewers involved with this activity have reported no relevant financial relationships with commercial interests.

DISCLAIMER*2018. All rights reserved. These materials, except those in the public domain, may not be reproduced without permission from InforMed. This publication is designed to provide general information prepared by professionals in regard to the subject matter covered. It is provided with the understanding that InforMed, Inc. is not engaged in rendering legal, medical or other professional services. Although prepared by professionals, this publication should not be utilized as a substitute for professional services in specific situations. If legal advice, medical advice or other expert assistance is required, the service of a professional should be sought.

FACULTY:

ACTIVITY PLANNER:

DISCLOSURE OF INTEREST:

COURSE SATISFIES

3Pain Management, Opioid Use

and Addiction.

81

INTRODUCTION

Opioid analgesic medications are important tools for relieving moderate to severe pain aris-ing from a wide range of conditions, disease states, or medical procedures. These drugs, however, may also be misused and abused, and overprescribing these agents can result in opi-oid use disorder or death from fatal overdose.1 The recognition of these problems has led in recent years to a re-thinking about the proper role of opioids, particularly for treating chronic non-cancer pain, and, specifically, about ER/LA opioid analgesics.

In February, 2016, for example, Dr. Robert Califf, Deputy FDA Commissioner for Medical Products and Tobacco, along with other FDA leaders, announced a “far-reaching action plan” to re-assess the agency’s approach to opioid medi-cations with the aim of reversing the epidem-ic of abuse and overdose while still providing patients in pain with access to effective relief.2,3 The new initiative will:

• Re-examine the risk-benefit paradigm for opioids.

• Develop changes to immediate-release opioid labeling similar to the ER/LA opioid labeling that is currently required.

• Update REMS requirements after hearing recommendations from a new advisory committee that will review current require-ments.

• Improve access to naloxone and medica-tion-assisted treatments such as metha-done and buprenorphine for patients with opioid use disorders.

• Support non-opioid, alternative pain man-agement strategies.

Also in 2016, the Centers for Disease Control and Prevention released its Guideline for Pre-scribing Opioids for Chronic Pain, which was de-veloped using up-to-date data about the risks of opioids and an unusually comprehensive scientific review process.1 While acknowledging the continuing need for providing patients with adequate pain relief, the CDC guidelines go fur-ther than previous documents in recommending a very cautious approach to using opioids for chronic pain.

AN EPIDEMIC OF OPIOID ABUSE

The newly-announced steps by the FDA, as well as the new CDC guidelines, have come in response to the dramatic rise in the prescrip-tion and use of opioid analgesics in the past 20 years in the United States. Between 1999 and

2010, the use of opioids quadrupled.4 Much of this increase has been for the treatment of pain other than moderate-to-severe acute pain or intractable end-of-life pain, which have tra-ditionally been seen as appropriate targets for opioids. In the past two decades, opioids have become widely-prescribed for chronic non-can-cer conditions, such as back pain, osteoarthritis, fibromyalgia, and headache,5 despite an evi-dence base that is much weaker than has been generally appreciated by many physicians until recently.6

As opioid prescriptions rose, so, too, did rates of opioid abuse, addiction, and diversion for non-medical use. This is why the current level of prescription opioid abuse has been described as an “epidemic” by the Centers for Disease Con-trol and Prevention.4 Some data now suggest that prescriptions of opioids may have peaked in 2012. The data research firm IMS Health re-ported in May of 2016 that opioid prescriptions fell about 12% nationally between 2013 and 2015. 7 Thus far, however, the reduced numbers of prescriptions has not resulted in fewer opi-oid-related overdose deaths—approximately 28,000 people died from such overdoses in

2014 (this figure includes deaths from both prescription opioids and heroin).7

Significantly, despite the pronounced increase in opioid analgesic prescriptions in the U.S. over the past two decades, no overall national im-provements in disability rates or health status measures among patients prescribed opioids has been demonstrated.8

BALANCING RISKS AND BENEFITS

The rising tide of problems associated with opioid analgesics has created tension for some prescribers, who must balance an awareness of the ongoing problems of opioid over-prescrip-tion and abuse with the equally compelling need to relieve their patients’ pain. Pain remains the most common reason people seek health care.9

In fact, the incidence of chronic pain in the U.S. is estimated to be greater than that of diabetes, heart disease, and cancer combined.10,11 Inade-quately treating pain can lead to a wide range of adverse consequences (in addition to causing needless suffering) including diminished quality of life, and a higher risk for anxiety or depres-sion.12 Pain is also a major cause of work absen-teeism, underemployment, and unemployment.9

FIGURE 1. RATES* OF OPIOID PAIN RELIEVER (OPR) OVERDOSE DEATH, TREATMENT ADMISSIONS, AND KILOGRAMS SOLD IN THE UNITED STATES, 1999-2014

82

Nonetheless, ER/LA opioid analgesics pose many risks, including:13

• Overdose (since most ER/LA formulations contain more opioid than immediate-re-lease formulations)

• Life-threatening respiratory depression• Abuse by patient or household contacts• Misuse and addiction• Physical dependence and tolerance• Interactions with other medications and

substances• Risk of neonatal opioid withdrawal syn-

drome• Inadvertent exposure/ingestion by house-

hold contacts, especially children• Hypogonadism (decreased levels of FSH,

LH, estrogen, testosterone)

Balancing the potential risks and benefits of a treatment is common in medicine. In the case of opioids, however, decisions are complicated by the fact that the drugs are potentially addic-tive and avidly sought by recreational users. But many guidelines exist that map out reasonable and practical ways to consider opioid analgesics for patients in pain. The 2016 CDC Guidelines, for example, make the following recommenda-tions to clinicians about responsible opioid pre-scribing:1

• Do not prescribe ER/LA opioids for acute pain.

• Use opioid medications for acute or chronic pain only after determining that alternative therapies do not deliver adequate pain re-lief.

• The lowest effective dose of opioids should be used, and, for acute pain, the amount of opioids prescribed should be strictly limit-ed to cover only the expected duration of severe pain (3 days or less will often be sufficient; more than 7 days will rarely be needed).

• In addition to behavioral screening and the use of patient-provider opioid agreements, consider random, periodic, urine testing for opioids and other drugs for patients with non-cancer pain being treated with opioids for more than six weeks.

• If your state has a prescription drug mon-itoring program (PDMP), periodically re-quest, or check, a report on the history of opioid prescriptions to your patients by other providers.

• Use caution when prescribing opioids at any dosage, and carefully reassess evidence of benefits and risks when increasing dosage to ≥ 50 morphine milligram equivalents (MME)/day, and avoid increasing the dose to ≥ 90 MME/day.

• Consider offering naloxone when factors that increase risk of opioid overdose are present.

This CME program summarizes these and other evidence-based recommendations for prescrib-ing opioid analgesics, with a focus on ER/LA opi-oid formulations, which have been associated with higher levels of abuse and/or overdose.

FUNDAMENTAL CONCEPTS Traditionally, pain has been classified by its duration. Acute pain lasts for only a matter of days or, at most, a few weeks, arises from ob-vious tissue injury, and usually fades with heal-ing.5 Chronic pain, in contrast, lasts longer than would be anticipated for the usual course of a given condition. The International Association for the Study of Pain defines this as pain lasting 3 months or longer.14 The labels “acute,” and “chronic,” however, do not provide any informa-tion about the etiology or biological of the pain being experienced.

Pain, therefore, is also classified on the ba-sis of its pathophysiology. Nociceptive pain is caused by the activation of nociceptors (pain receptors), and is generally, though not always, short-lived, and associated with the presence of an underlying medical condition in response to injury.

Neuropathic pain, on the other hand, results ei-ther from an injury or disease affecting the so-matosensory system or from inadequately-treat-ed nociceptive pain. It is an abnormal response to a stimulus caused by aberrant neuronal firing in the absence of active tissue damage. It may be continuous or episodic and varies widely in how it is perceived. Neuropathic pain is complex and can be difficult to diagnose and to manage because available treatment options are limited. Both nociceptive and neuropathic pain can arise from, or be exacerbated by, sensitization, which is a state of hyperexcitability in either periph-eral nociceptors or neurons in the central ner-vous system. Sensitization may lead to either hyperalgesia (heightened pain from a stimulus that normally provokes pain) or allodynia (pain from a stimulus that is not normally painful).15 Sensitization may arise from intense, repeated, or prolonged stimulation of nociceptors, or from the influence of compounds released by the body in response to tissue damage or inflamma-tion.16 Many patients—particularly those with chronic pain—experience pain that has both nociceptive and neuropathic components, which complicates assessment and treatment.

It’s important for clinicians to distinguish be-tween nociceptive and neuropathic pain because the two types respond differently to pain treat-ments. Neuropathic pain, for example, typical-ly responds poorly to both opioid analgesics and non-steroidal anti-inflammatory (NSAID) agents.17 Other classes of medications, such as anti-epileptics, antidepressants, or local an-esthetics, may provide more effective relief for neuropathic pain.18

Pain associated with cancer is sometimes given a separate classification, even though the pain itself is either nociceptive or neuropathic (or both). Cancer-related pain includes pain caused by the disease itself, painful diagnostic or ther-apeutic procedures, or side effects from cancer therapies such as chemotherapy or radiation. ER/LA opioids often play a role in treating can-cer-related pain because such pain may be of exceptional severity and duration.

Chronic non-cancer pain may be caused by many kinds of conditions or disease states such as musculoskeletal injury, lower back trauma, dys-functional healing from a wound or surgery, or from autoimmune system disorders. With chron-ic non-cancer pain, the severity of pain experi-enced by a patient may not correspond well—or at all—to identifiable levels of tissue damage.

Related to the nomenclature of pain itself are terms used in the context of opioid analgesic medications. The American Society of Addiction Medicine (ASAM), the American Academy of Pain Medicine (AAPM), and the American Pain Society (APS) have recommended the following definitions:19

Tolerance. A state of adaptation in which expo-sure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Physical Dependence. A state of adaptation that often includes tolerance and is manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, and/or administration of an an-tagonist.

Addiction (also known as substance use disor-der). A primary, chronic, neurobiological dis-ease, with genetic, psychosocial, and environ-mental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: im-paired control over drug use, compulsive use, continued use despite harm, and craving.

83

Ralph is an 83-year-old who lives at home with his wife. He has a history of cardio-vascular disease and, 10 years earlier, had successful quadruple bypass surgery. He takes the following medications: fish oil, a statin, a thiazide diuretic, low-dose aspirin, and a non-benzodiazepine sedative to help him sleep. Lately he has been complain-ing of increasing pain and stiffness in his right knee and hip. He is physically decon-ditioned due to a lack of exercise, in part because walking is painful. He asks if you can prescribe something to ease his pain.

OVERVIEW OF PAIN MANAGEMENT STRATEGIESAlthough this monograph focuses on ER/LA opioid analgesics, a review of the many phar-macologic and non-pharmacologic approaches to treating painful conditions is appropriate because such options should usually be tried, or at least considered, before an opioid is con-sidered. Pain treatment options should be em-ployed using the following general principles:

• Identify and treat the source of the pain, if possible, although treatment can begin be-fore the source of the pain is determined. In some cases of chronic pain, an identifi-able source of pain may not be found.

• Initiate non-pharmacologic approaches first, such as physical therapy. If medica-tions are offered, try medications with the least severe potential side effects first (i.e., non-opioid).

• Establish a function-based management plan if treatment is expected to be long-term.

Five basic pain-management approaches exist, each of which will be more fully described be-low:

• Cognitive-behavioral approaches (may

help patients monitor and evaluate neg-ative or inaccurate thoughts and beliefs about their pain).

• Rehabilitative approaches (may improve physical function, alter physiological re-sponses to pain, help prevent recurrence of injury, and help reduce fear and anxi-ety).

• Complementary and alternative therapies (can reduce pain, induce relaxation, and enhance a sense of control over the pain or the underlying disease).

• Interventional approaches (wide range of surgical and other interventional ap-proaches to pain management including: trigger point injections; epidural injections; facet blocks; joint injections, sympathetic nerve blocks, targeted nerve blocks, ra-diofrequency denervation, pulsed radio frequency therapy, spinal cord stimulators; pain pumps, peripheral nerve stimulators, laminectomy; spinal fusion; and deep brain implants).

• Pharmacotherapy (NSAIDs, acetamino-phen, topical agents, cannabis, antidepres-sants, anticonvulsants, opioids).

These modalities can be used alone or in com-bination to maximize pain control and functional gains. Which options are used in a given patient

depends on the type of pain, the duration and severity of pain, patient preferences, co-occur-ring disease states or illnesses, patient life ex-pectancy, cost, and the local availability of the treatment option.

COGNITIVE-BEHAVIORAL APPROACHES

Psychological therapies of all kinds can be criti-cal for managing chronic non-cancer and cancer pain. Cognitive therapy techniques may help patients monitor and evaluate negative or inac-curate thoughts and beliefs about their pain. For example, some patients engage in an exagger-ation of their condition called “catastrophizing” or they may have an overly passive attitude to-ward their recovery which leads them to inap-propriately expect a physician to “fix” their pain without active self-management on their part. Individual, group, or family psychotherapy may be extremely helpful for addressing this and other psychological issues, depending on the specific needs of a patient. In general, psycho-logical interventions may be best-suited for pa-tients who express interest in such approaches, who feel anxious or fearful about their condition, have a history of trauma, or whose personal re-lationships are suffering as a result of chronic or recurrent pain.

Part 2 - Questions and Considerations: Spend 5 minutes considering the following questions as they relate to the case presented.

1. Is Ralph a good candidate for an ER/LA opioid? Why, or why not?

2. Would Ralph’s current medication need to be adjusted if he were to be prescribed an ER/LA opioid?

3. What kinds of non-opioid treatments might be tried to help Ralph with his pain?

EXERCISE 1Instructions: Read the case below and com-plete both learning activities that follow.

Part 1 – Application: Take 5 minutes re-viewing the scenario as it relates to either your clinical practice or the systems of care in which you work.

I. Evaluate application, or options for planned application, as it would apply in your own practice.

II. Consider the expected outcome(s) of those applications.

84

Unfortunately, the use of psychological ap-proaches to pain management can be hampered by such barriers as provider time constraints, unsupportive reimbursement policies, lack of access to skilled and trained providers, or a lack of awareness on the part of patients and/or physicians about the utility of such approaches for improving pain relief and overall functioning. Ideally this treatment modality should be provid-ed by a trained pain psychologist who can help the patient set pain-specific self-management goals as part of his or her treatment plan.

REHABILITATIVE APPROACHES

In addition to relieving pain, a range of active rehabilitative therapies can improve physical function, alter physiological responses to pain, and help reduce fear and anxiety. Treatments used in physical rehabilitation include exercises to improve strength, endurance, and flexibility, gait and posture training, stretching, and educa-tion about ergonomics and body mechanics. Ex-ercise programs that incorporate Tai Chi, swim-ming, yoga, or core-training work may also be useful. Other noninvasive, more passive, phys-ical treatments for pain include thermotherapy (application of heat), cryotherapy (application of cold), counter-irritation, and electroanalge-sia (e.g., transcutaneous electrical stimulation). Other types of rehabilitative therapies, such as occupational and social therapies, may be valu-able for selected patients.

INTERVENTIONAL APPROACHES

Although beyond the scope of this CME pro-gram, many surgical and other interventional approaches to pain management exist, includ-ing: trigger point injections; epidural injections; facet blocks; joint injections; sympathetic nerve blocks; targeted nerve blocks; radiofrequency denervation; pulsed radio frequency therapy; spinal cord stimulators; pain pumps; peripheral nerve stimulators; laminectomy; spinal fusion; deep brain implants, and regenerative therapies such as platelet rich plasma and stem cell ther-apies. Many of these novel strategies may offer very effective options for pain relief in selected patients.

NON-OPIOID PHARMACOTHERAPY

Many options exist to treat both acute and chronic pain that do not involve opioids. These options should be thoroughly explored before an opioid is considered.

ACETAMINOPHEN

Acetaminophen, first introduced in the US mar-ket in 1953, provides predictable, if modest, pain relief, and is often recommended as a first-step treatment. It is used as an analgesic and antipyretic (fever reducer), but has poor anti-in-flammatory properties. A Cochrane review found acetaminophen superior to placebo in pain re-duction in patients with hip/knee osteoarthritis (OA).21 Although “extra strength” doses are widely promoted, evidence suggests that doses of 1000 mg are no better than 650 mg in reliev-ing mild to moderate pain, which is significant because higher doses increase the potential for adverse events, especially in combination with other acetaminophen-containing products.

Although acetaminophen’s overall side effect profile is benign,21 this analgesic can pose risks for hepatotoxicity. Acetaminophen liver damage is the leading cause of drug-induced acute liv-er failure in the U.S.22 More than 35,000 ac-etaminophen-related overdose hospitalizations occur in the US every year, and acetaminophen accounts for 5% of all calls to US poison control centers. The most commonly implicated prod-ucts in overdoses are acetaminophen/opiate combinations.

The threshold dose for acetaminophen liver toxicity has not been established, although the FDA recommends that the total adult daily dose should not exceed 4 g/day in patients without liver disease (although a ceiling of 3 g/day is suggested for older adults).23

NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) have analgesic, anti-pyretic, and anti-inflam-matory properties. They are some of the most commonly-prescribed medications in the U.S., with over 111 million prescriptions written annu-ally, in addition to widespread use of the over-the-counter (OTC) NSAIDs.24,25

NSAIDs are moderately effective in reducing pain from a variety of conditions. While most studies compare an NSAID with a placebo, no consistent evidence shows that any NSAID con-fers greater analgesic efficacy than any other, at equipotent doses. A Cochrane review found celecoxib to be significantly better than place-bo in reducing pain in rheumatoid arthritis and osteoarthritis.26 In the treatment of chronic low back pain, NSAIDs are also significantly better than placebo, with a mean difference (between groups) in pain scale scores of 12 (on a 100 point scale).27

The most serious NSAID side effects involve the GI tract, heart, and kidneys. The risk of GI bleed-ing may be mitigated by adding a proton-pump inhibitor (PPI).28,29 In 2015, the FDA strength-ened existing “black box” warning for all NSIADs that these agents can increase the chance of a heart attack or stroke.

TOPICAL AGENTS

Topical capsaicin and topical salicylates can both be effective for short term pain relief and generally have fewer side effects than oral an-algesics, but their long term efficacy is not well studied.30,31 Topical NSAIDs and lidocaine have been reported to be effective for short term re-lief of superficial pain with minimal side effects, although both are more expensive than topical capsaicin and salicylates. None of the topical agents are useful for non-superficial pain. Topi-cal lidocaine and topical high dose capsaicin are FDA approved for postherpetic neuralgia, and topical diclofenac is FDA approved for osteoar-thritis.

ANTIDEPRESSANTS

Some antidepressants exhibit analgesic proper-ties that do not depend on antidepressant ac-tivity, and antidepressants are equally effective in patients with and without depression.32 While analgesia may occur at lower doses and sooner than antidepressant activity, maximum effica-cy may require high antidepressant doses and treatment of potentially lengthy duration.

Tricyclic antidepressants (TCAs) such as amitrip-tyline, nortriptyline, and imipramine, are used to treat a variety of types of chronic and neu-ropathic pain.33 Although often considered most effective for continuous burning pain or hyper-sensitivity conditions, TCAs also may relieve lancinating neuropathic pain.34

All TCAs are limited by anti-cholinergic side ef-fects (dry mouth, urinary retention) and som-nolence, which are dose-dependent. These side effects are less common with nortriptyline and desipramine than with amitriptyline. Side ef-fects occur more commonly in elderly, so dos-es should be titrated cautiously. TCAs can also cause cardiac conduction abnormalities and should be avoided in patients with existing car-diac disease.

Selective norepinephrine reuptake inhibitors (SNRIs) are effective for a variety of neuropathic pain syndromes and myofascial pain conditions, with duloxetine having the most efficacy data for a variety of pain syndromes including diabet-

85

ic peripheral neuropathy, fibromyalgia, and the non-neuropathic condition of musculoskeletal pain.35 The benefits of SNRIs appear to arise because of norepinephrine uptake effects in the spinal cord. The data for venlafaxine primarily support their use in diabetic neuropathy,36 and for milnacipran primarily for fibromyalgia.37,38 All SNRIs are limited by GI and CNS side effects, and should be taken on a full stomach.

The selective serotonin reuptake inhibitors (SSRIs) paroxetine and citalopram appear to be superior to placebo in relieving neuropathic pain, based on 2 small randomized trials (<50 patients each), but fluoxetine is not better than placebo in diabetic neuropathy.39,40 The SSRIs are associated with weight gain, sexual dysfunc-tion, and a minor increase in the risk of bleed-ing due to platelet dysfunction. In general, the SSRI’s are not particularly effective for pain, although they may be appropriate for patients with both chronic pain and a depressive disor-der.

ANTICONVULSANTS

The increasing use of antiepileptic drugs (AEDs) for neuropathic pain is based on their ability to reduce membrane excitability and sup-press abnormal discharges in pathologically al-tered neurons.41 The exact mechanism of action for their analgesic effects, however, is unclear. It does not appear to be specifically related to their antiepileptic activity. Other drugs that suppress seizures (e.g., barbiturates) do not relieve pain, and some AEDs with effective an-tiepileptic activity do not necessarily have good analgesic activity.18

AEDs are used to treat neuropathic pain, es-pecially lancinating (i.e., episodic shooting, stabbing, or knife-like) pain from peripheral nerve syndromes (e.g., diabetic neuropathy or fibromyalgia) and neuropathic pain arising from spinal cord injury. A Cochrane review of pregab-alin for analgesia found a daily dose of 150 mg to be no more effective than placebo, but daily doses of 300-600 mg were significantly better than placebo.42 The most common side effects include peripheral edema, weight gain, and CNS side effects (including dizziness, somnolence, ataxia, and headache).42

Gabapentin also effectively reduces diabetic neuropathic pain and other forms of neuro-pathic pain. In a trial comparing gabapentin to placebo, pain on 10-point scale decreased from 6.4 to 3.9 in the treatment group as compared to 6.5 to 5.1 in the placebo group after 8 weeks of treatment.43 Side effects are similar to prega-

balin.43 The optimal dose of gabapentin is 600 – 1200 mg three times daily. The dose should be reduced in patients with severe kidney insuf-ficiency. A Cochrane review assessed 14 studies evaluating the efficacy of carbamazepine in the treatment of neuropathic pain (e.g., diabetic neuropathy and postherpetic neuropathy) and found that 70% of carbamazepine patients had some improvement in pain (versus 12% of pla-cebo).44 Carbamazepine is the standard of care for the treatment of trigeminal neuralgia pain.

CANNABIS

Cannabis sativa has been used for centuries to treat ailments ranging from nausea to glauco-ma. Cannabinoids act, at least in part, through the cannabinoid receptors CB-1 and CB-2, and an opioid receptor mechanism that increases dopamine concentrations in the nucleus ac-cumbens.45 The primary pain-relieving cannabi-noid is cannabidiol, which is not psychoactive. A meta-analysis of 18 randomized trials of canna-bis use in various chronic pain syndromes (1/3 of which were cancer) found a standardized mean difference in pain improvement of -0.61 (-0.84 to -0.37) indicating a moderate treat-ment effect.46 However, the individual studies were small (sample size ranging from 10-177), short-term (mean duration 25 days) and of overall poor methodological quality. Many of the studies had an “open phase” in which patients took the drug before randomization, to screen out those with low tolerance for side effects. No significant differences for dysphoria were observed between cannabis and placebo. Side effects of cannabis included euphoria, alter-ations in perception, events relating to cognitive function, and events concerning motor function.

Lynch et al., in a 2011 systematic review of RCTs of cannabinoids for CNCP (e.g., neuropath-ic pain, fibromyalgia, and rheumatoid arthritis), found that 15 of 18 trials demonstrated “signif-icant analgesic effects compared to placebo.”47 Adverse effects in this review were generally well-tolerated, and cannabinoids were found to be “moderately effective” in neuropathic pain.

Cannabis has been used to help stabilize pa-tients on methadone maintenance treatment and cannabis use has been associated with modest reductions in opioid withdrawal symptoms for such patients.48 Cannabis use has also been associated, on a state-wide level, with reduced rates of opioid overdose. Bachhuber et al., in a time-series analysis, found that between 1999 and 2010 states with medical cannabis laws had a 24.8% lower mean annual opioid over-dose mortality rate (95% CI: -37.5% to -9.5%;

p=0.003) compared with states without medical cannabis laws.49

Smoking cannabis has been associated with twice the odds of pulmonary symptoms (cough, sputum, wheezing) but not associated with changes in lung function.137 Acutely, marijuana can impair short term memory, motor coordina-tion, and judgement. Psychosis and paranoid ideation can also occur. Retrospective cohorts have found cannabis use may be associated with an “amotivational syndrome” and reproductive system changes (including reduced testoster-one and libido in men, and increased prolactin in women).50 Amotivation can be particularly prob-lematic for patients who have chronic pain be-cause it can impair their ability to perform self-care. The use of cannabis can also lead to the development of marijuana use disorder, which in severe cases can take the form of addiction.

OPIOIDS

OPIOID MECHANISMS OF ACTION

Opioid analgesics work by binding to one or more of the three major types of opioid re-ceptors in the brain and body: mu, kappa, and delta receptors. Opioids inhibit both ascending transmission of nociceptive information as well as descending pain control circuits. The most common opioid pain medications are “mu ag-onists” because they bind to and activate mu opioid receptors. Mu agonists include morphine, codeine, hydromorphone, oxycodone, and hy-drocodone. The antagonists naloxone and nal-trexone competitively bind to opioid receptors, blocking or disrupting agonists without causing the receptor to respond.

The binding of mu agonist opioids to receptors in various body regions results in both thera-peutic effects (such as pain relief) and side ef-fects (such as constipation). Tolerance develops for some effects of opioids, but not others. For example, some tolerance develops to respirato-ry suppressant effects within 5-7 days of con-tinuous use, whereas tolerance to constipating effects never occurs. Tolerance to analgesia may develop early, requiring an escalation of dose, but tolerance may lessen once an effective dose is identified and administered regularly, as long as the associated pathology or condi-tion is stable.51 Prescribers should understand the specific opioid tolerance criteria defined in product labeling, and summarized in Table 1 of this document.

86

GENERAL CONSIDERATIONS IN OPIOID SELECTION

Opioids as a class include many specific agents available in a wide range of formulations and routes of administration, (all of them scheduled under the Controlled Substances Act) including: • Oral (e.g., tablets, capsules, solutions, lol-

lipops)• Transdermal• Transmucosal• Rectal• Intrathecal• Intravenous• Epidural

Little evidence exists that specific analgesic for-mulations or dosing schedules affect efficacy or addiction risk, so selection of agent should be based on the patient’s pain complaint, lifestyle, and preferences.52 Generally, if opioids are used at all, it is better to offer short-acting opioids PRN as these are believed to present a lower risk of abuse or addiction. Long-acting (LA) or extended-release (ER) opioids may be helpful for patients who have difficulty managing an “as needed” regimen, or who are physically depen-dent on opioid analgesics and require continued use to maintain their functioning. (Prescribers, of course, should be aware of all relevant fed-eral and state regulations pertaining to opioids prior to prescribing.)

Scheduled long-acting opioids have the advan-tage of producing a steady state, without the cycling effect of pain relief and withdrawal as-sociated with short-acting opioids, which could, theoretically, lead to problematic behavior pat-

terns.53 With ER/LA agents, however, patients may end up using more drug than is actually needed, and adaptations to the steady state may ultimately decrease efficacy.54 Clinicians should warn pa-tients that oral ER/LA opioids should not be bro-ken, chewed, or crushed, and patches should not be cut or torn prior to use, since this may lead to rapid release of the opioid and could cause overdose or death.

AVOID ER/LA OPIOIDS FOR ACUTE PAIN

As mentioned earlier, ER/LA opioids should NOT be used to treat acute pain.1 However, cautious use of short-acting opioids for moderate or se-vere acute pain may be considered for careful-ly-selected patients whose pain is not controlled with acetaminophen or NSAIDs, or for whom such medications are contraindicated. The opi-oid should be used at a minimum effective dose, and for a limited period of time, usually less than 2-3 days. Opioids should be used only as one part of a comprehensive pain care plan, and extended release opioids should be avoided in acute pain patients.55

Studies show that physicians routinely over-pre-scribe opioids for acute pain. For example, Rod-gers et al., found that after outpatient orthope-dic surgery, most patients were prescribed 30 pills of an opioid analgesic, although the mean patient consumption of those analgesics was only 10 pills.56 Another study found that 72% of people who had been prescribed an opioid had leftover medication.57 This guideline recom-mends that no more than a one-week supply be prescribed following surgery.

By definition, treatment of acute pain should not last longer than the time required for the healing or resolution of the trauma or condition. Hence, it is unlikely that opioids, or any other analgesic, will be needed beyond 90 days from initiation of treatment. Research shows that after 90 days of continuous opioid use, treatment is more likely to become life-long.58,59,60,61 The 90-day mark, therefore, should be considered a “red flag” point at which use should be re-evaluated and patients should be offered opioid taper.

CAUTIONS ABOUT OPIOIDS FOR CHRONIC NON-CANCER PAIN

A broad consensus is developing that opioid an-algesics are not, in fact, suited for many patients with chronic non-cancer pain. Clinical guidelines for the use of opioids in chronic non-cancer pain have shifted to stress the risks of opioids and strengthen procedures that prescribers should use to reduce the risk of addiction and mis-use.62,63,64

Little evidence supports the assertion that long-term use of opioids provides clinically signif-icant pain relief or improves quality of life or functioning.65 The Agency for Healthcare Re-search and Quality (AHRQ), for example, recent-ly found no studies that compare opioid therapy with either a placebo or a non-opioid treatment for long-term (>1 year) pain management.66

A Cochrane review of opioids for long-term treatment of non-cancer pain found that many patients discontinue long-term opioid therapy (especially oral opioids) due to adverse events or insufficient pain relief.65

Long acting opioids Immediate release opioids

Buprenorphine patch (Butrans) Codeine (generics)

Fentanyl patch (Duragesic) Fentanyl – transmucosal (Abstral, Actiq, Fentora, Lazanda, Onsolis, Subsys)

Hydrocodone (Zohydro ER, Hysingla ER) Hydrocodone+acetaminophen (generics, Norco, Vicodin, Xodol)

Hydromorphone ER (generics, Exalgo) Hydromorphone (generics, Dilaudid)

Methadone (generics, Dolophine, Methadose) Levorphanol (generics)

Morphine ER (generics, Avinza, Kadian, MS Contin, Embeda) Meperidine (generics, Demerol, Meperitab)

Oxycodone (Oxycontin, Targiniq ER, Xtampza ER) Morphine (generics)

Oxymorphone ER (generics, Opana ER) Oxycodone (generics, Roxicodone)

Tapentadol (Nucynta ER) Oxymorphone (generics, Opana)

Tramadol ER (generics, ConZip, Ultram ER) Tapentadol (Nucynta)

Tramadol (generics, Ultram)

TABLE 1. LONG-ACTING VS. IMMEDIATE-RELEASE OPIOIDS

87

Much evidence, on the other hand, shows that opioids pose many significant risks for adverse effects, abuse, addiction, and accidental over-dose leading to death from respiratory depres-sion. Estimating the magnitude of such risks is difficult because rigorous, long-term studies in patients without co-existing substance-use dis-orders have not been conducted.57 A few sur-veys conducted in community practice settings, however, estimate rates of prescription opioid abuse of between 4% to 26%.67,68,69,70 Risk ris-es with higher doses and longer durations.71 A 2011 study of a random sample of 705 pa-tients undergoing long-term opioid therapy for non-cancer pain found a lifetime prevalence rate of DSM-5-defined opioid-use disorder of 35%.72

The variability in such results probably reflects differences in opioid treatment duration, the short-term nature of most studies, disparate study populations, and different measures used to assess abuse or addiction. Nonetheless, the levels of risk suggested by these studies are significant enough to warrant extreme caution in the prescription of any opioid for a chronic pain condition.

Caution is also required because many patients do not use opioids as prescribed by their phy-sicians. Fleming et al., conducted in-depth in-terviews with 801 patients receiving long-term opioid therapy and found the following:68

• 39% of patients increased their dose with-out direction from a health care provider.

• 26% engaged in purposeful over-sedation.• 20% drank alcohol concurrent with opioid

use. • 18% used opioids for purposes other than

pain relief.• 12% hoarded their pain medications. • 8% obtained extra opioids from other doc-

tors.

As already mentioned, the risk of overdose with opioid analgesics is significant and, as with risk of opioid use disorder, rises with both dose and duration.73 (FIGURE 2)

In addition to the risks already mentioned, opi-oids can exert a wide range of uncomfortable or harmful adverse effects, the most common of which are neurologic (somnolence, dizziness), endocrine (hypogonadism), gastrointestinal (nausea, vomiting, and constipation), sexual (erectile dysfunction), and cutaneous (pruri-tus). In randomized trials of opioids, 50%-80% of patients report a side effect, and about 25% withdraw due to an adverse event.65,74,75

Although less common, there is also a dose-de-pendent increase in risk of fractures among patients prescribed opioids compared to pa-tients not prescribed opioids, with risk highest just after an opioid was started.76,77 Another concern is the possibility that chronic opioid

use may be immunosuppressive.78 Dublin et al., in a population-based case-control study, found a significantly higher risk of pneumonia in immunocompetent older adults who were prescribed opioids.79 The risk was particularly high for adults taking ER/LA opioids.79 Finally, prescription opioid use in pregnant women has been associated with a range of adverse new-born outcomes, including low birth weight, pre-mature birth, and hypoxic-ischemic brain injury, although it is difficult to separate the effects of opioid use from other maternal factors that may contribute to these adverse outcomes.

There are two specific situations in which opi-oids are contraindicated in current guidelines: clinicians should avoid using intravenous or in-tramuscular opioid injections for patients with exacerbations of chronic non-cancer pain, and opioids should also be avoided pre-surgically in instances of acute trauma or chronic degenera-tive diseases.

WHEN, AND HOW, TO PRESCRIBE OPIOIDS FOR CHRONIC NON-CANCER PAIN

The risks reviewed above suggest that only a mi-nority of patients with chronic non-cancer pain should be considered as potential safe candi-dates for opioid therapy. Nonetheless, an opioid may be appropriate for chronic pain in certain limited circumstances, such as: when the pain is severe and refractory to other treatments; when

FIGURE 2. PERCENT OF ANNUAL OVERDOSE RATES RISES WITH DAILY OPIOID DOSE73

No recent opioids 1-20 mg 20-50mg 50-99mg >100mg

Perc

ent o

f an

nual

ove

rdos

e ra

te

1

0.5

2

1.5

0.20.04

1.8

0.3

0

0.7

88

it adversely impacts function or quality of life; when other pharmacologic agents are contra-indicated, and when the potential therapeutic benefits outweigh, or are likely to outweigh, po-tential harms.5 In these cases, clinicians should follow published guidelines to maximize the ef-fectiveness of an opioid and minimize its risk to the patient and to society at large. This section reviews these steps in detail.

PATIENT SELECTION AND RISK STRATIFICATION

Pain assessment includes recording of: chief complaint; nature and intensity of pain; history of present illness; past medical, surgical, and psychosocial history; past treatments; co-morbid conditions; family history; physical examination; and examination of imaging and other diagnostic studies or tests (Table 2). As with every patient, clinicians should take the time to look beyond the specific complaint or body part/system and evaluate holistically the broader mental, cultur-al, and socioeconomic contexts within which the chief complaint may be embedded.

PAIN ASSESSMENT TOOLS

Unidimensional pain scales (e.g., numeric or “faces”) are seldom useful for guiding a deci-sion to treat chronic pain because such pain is variable and scores from pain assessment tools are highly subjective. Multidimensional tools provide more information, such as the effects of pain on daily life. These tools can typically be administered in an office, examination room, or other clinical setting by either a physician or another health care professional, or they could be filled out by the patient, if appropriate. Ex-amples of some multidimensional tools include:

• Initial Pain Assessment Tool80 • Brief Pain Inventory81 • McGill Pain Questionnaire (short-form

available)82

• Pain, Enjoyment, and General Activity Scale83

ASSESSING ABUSE RISK

Another key component of assessment is ascer-taining the patient’s risk of substance abuse, misuse, or opioid use disorder.5 Although the available evidence base is weak, professional guidelines suggest that the following patients or pain conditions are unlikely to benefit from opioid analgesics:5

• Poorly-defined pain conditions• Daily headache• Fibromyalgia• A likely or diagnosed somatoform disorder• Patients with unresolved workers compen-

sation or legal issues related to pain or injury

Region Rationale, Methods, and Potential findings

General Observe and/or identify:• Patient’s general appearance and vital signs• Evidence of overt abnormalities (e.g., weight loss, muscle

atrophy, deformities, trophic changes)• Any subjective manifestations of pain (e.g., grimacing,

splinting)

Site of pain Inspect the pain site(s) for abnormal appearance or color of overlying skin or visible muscle spasm

Palpate the site(s) to assess for tenderness and correlate tender-ness with any associated subjective or objective findings

Use percussion (or jarring) to elicit, reproduce, or evaluate the pain and any tenderness on palpation

Use the brush, pinch, pin prick, and/or scratch tests to assess for allodynia, hyperalgesia, or hyperesthesia

Determine the effects of physical factors (e.g., motion, applied heat or cold, deep breathing, changes in position) on pain

Other regions Examine other regions as directed by the patient history or assessment of pain site

Neurological system At minimum, perform a screening neurological examination (i.e., assess cranial nerves, spinal nerves, sympathetic nervous system

function, coordination, and mental status) to screen for:• Sensory deficits (e.g., impaired vision or hearing) or abnor-

mal sensations (e.g., paresthesia, dysesthesia, allodynia, hyperpathia)

• Motor abnormalities or deficits (e.g., weakness, exaggerated or diminished reflexes)

• Lack of coordination• Evidence of sympathetic nervous system dysfunction (e.g.,

skin flushing, unusual sweating)• Abnormalities or deficits in orientation, recent or remote

memory, parietal sensory function, language function, and mood

Musculoskeletal system Observe and/or identify:• Body type, posture, and overall symmetry• Abnormal spine curvature or limb alignment and other

deformities• Abnormal movements and/or irregular gait during walking• Range of motion (spine, extremities)

For muscles in neck, upper extremities, trunk, and lower extremi-ties:

• Assess multiple parameters (e.g., tone, volume, contour, strength and power, range of motion)

• Observe for any abnormalities (e.g., weakness, atrophy, hypertrophy, irritability, tenderness, trigger points)

TABLE 2. PHYSICAL EXAMINATION OF A PATIENT WITH PAIN

89

Assessing a patient’s risk of opioid use disor-der is at least somewhat subjective, and opin-ions differ about which patients should be more rigorously assessed. Some favor a “universal precautions” approach, in which all pain pa-tients are considered to have some degree of vulnerability to opioid use disorder and, hence, all patients are given the same screenings and diagnostic procedures.84 Some patient charac-teristics, however, do appear to be predictive of a potential for drug abuse, misuse, or oth-er aberrant behaviors, particularly a personal or family history of substance use disorder.5 Some studies also show that younger age and the presence of psychiatric conditions are as-sociated with aberrant drug-related behaviors.5

Relatively brief, validated tools can help for-malize assessment of a patient’s risk of having a substance use problem (Table 3) and these

should be considered for routine clinical use.5

USE A HOLISTIC APPROACH TO PSYCHOSOCIAL EVALUATIONPain can perturb all aspects of a patient’s life, hence clinicians need to be alert to the ways

pain may be impacting, or may be affected by, psychosocial elements of a patient’s life. For example, clinicians must check for signs of de-pression or anxiety, which are common in pain patients. Be particularly alert for suicidal

Tool Who Administers? Length

Diagnosis, Intractability, Risk, Efficacy (DIRE)

Clinician 7 items

Opioid Risk Tool (ORT) Clinician or patient self-report

5 yes/no questions

Screener and Opioid Assess-ment for Patients with Pain, Version 1 and Revised (SOAPP, and SOAPP-R)

Patient self-report 24 items

TABLE 3. TOOLS FOR INITIAL PATIENT RISK ASSESSMENT

Hannah is a 62-year-old woman who has been coping with persistent pain for more than a year since she was involved in a car accident. Her initial severe neck and low back pain was thought to be due to cervi-cal and lumbar sprain/strain. She was pre-scribed a short-acting opioid, which she said helped with the pain, but led to con-stipation. After three months of using the opioid, Hannah decided to stop because she did not like the constipation and “brain fog” from the drug. She tried several types of alternative therapies, such as massage and acupuncture, both of which provided short-term relief, although the pain later returned. At 6 months post-accident, X-ray and MRI imaging revealed no obvious spinal patho-physiology, although Hannah reported the pain was spreading to her legs and arms. Hannah has a BMI of 31 and has been di-agnosed with metabolic syndrome. She is physically inactive but currently takes no medications.

Part 2 - Questions and Considerations: Spend 5 minutes considering the following questions as they relate to the case presented.

1. Given the subjective nature of pain, how can a clinician assess the kind of pain reported by patients such as Hannah?

2. Does the lack of obvious pathophysiology on imaging suggest that Hannah is a hypochondriac?

3. Would Hannah be a good candidate for an ER/LA opioid? Why or why not?

EXERCISE 2Instructions: Read the case below and com-plete the activities that follow.

Part 1 – Application: Take 5 minutes re-viewing the scenario as it relates to either your clinical practice or the systems of care in which you work.

I. Evaluate application, or options for planned application, as it would apply in your own practice.

II. Consider the expected outcome(s) of those applications.

90

thoughts since the risk of suicide is roughly double for patients with chronic pain.85 Some free instruments for gathering a psychiatric history are the Depression Anxiety & Positive Outlook Scale (www.dapos.org) or the Patient Health Questionnaire (PHQ Screeners (www.phqscreeners.com). Referral to a mental-health professional is warranted if you suspect a pa-tient has active psychological issues beyond your expertise.

Clinicians should also probe for ways in which pain may be affecting the patient’s family sys-tem, work, or social activities. Pain can seriously erode these spheres of life and evaluating these challenges and addressing them during treat-ment (for instance by referral to a vocational counselor or social worker) is just as important as treating the more immediate medical issues that may be contributing to chronic pain.

PATIENT/PROVIDER AGREEMENTSAn opioid “medication agreement” or “manage-ment plan” can help educate patients, clarify ex-pectations, and establish goals, all of which may help a patient adhere to a pain management reg-imen.5 These agreements should be written and signed by the provider and the patient. (Table 4)

Avoid framing patient/provider agreements in terms of punishments for misbehaviors and avoid using language that is stigmatizing, dom-inating, or pejorative. Since written agreements must be clearly understood by the patient, they should be written at the sixth- to seventh-grade level, and translated into the patient’s language, if possible (in-person translators may also be used).86 When administering an agreement, al-low time for patients to ask questions, and to ensure patients understand what they are being told. Some, or all, of these tasks may be han-dled by trained personnel (or staff members) rather than physicians.

Be aware that although the terms “agreement” or “plan” are more patient-friendly than the word “contract,” from a legal standpoint, any written or oral agreement between a prescrib-er and a patient may be considered a binding “contract.”87

TAKE A FUNCTIONAL APPROACHSince pain itself cannot be measured objec-tively, opioid management plans and provider/patient agreements should not be framed sole-ly in terms of pain relief; functional goals are preferable. Chronic pain often impairs function-ing in daily life, such as the ability to be phys-ically active, mentally focused, and well-rested. Even relatively modest reductions in pain (e.g.,

a 20% reduction on a pain score) can allow for significant functional improvements.88 (Table 5)

By using functional goals a prescriber can make more objective decisions about prescribing, dose adjustments, and/or treatment termina-tion. Objective data can be used such as atten-dance at physical therapy appointments, num-ber of days sleeping in a bed instead of a chair, or distance walking (a pedometer is a good way to measure this). Taking a functional approach to pain management may also help you spot patients who are addicted to an opioid because addiction typically leads to decreased function-ing, while effective pain relief typically improves functioning.63

Functional treatment goals should be realistic and tailored to each patient. Because patients with long-standing chronic pain are frequently physically deconditioned, progress in achieving functional goals can be slow or interrupted with

“setbacks.” It is better to set goals slightly too low than slightly too high. Raising goals after a patient has “succeeded” is preferable—and more motivational—than lowering goals after a patient has “failed.”63

INFORMED CONSENT Informed consent is a fundamental part of ethim ical treatment, and is particularly important when considering an opioid or other controlled sub-stance, given their potential risks. Well-crafted informed consent documents that are explained clearly and carefully can actually improve the clinician/patient relationship. In creating and using informed consent documents, keep the following four questions in mind:89

1. Does the patient understand their treat-ment options?

2. Has the patient been told of the potential benefits and risks associated with each of those options?

Functional Goal Evidence

Begin physical therapy Letter from physical therapist

Sleeping in bed as opposed to lounge chair Report by family member or friend (either in-per-son or in writing)*

Participation in pain support group Letter from group leader

Increased activities of daily living Report by family member or friend

Walk around the block Pedometer recordings or written log of activity

Increased social activities Report by family member or friend

Resumed sexual relations Report by partner

Returned to work Pay stubs from employer or letter confirming the patient is off of disability leave

Daily exercise Gym attendance records or report from family member or friend

TABLE 5. EXAMPLES OF FUNCTIONAL GOALS AND EVIDENCE USED TO ASSESS PROGRESS

Rationale (what you are treating and why)

Risks of the drug (side effects as well as risk of dependence, tolerance, addiction, misuse, and over-dose; and risk of driving, working, etc., under the influence of the drug)

Treatment goals (pain level, function level)

Monitoring plan (how often to return for follow up)

Refill policy

Action plan for suspected aberrant behavior (may include urine drug screens to ensure the patient is not diverting the medication)

Conditions for discontinuing opioids (lack of efficacy, pain resolution, aberrant behavior)

TABLE 4: COMMON COMPONENTS OF OPIOID MEDICATION AGREEMENTS5

SOURCE: FISHMAN SM. RESPONSIBLE OPIOID PRESCRIBING: A CLINICIAN’S GUIDE, 2ND ED. WATERFORD LIFE SCIENCES. 2012.

* INVOLVING OTHER PERSONS REQUIRES EXPLICIT PERMISSION FROM THE PATIENT, AND THIS

PERMISSION SHOULD BE DOCUMENTED, PREFERABLY IN WRITING.

91

WHO ARE PAIN MEDICINE SPECIALISTS?

Pain Medicine is the medical specialty dedicat-ed to the prevention, evaluation and treatment of people with chronic pain. While most physi-cians, advanced practice nurses, and physician assistants have some training and experience in the management of chronic pain, Pain Med-icine Specialists (physicians) have fellowship training from The American Board of Medical Specialties (ABMS), the American Osteopathic Association (AOA), or additional training in pain medicine sufficient to obtain ABPM diplomat sta-tus. Current protocols regarding the delineation of prescribing authority to and supervision of Advanced Practice Nurses with certificate of fit-ness for prescribing and Physicians Assistants for prescribing to treat chronic pain continue to apply. Pain Medicine Specialists may deal with patients being treated with more than 90 milli-gram morphine equivalents daily dose because they are at least eleven times more likely to suf-fer an adverse effect including overdose death.

3. Is the patient free to choose among those options (meaning free from coercion by the healthcare professional, the patient’s fam-ily, or others?)

4. Does the patient have the cognitive and sensory capacity to communicate his or her preferences—verbally or in other ways?

Informed consent can be documented on paper or electronically, and the informed consent lan-guage can be incorporated into a larger treat-ment plan or patient/provider agreement.

INITIATING OPIOIDSBefore prescribing any opioid, confirm that:

• Other treatments with more optimal risk-benefit profiles have been exhausted

• The patient’s physical and psychosocial condition has been fully assessed

• Level of opioid tolerance has been deter-mined or estimated (see below)

• Informed consent has been obtained and a management plan is in place

Opioid selection, initial dosing, and titration must be individualized to the patient’s health status, previous exposure to opioids, and treatment plan.5 Patients who are opioid-naïve or have modest previous opioid exposure should be started at a low dose, generally of a short-acting opioid because these confer a low-er risk of overdose, and titrated slowly upward to decrease the risk of opioid-related adverse effects.5 If it is unclear whether a patient has

recently been using opioids (either prescribed or non-prescribed), the clinician should as-sume that the patient is opioid-naïve (i.e., not tolerant) and proceed as just described. Some patients, such as frail older persons or those with comorbidities, may require an even more cautious therapy initiation. Prescribers should understand the warning signs and symptoms of significant respiratory depression (i.e., shallow, slow breathing, pinpoint pupils, cyanosis), com-municate this information to patients, and be alert for the possibility of respiratory depres-sion at the time of treatment initiation or dosage increase.

Prescribe opioids cautiously in patients with conditions that may be complicated by adverse effects from opioids, such as chronic obstructive pulmonary disease (COPD), congestive heart failure, sleep apnea, current or past substance use disorder, mental illness, advanced age, or patients with a history of renal or hepatic dys-function.5

Because of the risk of neonatal opioid with-drawal syndrome with prolonged use of an opi-oid during pregnancy, newly pregnant women should have a urine drug test administered to ascertain previous use, and, for women who are not pregnant, providers should discuss a birth control plan to prevent unintended pregnancy. In general, opioids should be avoided in this population.5

Opioid prescriptions should be handled by a single provider or practice and all prescriptions should be filled in a single pharmacy, unless the provider is informed and agrees that the patient can go to another pharmacy for a specific rea-son. Prescribers should tell patients and care-givers to read the specific ER/LA opioid analge-sic Medication Guide that they receive from the pharmacy and to tell their doctor about any side effects or adverse events they experience.An initial trial of an opioid should be assessed using the following outcome measures:63

• Progress toward meeting functional goals• Presence and nature of adverse effects• Changes in the underlying pain condition• Changes in medical or psychiatric comor-

bidities• Degree of opioid tolerance in the patient• Identification of aberrant behaviors, mis-

use, or diversionFurther studies are needed to confirm more consistent control of pain and improved adher-ence to prescribed therapy with use of ER/LA opioids.90 Although low-dose, short-acting opi-oids may offer the greatest safety for initiating

opioid therapy, clinicians must recognize that short-acting opioids are not intrinsically saf-er than other formulations, and stress to their patients the importance of strict adherence to prescribed doses/administration.90

The CDC recommends that patients on opi-oid doses of 90 morphine-equivalent dose/day (MEDD) or greater should be referred to a pain specialist for consultation and/or man-agement.90 If a provider cannot make the re-quired consultation, it is recommended that he/she should clearly document why not. (Note: a pain specialist is a physician who has undergone fellowship training from the American Board of Pain Medicine or other training sufficient to ob-tain diplomat status.) In general, current guide-lines suggest that doses of >90 MEDD should be avoided.1

PATIENT EDUCATIONWhenever an opioid is prescribed, the patient should be thoroughly educated about the safe use, storage, and disposal of opioid medica-tions. This can be done by a non-physician, if desired, and the key points can be included in patient/provider agreements or treatment plans. (Prescribers should use the Patient Counseling Document as part of the discussion when pre-scribing opioid analgesics—see Table 11). Safe use means following clinician instructions about dosing (including how to handle missed doses), not using concurrent alcohol or seda

tives, not sharing medications, not breaking, chewing, or crushing medicines, and not using transdermal products if they are broken or torn. (If a patient cannot swallow a capsule whole, prescribers should refer to the product labeling to determine if it is appropriate to sprinkle the contents of a capsule on applesauce or admin-ister via a feeding tube.) Patients should also be warned not to abruptly discontinue or reduce their ER/LA opioid analgesic, and be informed about the potential risks of falls, driving, and working with heavy machinery (particularly after dose initiation or an upward change in dose).

Prescribers should instruct patients and care-givers to tell all of their doctors about all med-ications the patient is taking. Furthermore, pre-scribers should strongly discourage the use of benzodiazepine medications and other respira-tory depressants, including alcohol, concurrent with an opioid. Safe storage means remindingpatients that pain medications are sought-af-ter by many people, and that opioids should be stored in a locked cabinet or other secure storage unit. If a locked unit is not available, patients should, at least, not keep opioids in a

92

place that is obvious to, or easily accessed by others, since theft by friends, relatives, and guests is a known route by which opioids be-come diverted.91 Storage areas should be cool, dry, and out of direct sunlight.

Proper disposal means getting rid of unused medications by: returning the medications to a pharmacy, health center, or other organization with a take-back program; flushing them down a toilet (unless prohibited by state law); or mixing the medication with an undesirable substance and putting it in the trash. In 2014, the DEA loosened regulations to allow pharmacies, hos-pitals, clinics, and other authorized collectors to serve as drop-off sites for unused prescription opioid drugs.

OPIOID SELECTIONOpioid analgesics are available in a wide range of formulations and routes of administration (Table 6). Little evidence exists that specific analgesic formulations affect efficacy or risk of opioid use disorder, so selection of an agent should be based on the patient’s pain complaint, lifestyle, and preferences.52 Generally, if opioids are used at all, it is better to offer short-act-ing opioids used on an as-needed basis. ER/LA opioids produce a more steady state of analge-sia without the cycling effect of pain relief and withdrawal associated with short-acting opioids, which may be helpful for certain patients.53 With ER/LA agents, however, patients may end up using more drug than is actually needed, and physiological adaptations to the steady state may ultimately decrease analgesic efficacy.54 In addition, ER/LA opioids pose a higher risk for being abused or misused.

Prescribers should educate themselves about the general characteristics, toxicities, and drug interactions for ER/LA opioid products. [For detailed information on current ER/LA opioid analgesics, see the FDA Blueprint for Prescrib-er Education at the end of this document]. For example, some ER/LA formulations may rapidly release opioid (dose dump) when exposed to alcohol.13 In addition using opioids with mono-amine oxidase inhibitors (MAOIs) may increase the risk of respiratory depression and serotonin syndrome.13 Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone (ADH).

Combination products join an opioid with a non-opioid analgesic, usually for use in pa-tients with moderate pain. Using a combination product when dose escalation is required risks increasing the adverse effects from the non-opi-oid co-analgesic, even if an increase of the opi-oid dose is appropriate. In such cases, using a

pure opioid is preferable. Particular care must be made to not exceed maximal daily doses of acetaminophen.

THE SPECIAL CASE OF METHADONEMethadone has received growing attention be-cause it is frequently involved in unintentional overdose deaths.92 These deaths have escalated as methadone has increasingly been used as an analgesic drug for chronic pain.90 At one time, methadone had been used almost exclusively in opioid maintenance therapy programs to treat opioid use disorder. Its relatively long plasma elimination half-life compared to its relatively short analgesic half-life makes it optimal for maintenance, allowing for once-daily dosing. But methadone only exerts potent analgesic effects in the early phase of its elimination half-life (about 4 hours), and this, along with the fact that it is among the least expensive opioids, has led to a dramatic increase in its use for alleviat-ing chronic non-cancer pain.5

Methadone has unique pharmacokinetic and pharmacodynamic characteristics that add sub-stantial risk to its use. Although its chemical structure is different from classic opioids such as morphine, methadone acts on the same set of opioid receptors, though with different affin-ities for the various opioid receptor subtypes.93 In addition, methadone possess non-opioid receptor effects that may explain some of its potential special efficacy. These varied effects across opioid receptors, along with its non-opi-oid properties, have garnered methadone the reputation of being a “broad spectrum opioid.” For a number of reasons, however, methadone must be titrated very carefully in order to avoid overdose. These reasons include:93

• An analgesic half-life much shorter than its elimination half-life (leading to accumula-tion)

• Metabolism by a group of liver enzymes that differ from those associated with most other opioids, hence leading to unexpected drug-drug interactions

• Significant genetic variations in the liv-er enzymes that metabolize methadone, which contribute to the unpredictability of methadone’s effects and side effects

• Metabolism may be affected by cigarette smoking (which accelerates elimination) and alcohol consumption (which can aug-ment methadone toxicity acutely and accel-erate metabolism with chronic use)

The APS/AAPM guidelines recommend a starting dose in most opioid-naive patients of 2.5 mg every 8 hours, with dose increases occurring no more frequently than weekly.5 The lowest possible dose titration should be followed even

in opioid-tolerant patients because methadone appears to be more potent in patients who have been using higher doses of the pre-switch opi-oid. The total daily dose of methadone on the first day of treatment should not ordinarily ex-ceed 30-40 mg/d regardless of prior exposure.5 In older patients or those with renal or hepatic comorbidities, lower starting doses, less fre-quent dosing, and more cautious dose titration are recommended. Because of its long half-life and variable pharmacokinetics, methadone is not recommended to treat breakthrough pain or as an as-needed medication.

When rotating from another opioid to metha-done, extreme caution must be used when re-ferring to equianalgesic conversion tables. The consensus recommendations from an expert panel suggest a 75 to 90% decrement in the equianalgesic dose from conventional conver-sion tables when a switch is made from another opioid to methadone.94

Because the risk of overdose is particularly acute with methadone, patients should be ed-ucated about these risks and counseled to use methadone exactly as prescribed. They should also be warned about the dangers of mixing unauthorized substances with their medication. Benzodiazepines, in particular, pose a threat. Death investigations often find that benzodiaze-pines have been used in combination with meth-adone and other opioids.92 Other respiratory de-pressants, including alcohol, pose similar risks. Dosing should, therefore, be conservative and cautious until patients demonstrate the ability to tolerate and use the drug safely.

In 2006, the FDA issued a public health advi-sory warning that methadone can cause serious cardiac conduction disturbances, including QT interval prolongation and Torsades de Pointes, a potentially fatal ventricular arrhythmia.95 It appears that methadone-related corrected QT (QTc) interval prolongation (>450 ms) and cardiac arrhythmias can occur at any dose but are more likely at higher doses or with concom-itant use of drugs that interact with methadone or that themselves prolong QTc. Although un-common, the cardiac arrhythmias that can be induced by methadone can be lethal if not de-tected. The cardiac health of patients who are candidates for methadone should be assessed, with particular attention paid to any history of heart disease or arrhythmias.96 An initial ECG may be advisable prior to starting methadone, par-ticularly if a patient has a specific cardiac disease or cardiac risk factors or is taking agents that may interact with methadone. Alternative treatments should be considered when the QTc is >450 ms.

93

Oral By mouth (per os)Requires functioning GI tract, intact swallowing mechanism, sufficient GI tract for absorption to occur

NSAIDS, opioids, adjuvant analgesics (TCA, Antiepileptics, SNRI)

Advantages: convenient, noninvasive, usually cost-effective, flexible, less discomfort than injections with comparable efficacyDisadvantages: requires functional GI system; slow onset of action and relatively delayed peak effects; requires patient compliance

Rectal Insertion of suppository into rectum

Opioids Useful in patients who cannot take medications by mouthAny opioid may be compounded for rectal administration

Intramus-cular

Injection into large muscle (e.g., gluteus or vastus lateralis)

Opioids IM administration should not be used, especially for chronic treat-ment, due to multiple disadvantages:• Painful injections• Wide fluctuations in drug absorption make it difficult to main-

tain consistent blood levels• Rapid fall-off of action compared with PO administration• Chronic injections may damage tissue (fibrosis, abscesses) IV

and SC injections are appropriate alternatives

Intravenous Injection into vein; may be single or repetitive bolus or continuous infusion with or without PCA

NSAIDS, opioids, ketamine, acetamin-ophen

IV is most efficient ROA for immediate analgesia and permits rapid titrationIV bolus produces rapid onset of effect, but shorter duration of action than IM; not recommended for drugs with long half-livesContinuous IV infusion provides steadier drug blood levels, which maximize pain relief while minimizing side effects

Subcutane-ous

Placement of drug just under skin with small needleContinuous SC infusion can be obtained with a small needle

Some opioids Advantages: produces steady blood levels; time until onset of effect is comparable to IM administration and effects are longer lasting, with less painful administration; cheaper than IV adminis-tration; obviates need for GI functionDisadvantages: slower onset and offset and lower peak effects than IV administration, time consuming, often disliked by patients

Topical Applied directly to the skin, where the drug penetrates

NSAIDs, local anesthetics(e.g., lidocaine patch and gel, EMLA®), capsaicin

Advantages: local effect (i.e., no significant serum levels) limits side effects to local reactions; no drug-drug interactions; easy to use, no titration neededDisadvantages: may cause local skin reactions

Transdermal Absorbed through skin with gradual release into the system-ic circulation

Some opioids Advantages: convenient, noninvasive, provides prolonged, relative-ly stable analgesiaDisadvantages: delayed onset of action with first dose, drug absorption influenced by internal or external heat, may cause skin irritation

Oral trans-mucosal

Delivery of drug to mouth, including sublingual (under tongue) and buccal/gingival administration

Some opioids Advantages: easy, requires little staff supervision; avoids significant liver metabolism associated with oral opioidsDisadvantages: variable absorption, bitter taste, dose is limited

OTFC Fentanyl incorporated into a sweetened matrix on a stick for consumption

Fentanyl Some absorption via oral mucosa, but most via GI tract; yields higher drug levels and better bioavailability than oral fentanyl

Intranasal Small aerosol device placed inside nostril that delivers a calibrated dose of a drug

Butorphanol, sumatriptan, fentanyl, naloxone

Takes advantage of rich blood supply to nose and also avoids significant liver metabolism associated with some drugs

Intraspinal Epidural and intrathecal adminis-tration (see Table 29)

Other(-sublingual, vaginal)

Placement of drug under the tongue (sublingual) or in the vagina

Opioids, benzodiazepines (intravag-inal)

Most opioids can be absorbed sublingually or vaginally in patients who have problems such as impaired swallowing, short gut syn-drome, or poor IV access

ROUTE DEFINITION AND NOTES DRUG TYPES COMMENTS

TABLE 6. ROUTES OF ADMINISTRATION

94

ABUSE-DETERRENT FORMULATIONSConcern about opioid misuse and abuse has spurred efforts to create abuse-deterrent opioid formulations. Three agents are currently available, which are co-formulated with an opioid antagonist: Targiniq ER (oxycodone and naloxone), Embeda ER (morphine and naltrexone), and Troxyca ER (oxy-codone HCL-naltrexone capsules). Abuse-deterrent forms of oxycodone ER, Hysingla ER, Zohydro ER, Exalgo, Opana ER, and Xtampza ER contain a variety of substances that make the pills difficult to crush, snort, or melt or which inactivate the opioid in other ways if a pill or capsule is altered. Transdermal opi-oid formulations were thought to be less vulnerable to misuse, but such formulations can be abused.97

PATIENT MONITORINGIf an opioid medication appears to be beneficial (as determined by the functional goals outlined in the management plan) and therapy is continued, regular review and monitoring should be performed for the duration of treatment based on the needs and characteristics of each patient. Clinicians must evaluate progress against agreed-upon treatment goals for both pain relief and function, assess for physical and behavioral adverse effects, and confirm adherence to prescription regimens by performing medication reconciliation as indicated. Clinicians should also re-evaluate a patient’s un-derlying medical condition if the patient’s clinical presentation changes with time.13

The intensity and frequency of monitoring is guid-ed, in part, by the clinician’s assessment of the pa-tient’s risk for abuse, diversion, or addiction. Tools and techniques similar or identical to those used during an initial assessment of a patient’s risk can be used to re-assess or monitor risk on an on-going basis.

Patients who may need more frequent or intense monitoring include:

• Those with a prior history of an substance use disorder or other aberrant use

• Those in an occupations demanding mental acuity

• Older adults• Patients with an unstable or dysfunctional so-

cial environment • Those with comorbid psychiatric or medical

conditions• Patients on higher doses of opioids (>90 mg

MEDD)

Patient monitoring includes re-evaluation of the patient’s underlying medical condition if the clinical presentation changes over time.

CAUTION ABOUT DOSE ESCALATIONWhen treating chronic pain with opioids, dose escalation has not been proven to reliably re-duce pain or increase function, but it can in-crease risks.98 Prescribing high-dose opioid ther-apy (≥90 mg MEDD) is not supported by strong evidence, and, indeed, a recent cohort study of 9,940 patients receiving opioid analgesics for chronic non-cancer pain found that patients re-ceiving 100 mg or more per day had an 8.9-fold increase in overdose risk compared to patients receiving 1-20 mg. of opioids per day.73 No ran-domized trials show long-term effectiveness of high opioid doses for chronic non-cancer pain. Many patients on high doses continue to have substantial pain and related dysfunction.98 As noted earlier, higher doses of opioids are as-sociated with increased risks for adverse events and side effects including overdose, fractures, hormonal changes, and increased pain sensitiv-ity.

URINE DRUG SCREENSUrine drug testing is an imperfect science, but such testing can be a helpful component of responsible opioid prescribing. Drug testing should be conducted in a consensual manner as part of an agreed-upon opioid management plan and with the idea that such testing benefits both the patient and the provider. The potential benefits of urine drug testing include:

• Serving as a deterrent to inappropriate use• Providing objective evidence of compliance

with prescribed drugs, or evidence that non-prescribed drugs are being used

• Evaluating for diversion• Monitoring response to treatment• Helping patients allay concerns by family

members, employers, or law-enforcement• Demonstrating to regulatory authorities a

clinician’s dedication to “best practices”

Zeke is a 25-year-old construction worker who is currently taking workman’s compen-sation to recover from a compound fracture of his right foot and ankle sustained when a cement block slipped off of a pallet and landed on his foot. The fractures required two surgeries to correct, with the implan-tation of several internal fixation devices. Zeke was prescribed a short-acting opioid after each surgery, which he has continued to use. He has been regularly attending physical therapy sessions to restore muscle tone in his right leg, but has come into the clinic today seeking an ER/LA opioid. The short-acting medication, he says, is “chop-py” and allows his pain to return at the end of each dosing cycle. He says friends have suggested that a long-acting opioid would be easier to use and would provide him more steady pain relief.

Part 2 - Questions and Considerations: Spend 5 minutes considering the follow-ing questions as they relate to the case presented.

1. What steps might you take before agree-ing to a trial of an ER/LA medication for Zeke?

2. What specific kind of ER/LA medication might be most appropriate for Zeke if no

contraindications were found in the pain and substance abuse assessment?

3. Name three specific functional goals that might be used as the basis for a pain

management agreement with Zeke.

EXERCISE 3

Instructions: Read the case below and com-plete both learning activities that follow.

Part 1 – Application: Take 5 minutes re-viewing the scenario as it relates to either your clinical practice or the systems of care in which you work.

I. Evaluate application, or options for planned application, as it would apply in your own practice.

II. Consider the expected outcome(s) of those applications.

95

In primary care settings, unobserved urine col-lection is usually acceptable, however, clinicians should be aware of the many ways in which urine specimens can be adulterated. Specimens should be shaken to determine if soap products have been added, for example. The urine color should be noted on any documentation that accompa-nies the specimen for evaluation, since unusu-ally colored urine could indicate adulteration. If possible, urine temperature and pH should be measured immediately after collection.99

Prescribers should be familiar with the metab-olites associated with each opioid that may be detected in urine, since the appearance of a me-tabolite can be misleading. A patient prescribed codeine, for example, may test positive for mor-phine because morphine is a codeine metabo-lite. Similar misunderstandings may occur for patients prescribed hydrocodone who appear positive for hydromorphone or patients pre-scribed oxycodone who test positive for oxymor-phone. In the event of an unexpected urine drug screen, prescribers should consider a differen-tial diagnosis that includes: drug abuse or ad-diction; self-treatment of poorly-controlled pain; psychological issues; or diversion (which may be suggested by absence of prescribed opioids).5

PROTECTING AGAINST OPIOID-INDUCED ADVERSE EVENTSThe Veterans Administration/Department of Defense (VA/DoD) clinical practice guideline outlines a number of evidence-based strategies to reduce opioid-related adverse effects, sum-marized in Table 7.100 Prophylaxis for constipa-tion—the most common opioid-induced adverse event—has been facilitated by the approval of methylnaltrexone subcutaneous administration and naloxegol oral administration for patients with chronic non-cancer pain. Note that one of the potential complications of treatment is opioid use disorder, and practitioners should be prepared to educate patients about this risk and to provide direct addiction treatment or referral to an addiction treatment program if needed.

Both male and female patients on long-term opioid therapy are at risk for hypogonadism, thus current guidelines suggest that the endo-crine function of all patients should be assessed at the start of long-term opioid therapy and at least annually thereafter. The symptoms of hypogonadism in both genders may include fa-tigue, mood changes, decreased libido, loss of muscle mass, and osteoporosis. Although there are insufficient data to recommend routine en-docrine screening of asymptomatic patients, current guidelines do recommend such testing for patients exhibiting any of the aforemen-tioned signs and symptoms.5

OPIOID ROTATIONSwitching from one opioid to another may be needed to reduce side effects, improve efficacy, avoid dose limitations of co-compounded acet-aminophen, or because of a patient’s inability to absorb the medication in its present form. Opioid rotation must be done cautiously be-cause of the many pharmacokinetic and phar-macodynamic variables involved.63 An equian-algesic chart should be used when changing from one opioid to another or from one route of administration to another. Such charts must be used carefully, however. A high degree of variation has been found across the various charts and online calculators, and may account for some overdoses and fatalities.92 The optimal dose for a specific patient must be determined by careful titration and appropriate monitoring, and clinicians must remember that patients may exhibit incomplete cross-tolerance to different types of opioids because of differences in the receptors or receptor sub-types to which differ-ent opioids bind. Do not simultaneously switch both an agent and a route of administration or type of release (e.g., ER/LA)

MANAGING PAIN FLARE-UPSPain is dynamic, and ER/LA analgesics may not control pain flare-ups. Having patients track flare-ups with paper or electronic pain diaries can help

them spot correlations between the flare-ups and variables in their lives. If specific triggers are identified, patients may be able to make changes that will reduce the prevalence of episodes with-out recourse to increased medication.63

Non-opioid methods of dealing with pain flare-ups (e.g., cold or warmth, massage, yoga, acu-puncture, meditation, electrical stimulation) should be tried—or at least considered—be-fore the dose of an opioid is increased. As with the management of the underlying chronic pain condition, clinicians should use an agreed-upon set of functional goals as a way to monitor, and if necessary, adjust, the use of as-needed opi-oid medications for pain flares.

USING PRESCRIPTION MONITORING PROGRAMS Prescription drug monitoring programs (PDMPs) offer point-of-care access to pharmacy dis-pensing records of controlled substances from prescribers. From these, clinicians can quickly assess patterns of prescription drug use that can be helpful in confirming or refuting suspi-cions of aberrant behaviors. Information from the PDMP may also reveal that a patient is be-ing prescribed medications whose combinations are contraindicated. By reviewing the PDMP each prescriber can identify other prescribers involved in the care of their patient. This can be

Constipation Methylnaltrexone or naloxegolProphylactic mild peristaltic stimulant (e.g. bisacodyl or senna)If no bowel movement for 48 hours, increase dose of bowel stimulantIf no bowel movement for 72 hours, perform rectal examIf not impacted, provide additional therapy (suppository, enema, magne-sium citrate, etc.)

Nausea orvomiting

Consider prophylactic antiemetic therapyAdd or increase non-opioid pain control agents (e.g. acetaminophen)If analgesia is satisfactory, decrease dose by 25%Treat based on cause

Sedation Determine whether sedation is due to the opioidEliminate nonessential CNS depressants (such as benzodiazepines)Reduce dose by 10-15%Add or increase non-opioid or non-sedating adjuvant for additional pain relief (such as NSAID or acetaminophen)so the opioid can be reduced Add stimulant in the morning (such as caffeine)Change opioid

Pruritus Consider treatment with antihistaminesChange opioid

Hallucination or dysphoria Evaluate underlying causeEliminate nonessential CNS acting medications

Sexual dysfunction Reduce doseTestosterone replacement therapy may be helpful (for men)Erection-enhancing medications (e.g., sildenafil)

Table 7: Recommendations for preventing or treating opioid-induced side effects100

96

especially useful for new patients to a practice on high dose opioids, with suspect or concern-ing behaviors.

ADDRESSING CONCERNS ABOUT PRESCRIPTION ACTIVITYSuspicion that a patient is non-adherent to a prescription or is engaging in aberrant drug-re-lated behaviors should prompt a thorough in-vestigation of the situation, including an honest evaluation of the patient/provider relationship, which may be strained by such behaviors.63 Pos-sible reasons for non-adherence include:

• Inadequate pain relief• Misunderstanding of the prescription • Misunderstandings related to lack of fluen-

cy with English• Attempts to “stretch” a medication to save

money• Cultural or familial pressure not to take a

medication • Stigma about taking a pain medication • Patient fears about addiction• Misuse, abuse, addiction• Diversion

Here are some possible ways to respond to con-cerns about a patient’s prescription activity:

• Discuss the situation with the patient: express concern over the pattern of be-havior; discuss how opioid use disorder begins; and emphasize its negative conse-quences on health, employment, finances, friends and family, etc.

• Clarify expectations (e.g., receiving con-trolled medications from only one prescrib-er, using only one pharmacy) and review existing patient/provider agreements

• Increase the intensity of patient monitoring (e.g., urine toxicology, pill counts and early refills) and establish limits on refills or lost medications

For persistent non-compliance, options include one or more of the following:

• Tapering drug therapy over several weeks to avoid withdrawal; consider incorporating non-opioid pain treatments

• Referral to specialists, e.g., a pain special-ist, for evaluation of continued controlled substance prescribing

• Referral to an addiction management program

Patients with opioid use disorder and/or com-plex chronic pain problems should maintain a relationship with a primary care provider, even if the management of the pain and/or opioid use disorder will be conducted by specialists. Providers are not required to take action that

they believe to be contrary to the patient’s best interests. If the provider believes that a crime has been committed, he or she has the right to contact law enforcement and/or other providers. In criminal matters HIPAA restrictions generally do not apply. Legal input in difficult cases may be helpful.

DISCONTINUING OPIOID THERAPYStopping long-term opioid therapy is often more difficult than starting it.101 For most patients, a slow weaning is preferred (reducing MEDD by 10% weekly) although a faster weaning (i.e., 25% MEDD reduction weekly) may be possi-ble in selected patients. The longer the patient has been on the drug, and the higher the initial dose, the slower should be the taper.100 Use cau-tion when discontinuing opioids in patients with unstable angina or who are pregnant. Withdraw-al symptoms can be eased with clonidine (0.2 mg po BID) or tizanidine (2 mg po TID).

Discontinuing an opioid may be needed for a variety of reasons, including the healing of an injury or condition, an inability to achieve ad-equate analgesia, the lack of progress toward functional goals, or the experience of intolera-ble side effects. If inappropriate use of an opi-oid is confirmed, treatment must usually be sus-pended, although provisions should be in place for continuing some kind of pain treatment and/or referral to other professionals or members of a pain management team. Discharge solely for opioid use disorder is not acceptable.

Some clinicians may be willing and able to con-tinue a regimen of opioid therapy even after the discovery of aberrant behavior, although this would require intensified monitoring, patient counseling, and careful documentation of all directives. This level of vigilance and risk man-agement, however, may exceed the abilities and resources of primary care physicians. In such cases, referral to a provider with specialized skill or experience in dealing with high-risk patients may be prudent.

EXERCISE 4

Instructions: Read the following case and com-plete the activities that follow.

Part 1 – Application: Take 5 minutes reviewing the scenario as it relates to either your clinical practice or the systems of care in which you work.

I. Evaluate application, or options for planned application, as it would apply in your own practice.

II. Consider the expected outcome(s) of those applications.

Part 2 - Questions and Considerations: Spend 5 minutes considering the following questions :

1. Would treatment with an NSAID be appro-priate for Clara? Why or why not?

2. Would treatment with an ER/LA opioid be appro-priate for Clara? If so, what specific route of administration and/or agent might be best?

3. What aspects of Clara’s case should be considered when thinking about an initial dose selection of an ER/LA medication?

Clara is a 77-year-old who has been diag-nosed with lumbar spinal stenosis, which is causing a burning pain that radiates across her back and down into her buttocks. She has stage 2 kidney failure, although she is not on dialysis. In the previous two years, she has fallen twice at home, sustaining a subdural hematoma on one occasion and a sprained shoulder on the other. She lives alone and is fiercely independent, continu-ing to drive and adequately maintaining activities of daily living. She has tried nu-merous non-drug treatments for her pain, including physical therapy, acupuncture, massage, yoga, and even medical canna-bis (which she said did help with the pain, but which she didn’t continue because she didn’t like the cognitive effects). She con-tinues to have pain which disrupts her sleep and reduces her incentive to walk.

97

PATIENTS ON WORKERS’ COMPENSATIONOpioids and other associated analgesic medi-cations represent a very significant portion of Workers’ Compensation claims, and the use of opioids is associated with longer periods of disability and lost-work time.102 Effective over-sight and appropriate use of these medications reduce their abuse and diversion, return injured workers to employment sooner, decrease long term disability, improve longevity, and improve patient function.

This population of patients presents its own unique circumstances. Injured workers are gen-erally sent to an occupational medicine facility for treatment. Ideally, the injured worker recov-ers and returns to work in full capacity. If re-covery or healing does not occur as expected, early triage and appropriate, timely treatment is essential to restore function and facilitate a return to work.

The use of opioids in this population of patients can be problematic. Some evidence suggests that early treatment with opioids may actually delay recovery and a return to work.102 Conflicts of motivation may also exist in patients on work-er’s compensation, such as when a person may not want to return to an unsatisfying, difficult, or hazardous job. Clinicians are advised to ap-ply the same careful methods of assessment, creation of treatment plans, and monitoring used for other pain patients but with the add-ed consideration of the psycho-social dynamics inherent in the workers’ compensation system. Injured workers should be afforded the full range of treatment options that are appropriate for the given condition causing the disability and impairment.

When a Workers’ Compensation patient is being prescribed chronic opioids, and that patient is also being prescribed other scheduled medica-tions for a co-morbid mental or sleep disorder by a non-psychiatrist, use of chronic opioids for pain is generally not appropriate. If a co-morbid mental illness appears during tapering to re-quire continued treatment with one or more oth-er scheduled medications or anti-psychotics or anti-convulsants, a psychiatrist should be con-sulted for help with managing the mental illness during chronic pain management. The psychiat-ric evaluation and treatment is not the financial responsibility of the employer/insurer, unless the mental illness is accepted as work related.

The physician should do a face-to-face exam-ination at least six times yearly if the patient is on any schedule II or III medication concurrently for chronic pain management and mental illness.

Reexamination must be performed by the autho-rized treating physician/qualified physician/pain medicine specialist in person at least every 90 days (except in the special cases of catastrophic injury and persistent pain syndromes on long term stable opioid use for over two years).

In order to justify the continued use of opioids, the treating physician must document that with the use of opioids, the pain level has been measurably improved (based on Visual Analog Scores, in comparison of pain levels without use of opioids) and there has been a definite improvement in function with the use of the opioids, as measured by an objective function-al assessment tool/questionnaire (such as the Physical Functional Ability Questionnaire).

In the absence of objective functional improve-ment, the physician must give a written opinion that “the present regimen is the best that can be done and that without it, deterioration in function or daily activities would likely occur. “ An annual attempt should still be made to wean/taper the scheduled medications.

PEDIATRIC PATIENTSBecause of their more robust inflammatory re-sponse and immature central inhibitory influ-ences, infants and young children may actually experience greater pain sensations and pain-re-lated distress than adults.103 Effective pain man-agement in the pediatric population is critical since children and adolescents experience a va-riety of acute and chronic pain conditions asso-ciated with common childhood illnesses and in-juries, as well as some painful chronic diseases that typically emerge in childhood such as sickle cell anemia and cystic fibrosis.

The same basic principles of appropriate pain management for adults apply to children and teens, which means that opioids have a limited place in the treatment armamentarium. Develop-mental differences can make opioid dosing chal-lenging, especially in the first several months of life. In the first week of a newborn’s life, for example, the elimination half-life of morphine is more than twice as long as that in older children and adults, as a result of delayed clearance.104 For older children, dosing must be adjusted for body weight.

The American Pain Society and the American Academy of Pediatrics have issued the following recommendations for pain management in chil-dren and teens:105

• Provide a calm environment for procedures that reduce distress-producing stimulation

• Use age-appropriate pain assessment tools and techniques

• Anticipate predictable painful experiences, intervene, and monitor accordingly

• Use a multimodal approach (pharmaco-logic, cognitive, behavioral, and physical) to pain management and use a multidisci-plinary approach when possible

• Involve families and tailor interventions to the individual child

• Advocate for the effective use of pain med-ication for children to ensure compassion-ate and competent management of their pain

OPIOIDS AND PREGNANCYThere are no adequate and well-controlled studies of ER/LA opioid analgesics in pregnant women. Current American Pain Society-American Academy of Pain Medicine (APS-AAPM) guide-lines suggest that clinicians should avoid pre-scribing opioids during pregnancy unless the potential benefits outweigh risks.5 Some data suggest an association between the use of long-term opioid therapy during pregnancy and ad-verse outcomes in newborns, including low birth weight and premature birth, though co-related maternal factors may play a role in these asso

OTHER DRUGS OF CONCERN RELATED TO PAIN MANAGEMENT

In addition to opioids, three other drug classes are of concern to public health officials: ben-zodiazepines; barbiturates; and the muscle

relaxant carisoprodol.• Benzodiazepines and barbiturates are

generally used as anti-anxiety medica-tions and share with opioids the poten-tial for abuse, addiction, and respiratory depression. For this reason they should not be prescribed concurrently with any opioid analgesic, and patients should be educated about the hazards of combined

use.• Carisoprodol is a centrally-acting skeletal

muscle relaxant. It’s primary active me-tabolite is meprobamate, which is a con-trolled substance (carisoprodol itself is classified in Schedule IV). Meprobamate has an addictive potential similar to ben-zodiazepines and is pharmacologically similar to barbiturates. Its clinical effec-tiveness is low and its side effect profile

is high. • Patients have been reported to substi-

tute the easily-obtained carisoprodol for the more strictly controlled opioids and

benzodiazepines.

98

ciations and causality is not certain.5 Exposure to these medications has also been associated with birth defects in some studies. Opioid with-drawal can be expected in up to half of new-borns of opioid-dependent mothers (neonatal abstinence syndrome).5 If a mother is receiving long-term opioid therapy at or near the time of delivery, a professional experienced in the management of neonatal withdrawal should be available.

REDUCING THE RISK OF OVERDOSEOpioid overdose is reversible through the timely administration of the medication naloxone. Nal-oxone is a prescription drug, but it is not a con-trolled substance and has no abuse potential. It is regularly carried by medical first responders and, in many states, can be prescribed like any other medication.

As an opioid antagonist, naloxone can quickly restore normal respiration to a person whose breathing has slowed or stopped as a result of heroin or prescription opioid overdose. It’s crit-ical to point out, however, that if a person was using an ER/LA medication, the duration of the opioid effect may last longer than the duration of the naloxone antagonism and, hence, the pa-tient may regress into respiratory depression.

As of 2010, programs that distribute naloxone to nonmedical personnel had reported more than 10,000 overdose reversals nationwide since 1996.106 As of November 2014, 23 states had statutes allowing for “third-party” prescrip-tions of naloxone (i.e. the prescription can be written to a friend, relative, or person in a posi-tion to assist a person at risk of experiencing an opioid overdose).

Given the effectiveness of naloxone in overdose reversal, the FDA has encouraged innovations in more user-friendly naloxone delivery systems such as auto-injectors, made particularly for lay use outside of health care settings. The FDA ap-proved such an auto-injector in 2014 (Evzio), and an intranasal form called Narcan in 2016.

OLDER ADULTSThe prevalence of pain among communi-ty-dwelling older adults has been estimated be-tween 25% and 50%.107 The prevalence of pain in nursing homes is even higher. Unfortunately, managing pain in older adults is challenging due to: underreporting of symptoms; presence of multiple medical conditions; polypharmacy; de-clines in liver and kidney function; problems with communication, mobility, and safety; and cogni-tive and functional decline in general.

Acetaminophen is considered the drug of choice for mild-to-moderate pain in older adults be-cause it lacks the gastrointestinal, bleeding,

renal toxicities, and cognitive side-effects that have been observed with NSAIDs in older adults (although acetaminophen may pose a risk of liv-er damage). Opioids must be used with partic-ular caution, and clinicians should “Start low, go slow” with initial doses and subsequent titration. Clinicians should consult the American Geriatrics Society Updated Beers Criteria for Potentially In-appropriate Medication Use in Older Adults for further information on the many medications that may not be recommended. Early referral and/or consultation with geriatric specialists or pain specialists may be advisable.

CANCER PAINPain is one of the most common, and most-feared symptoms of cancer. Pain is experienced by about 30% of patients newly diagnosed with cancer, 30% - 50% of patients undergoing treat-ment, and 70% - 90% of patients with advanced disease.11 Unrelieved pain adversely impacts motivation, mood, interactions with family and friends, and overall quality of life. Survival it-self may be positively associated with adequate pain control.108 ER/LA opioid pain medications are the mainstay of cancer pain management and a trial of opioid therapy should be adminis-tered to all cancer patients with moderate or se-vere pain, regardless of the known or suspected pain mechanism.109

ER/LA opioid formulations may optimize an-algesia and lessen the inconvenience associ-ated with the use of short-acting opioids. Pa-tient-controlled analgesia with subcutaneous administration using an ambulatory infusion device may provide optimal patient control and effective analgesia.110 If cancer pain occurs in the context of a patient nearing the end of life, other treatment and care considerations may be appropriate. In these cases, patient care inte-grated with a specialist in palliative care medi-cine may be advisable.

PAIN AT THE END OF LIFE Pain management at the end of life seeks to im-prove or maintain a patient’s overall quality of life. This focus is important because sometimes a patient may have priorities that compete with, or supersede, the relief of pain. Some patients want to be mentally alert to allow them to have meaningful interactions with loved ones, even if this means enduring greater pain.

Since dying patients may be unconscious or only partially conscious, assessing their level of pain can be difficult. Nonverbal signs or cues must sometimes be used to determine if the patient is experiencing pain and to what degree an an-algesic approach is effective. In general, even ambiguous signs of discomfort should usually

be treated, although caution must be exercised in interpreting such signs.111 Reports by fami-ly members or other people close to a patient should not be overlooked. In the Study to Under-stand Prognosis and Preference for Outcomes and Risks of Treatment (SUPPORT) , surrogates for patients who could not communicate verbally had a 73.5% accuracy rate in estimating pres-ence or absence of the patient’s pain.97,112

ER/LA opioids are critical to providing effective analgesia at the end of life, and they are available in such a range of strengths, routes of administration, and duration of action that an effective pain regimen can be tailored to nearly each patient. No specific opioid is superior to another as first-line therapy. Rectal and transdermal routes of administration can be valuable at the end of life when the oral route is precluded because of reduced or absent consciousness, difficulty swallowing, or to reduce the chances of nausea and vomiting.113

Clinicians should be aware, however, that for transdermal products, external heat, fever, and exertion can increase absorption of the opioid, leading to potential overdose. Also, transdermal products with metal foil backings are not safe for use in MRIs.

When selecting an opioid, clinicians should also consider cost, since expensive agents can place undue burden on patients and families.

Fear of inducing severe or even fatal respiratory depression may lead to under-prescribing and reluctance by patients to take an opioid medication.28 Despite this fear, studies have revealed no correlation between opioid dose, timing of opioid administration, and time of death in patients using opioids in the context of terminal illness.114 A consult with a specialist in palliative medicine in these situations may be advisable.

TABLE 8: POTENTIAL PATIENT-CENTERED GOALS OF CARE

• Longer life• Symptom relief• Time at home• Ability to travel• Mental clarity• Physical mobility• Ability to interact with loved ones• Minimizing burdens on loves ones• Personal/Spiritual growth• “Dignity” (though meanings will vary)Source: Forrow L, Smith HS. Pain Management in End of Life: Palliative Care. In Principles & Practice of Pain Medicine, 2nd Ed. Warfield CA and Bajwa ZH Eds. 2004. McGraw-Hill, New York, NY.

99

SPECIFIC DRUG INFORMATION FOR ER/LA OPIOID ANALGESIC PRODUCTSPrescribers should be knowledgeable about general characteristics, toxicities, and drug interactions for ER/LA opioid analgesic products. Table 9 provides general drug information common to the class of ER/LA opioid analgesics.

In addition, prescribers should know specific characteristics of the ER/LA opioid analgesic products they prescribe, including the drug substance, formulation, strength, dosing interval, key instructions, specific information about conversion between products where available, specific drug interactions, use in opioid-tolerant patients, product-specific safety concerns, and relative potency to morphine. Table 10 provides specific drug information for extended-release and long-acting opioid analgesics

Exercises 5 and 6 covers general and specific information for ER/LA Opioid Analgesics, including Table 9 and Table 10. PLEASE SPEND THE ALLOTTED TIME COMPLETING THESE EXERCISES.

For detailed information, prescribers can refer to prescribing information available online via DailyMed at www.dailymed.nlm.nih.gov or Drugs@FDA at www.fda.gov/drugsatfda.

ConclusionsER/LA opioid analgesics can play an important, although limited, role in the treatment of patients with cancer pain, and end-of-life pain. Their use for treating chronic non-cancer pain is more problematic because of their known risks of abuse, addiction, and overdose, as well as the possibility of their being diverted for recreational or unprescribed use. The clinical evidence base supporting the use of ER/LA opioids for chronic non-cancer pain is much weaker than is often assumed, while the evidence for the many risks involved in long-term use of opioids is strong. The risks of ER/LA opioids are amplified among older adults; those with impaired renal or hepatic function; individuals with COPD, cardiopulmonary disorders, sleep apnea, or mental illness; and in patients who are likely to combine opioids with other respiratory depressants such as alcohol or benzodiazepines.

This monograph summarizes established methods for appropriately prescribing opioid analgesics, a task that can be challenging, but it is not inherently different from what physicians face in other treatment settings.

100

EXERCISE 5DRUG INFORMATION COMMON TO THE CLASS OF ER/LA OPIOID ANALGESIC PRODUCTS

Instructions: Spend 20-25 minutes completing the following

1. Conduct a detailed review of the information regarding general characteristics, toxicities, and drug interactions for ER/LA opioid analgesic products.

2. Read and Table 9 which includes additional general drug information common to ER/LA opioid analgesics.3. Complete the learning questions below related to General Drug Information for ER/LA Opioid Analgesic’s after completing steps 1 and 2.

LEARNING QUESTIONS EXERCISE 5COMPLETE ONLY AFTER CONDUCTING STEPS 1 AND 2 ABOVE

1. Are ER/LA opioids recommended for treating acute pain? Why or Why Not?

2. Can ER/LA opioids be safely stopped or tapered rapidly? What methodology is recommended for discontinuing opioid treatment?

3. Name three classes of drugs that should be avoided by patients who have been prescribed an ER/LA opioid analgesic. Describe the underlying reasoning for avoiding concurrent use of the drugs.

101

DRUG INFORMATION COMMON TO THE CLASS OF ER/LA OPIOID ANALGESIC PRODUCTS

Prescribers should be knowledgeable about general characteristics, toxicities, and drug interactions for ER/LA opioid analgesic products. For Example:

a. ER/LA opioid analgesic products are scheduled under the Controlled Substances Act and can be misused and abused.

b. Respiratory depression is the most important serious adverse effect of opioids as it can be immediately life-threatening.

c. Constipation is the most common long-term side effect and should be anticipated.

d. Drug-drug interaction profiles vary among the products. Knowledge of particular opioid-drug interactions, and the underlying

pharmacokinetic and pharmacodynamic mechanisms, allows for the safer administration of opioid analgesics.

i. Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in

profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative

treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of

respiratory depression and sedation.

ii. Some ER opioid formulations may rapidly release opioid (dose dump) when exposed to alcohol. Some drug levels may increase without

dose dumping when exposed to alcohol. See individual product labeling.

iii. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity(e.g., respiratory depression, coma). Certain ER/LA

opioids are contraindicated with MAOIs (tapentadol, morphine). See individual product labeling.

iv. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone (ADH).

v. Some opioids (methadone, buprenorphine) can prolong the QTc interval.

vi. Concomitant drugs that act as inhibitors or inducers of various cytochrome P450 enzymes can result in higher or lower than expected

blood levels of some opioids.

vii. See table 10 for product-specific information.

e. Tolerance to sedating and respiratory-depressant effects of opioids is critical to the safe use of ER/LA opioid analgesics.

i. For ER products, patients must meet the criteria for opioid tolerance, described in the table 10, before using:

a. certain products,

b. certain strengths,

c. certain daily doses, and

d. in specific indicated patient populations (e.g., pediatric patients).

ii. See the (table 10) for product-specific information.

f. ER/LA opioid analgesic tablets must be swallowed whole. ER/LA opioid analgesic capsules should be swallowed intact or when necessary,

the pellets from some capsules can be sprinkled on applesauce and swallowed without chewing.

g. For transdermal products, external heat, fever, and exertion can increase absorption of the opioid, leading to fatal overdose. Transdermal

products with metal foil backings are not safe for use in MRIs.

h. For buccal film products, the film should not be applied if it is cut, damaged, or changed in any way. Use the entire film.

i. Follow the instructions for conversion in the Dosage and Administration section (2.1) in the Prescribing Information of each product

when converting patients from one opioid to another.

102

Arymo ER (morphine sulfate ER tablets)Avinza (morphine sulfate ER capsules)Belbuca (buprenorphine buccal film)Butrans (buprenorphine transdermal system) Dolophine (methadone HCl tablets)Duragesic (fentanyl transdermal system)Embeda (morphine sulfate ER-naltrexone capsules) Exalgo (hydromorphone HCl ER tablets)Hysingla ER (hydrocodone bitartrate ER tablets) Kadian (morphine sulfate ER capsules)

MorphaBond (morphine sulfate ER tablets)MS Contin (morphine sulfate ER tablets)Nucynta ER (tapentadol HCl ER tablets)Opana ER (oxymorphone HCl ER tablets)OxyContin (oxycodone HCl ER tablets)Targiniq ER (oxycodone HCl/naloxone HCl ER tablets) Troxyca ER (oxycodone HCl-naltrexone capsules) Vantrela ER(hydrocodone bitartrate ER tablets) Xtampza ER (oxycodone ER capsules)Zohydro ER (hydrocodone bitartrate ER capsules)

Dosing Interval ◊ Refer to individual product information.

Key Instructions ◊ Limitations of usage:• Reserve for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• Not for use as an as-needed analgesic.• Not for mild pain or pain not expected to persist for an extended duration.• Not for use in treating acute pain.◊ Individually titrate to a dose that provides adequate analgesia and minimizes adverse reactions. ◊ The times required to reach steady-state plasma concentrations are product specific; refer to product information for titration interval◊ Continually reevaluate to assess the maintenance of pain control and

the emergence of adverse reactions. ◊ During chronic therapy, especially for non-cancer-related pain, periodically reassess the continued need for opioids. ◊ If pain increases, attempt to identify the source, while adjusting the

dose. ◊ When an ER/LA opioid analgesic is no longer required, gradually titrat downward to prevent signs and symptoms of withdrawal in the physically-dependent patient. Do not abruptly discontinue these products.

◊ Solid oral dosage forms:• Swallow tablets and capsules whole: crushing, chewing, breaking, cutting or dissolving may result in rapid release and absorption of a potentially fatal dose of opioid.• Some capsules can be opened and pellets sprinkled on applesauce for patients who can reliably swallow without chewing and used immediately. See individual product information.• Exposure of some products to alcoholic beverages or medications containing alcohol may result in the rapid release and absorption of a potentially fatal dose of opioid.• Dispose of unused product by flushing down the toilet.◊ Transdermal dosage forms:• Avoid exposure to external heat. Patients with fever must be monitored for signs or symptoms of increased opioid exposure.• Location of application must be rotated.• Prepare skin by clipping, not shaving hair, and washing area only with water.◊ See individual product information for the following: • Dosage reduction for hepatic or renal impairment.

Table 9: Drug Information Common to the Class of Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

103

Source: FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. May, 2017. https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM515636.pdf. Last Accessed January, 2018.

Drug Interactions Common to the Class • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in pro-found sedation, respiratory depression, coma, and death. Reserve con-comitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.

• Avoid concurrent use of mixed opioid agonist/antagonists (i.e., pentazocine, nalbuphine, and butorphanol) or partial opioid agonists (buprenorphine) in patients who have received or are receiving a course of therapy with a full opioid agonist. In these patients, mixed opioid agonist/antagonists and partial opioid agonists may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

• Opioids may enhance the neuro muscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.• Concurrent use with anticholinergic medication increases the risk of

urinary retention and severe constipation, which may lead to paralytic ileus.

Use in Opioid-Tolerant Patients ◊ Adult patients considered opioid-tolerant are those receiving, for one week or longer at least :

• 60 mg oral morphine/day

• 25 mcg transdermal fentanyl/hour

• 30 mg oral oxycodone/day

• 60 mg oral hydrocodone/day

• 8 mg oral hydromorphone/day

• 25 mg oral oxymorphone/day

• Pediatric patients (11 years and older) considered opioid-tolerant are those who are already receiving and tolerating a minimum daily opioid dose of at least 20 mg oxycodone orally or its equivalent (applicable to OxyContin’s pediatric indication only)

◊ See individual product information for which products:

• Have strengths or total daily doses only for use in opioid-tolerant patients.

• Are only for use in opioid-tolerant patients at all strengths.

Contraindications • Significant respiratory depression• Acute or severe asthma in an unmonitored setting or in the absence of

resuscitative equipment• Known or suspected paralytic ileus• Hypersensitivity(e.g.,anaphylaxis)• See individual product informationf or additional contraindications.

Relative Potency To Oral Morphine • These are intended as general guides.• Follow conversion instructions in individual product information.• Incomplete cross-tolerance and inter-patient variability require the use

of conservative dosing when converting from one opioid to another - halve the calculated comparable dose and titrate the new opioid as needed.

Table 9: Drug Information Common to the Class of Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Source: FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. May, 2017. https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM515636.pdf. Last Accessed January, 2018.

104

EXERCISE 6SPECIFIC DRUG INFORMATION FOR ER/LA OPIOID ANALGESIC PRODUCTS

Instructions: Spend 20-25 minutes completing the following

1. Conduct a detailed review of table 10, which includes information regarding Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics Review 2. Read and Table 9 which includes additional general drug information common to ER/LA opioid analgesics.3. Complete the learning questions below related to Specific Drug Information for ER/LA Opioid Analgesic’s only after completing steps 1.

LEARNING QUESTIONS EXERCISE 6COMPLETE ONLY AFTER CONDUCTING STEPS 1

1. Describe Interactions with other medications and substances for the following; Butran, Dolophine, Hysingla ER, MS Contin.

2. Discuss product safety concernts for the following: Arymo ER, Duragesic, Opana ER, Targiniq ER?

3. List and describe which products and which doses are indicated for use only in opioid-tolerant patients. Which products are indicated for use only in opioid tolerant-patients?

SPECIFIC DRUG INFORMATION FOR ER/LA OPIOID ANALGESIC PRODUCTS

Prescribers should be knowledgeable about specific characteristics of the ER/LA opioid analgesic products they prescribe, including: Drug Substance, Formulation, Strength, Dosing Interval, Key Instructions, Specific Information About Conversion Between Products Where Available, Specific Drug Interactions, Use In Opioid-Tolerant Patients, Product-Specific Safety Concerns, And Relative Potency To Morphine.

The following Table (TABLE 10) is a reference. For detailed information, prescribers can refer to prescribing information available online via DailyMed at www.dailymed.nlm.nih.gov or Drugs@FDA at www.fda.gov/drugsatfda.

105

Arymo ER Morphine SulfateExtended-Release Tablets, 15 mg, 30 mg, 60 mg

Dosing Interval Every 8 or 12 hours

Key Instructions • Initial dose in opioid-naïve and opioidnon-tolerant patients is15mg every 8 or 12 hours

• Dosage adjustment may be done every 1 to 2 days.• Take one tablet at a time, with enough water to ensure complete swal-

lowing immediately after placing in the mouth.

Specific Drug Interactions P-gp inhibitors (e.g. quinidine) can increase the exposure of morphine by about two-fold and increase risk of respiratory depression

Use in Opioid-Tolerant Patients A single dose of ARYMO ER greater than 60 mg, or total daily dose greater than 120 mg, is for use in opioid-tolerant patients only.

Product-Specific Safety Concerns • Do not attempt to chew, crush, or dissolve. Swallow whole.• Use with caution in patients who have difficulty in swallowing or have

underlying GI disorders that may predispose them to obstruction, such as a small gastrointestinal lumen.

Avinza Morphine Sulfate ERCapsules, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, and 120 mg

Dosing Interval Once a day

Key Instructions • Initial dose in opioid non-tolerant patients is 30 mg.• Titrate in increments of not greater than 30 mg using a minimum of 3

to 4 day intervals.• Swallow capsule whole (do not chew, crush, or \dissolve).• May open capsule and sprinkle pellets on applesauce for patients who

can reliably swallow without chewing; use immediately.• Maximum daily dose:1600 mg due to risk of serious renal toxicity by

excipient, fumaric acid.

Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result in the rapid release and absorption of a potentially fatal dose of morphine.

• P-gp inhibitors(e.g. quinidine) may increase the absorption/exposure of morphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients 90 mg and 120 mg capsules are for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Belbuca Buprenorphine Buccal Film, 75 mcg, 150 mcg, 300 mcg, 450 mcg, 600 mcg, 750 mcg, and 900 mcg

Dosing Interval Every 12 hours (or once every 24 hours for initiation in opioid naïve patients and patients taking less than 30 mg oral morphine sulfate equivalents)

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)

106

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)Key Instructions ◊ Opioid-naïve patients or patients taking less than 30 mg oral morphine

sulfate equivalents: Initiate treatment with a 75 mcg buccal film, onc daily, or if tolerated, every 12 hours.• Titrate to 150 mcg every 12 hours no earlier than 4 days after initiation.• Individual titration to a dose that provides adequate analgesia and

minimizes adverse reactions should proceed in increments of 150 mcg every 12 hours, no more frequently than every 4 days.

◊ When converting from another opioid, first taper the current opioid to no more than 30 mg oral morphine sulfate equivalents per day prior to initiating Belbuca.

• If prior daily dose before taper was 30 mg to 89 mg oral morphine sulfate equivalents, initiate with 150 mcg dose every 12 hours.• If prior daily dose before taper was 90 mg to 160 mg oral morphine

sulfate equivalents, initiate with 300 mcg dose every 12 hours.• Titration of the dose should proceed in increments of 150 mcg every

12 hours, no more frequently than every 4 days.◊ Maximum dose: 900 mcg every 12 hours due to the potential for QTc

prolongation◊ Severe Hepatic Impairment: Reduce the starting and incremental dose

by half that of patients with normal liver function.◊ Oral Mucositis: Reduce the starting and incremental dose by half that of

patients without mucositis◊ Do not use if the package seal is broken or the film is cut, damaged, or

changed in any way

Specific Drug Interactions • CYP3A4 inhibitors may increase buprenorphine levels.• CYP3A4 inducers may decrease buprenorphine levels.• Benzodiazepines may increase respiratory depression.• Class IA and III anti arrhythmics, other potentially arrhythmogenic

agents, may increase risk for QTc prolongation and torsade de pointes.

Use in Opioid-Tolerant Patients Belbuca 600 mcg, 750 mcg, and 900 mcg are for use following titration from lower doses of Belbuca.

Product-Specific Safety Concerns • QTc prolongation and torsade de pointes • Hepatotoxicit

Relative Potency To Oral Morphine Equipotency to oral morphine has not been established.

Butrans BuprenorphineTransdermal System, 5 mcg/hr, 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr, 20 mcg/hr

Dosing Interval One transdermal system every 7 days

107

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)Key Instructions • Initial dose in opioid non-tolerant patients when converting from less

than 30 mg morphine equivalents, and in mild to moderate hepatic impairment - 5 mcg/hr dose.

• When converting from 30 mg to 80 mg morphine equivalents - first taper to 30 mg morphine equivalent, then initiate with 10 mcg/hr dose.

• Titrate in 5 mcg/hour or 10 mcg/hour increments by using no more than two patches of the 5 mcg/hour or 10 mcg/hour system(s) with a minimum of 72 hours between dose adjustments. The total dose from all patches should not exceed 20 mcg/hour

• Maximum dose: 20 mcg/hr due to risk of QTc prolongation.• Application• Apply only to sites indicated in the Full Prescribing Information.• Apply to intact/non-irritated skin.• Skin may be prepped by clipping hair, washing site with water only• Rotate site of application a minimum of 3 weeks before reapplying to the same site.• Do not cut.• Avoid exposure to heat.• Dispose of used/unused patches by folding the adhesive side together

and flushing down the toilet.

Specific Drug Interactions • CYP3A4 Inhibitors may increase buprenorphine levels.• CYP3A4 Inducers may decrease buprenorphine levels.• Benzodiazepines may increase respiratory depression.• Class IA and III anti arrhythmics, othe rpotentially arrhythmogenic

agents, may increase risk for QTc prolongation and torsade de pointe.

Use in Opioid-Tolerant Patients Butrans 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr, and 20 mcg/hr transdermal systems are for use in opioid- tolerant patients only.

Drug-Specific Safety Concerns • QTc prolongation and torsade de pointe. • Hepatotoxicity• Application site skin reactions

Relative Potency To Oral Morphine Equipotency to oral morphine has not been established.

Dolophine Methadone Hydrochloride Tablets, 5 mg and 10 mg

Dosing Interval Every 8 to 12 hours

Key Instructions • Initial dose in opioid non-tolerant patients: 2.5 to10 mg• Conversion of opioid-tolerant patients using equianalgesic tables can

result in overdose and death. Use low doses according to the table in the full prescribing information.

• Titrate slowly, with dose increases no more frequent than every 3 to 5 days. Because of high variability in methadone metabolism, some patients may require substantially longer periods between dose increases (up to 12 days).• High inter-patient variability in absorption,metabolism,and relative

analgesic potency.• Opioid detoxification or maintenance treatment shall only be provided

in a federally certified opioid (addiction) treatment program (Code of Federal Regulations, Title 42, Sec 8).

108

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)Specific Drug Interactions ◊ Pharmacokinetic drug-druginteractions with methadone are complex.

• CYP450 inducers may decrease methadone levels.• CYP450 inhibitors may increase methadone levels.• Anti-retroviral agents have mixed effects on methadone levels.◊ Potentially arrhythmogenic agents may increase risk for QTc prolonga-

tion and torsade de pointe.◊ Benzodiazepines may increase respiratory depression

Use in Opioid-Tolerant Patients Refer to full prescribing information.

Product-Specific Safety Concerns • QTc prolongation and torsade de pointe.• Peak respiratory depression occurs later and persists longer than

analgesic• effect.• Clear ance may increase during pregnancy.• False positive urine drug screens possible.

Relative Potency To Oral Morphine Varies depending on patient’s prior opioid experience.

Duragesic FentanylTransdermal System, 12, 25, 37.5*, 50, 62.5*, 75, 87.5*, and 100 mcg/hr (*These strengths are available only in generic form)

Dosing Interval Every 72 hours (3 days)

Key Instructions ◊ Use product specific information for dose conversion from prior opioid◊ Use 50% of the dose in mild or moderate hepaticorrenal impairment,

avoid use in severe hepatic or renal impairment◊ Application• Apply to intact/non-irritated/non-irradiated skin on a flat surface.• Skin may be prepped by clipping hair, washing site with water only• Rotate site of application.• Titrate using a minimum of 72 hour intervals between dose adjustments.• Do not cut.◊ Avoid exposure to heat.◊ Avoid accidental contact when holding or caring for children.◊ Dispose of used/unused patches by folding the adhesive side together

and flushing down the toilet.Specific contraindications:• Patients who are not opioid-tolerant.• Management of acute or intermittent pain, or in patients who require opioid analgesia for a short period of time.• Management of post-operative pain, including use after out-patient or day surgery.• Management of mild pain.

Specific Drug Interactions • CYP3A4 inhibitors may increase fentanyl exposure.• CYP3A4 inducers may decrease fentanyl exposure.• Discontinuation of a concomitantly used cytochrome P450 3A4 inducer• may result in an increase in fentanyl plasma concentration.

Use in Opioid-Tolerant Patients All doses of Duragesic are indicated for use in opioid-tolerant patients only.

Product-Specific Safety Concerns • Accidental exposure due to secondary exposure to unwashed/unclothed application site.

• Increased drug exposure with increased core body temper atureor fever.• Bradycardia• Application site skin reactions

109

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)Relative Potency To Oral Morphine See individual product information for conversion recommendations from

prior opioid

Embeda Morphine Sulfate ER-NaltrexoneCapsules, 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, 100 mg/4 mg

Dosing Interval Once a day or every 12 hours

Key Instructions • Initial dose as first opioid: 20mg/0.8mg.• Titrate using a minimum of 1 to 2 day intervals.• Swallow capsules whole(do not chew, crush, or dissolve)• Crushing or chewing will release morphine, possibly resulting in fatal overdose, and naltrexone, possibly resulting in withdrawal symptoms.• May open capsule and sprinkle pellets on applesauce for patients who

can reliably swallow without chewing, use immediately.

Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result in the rapid release and absorption of a potentially fatal dose of morphine.

• P-gpinhibitors(e.g.quinidine)mayincreasetheabsorption/exposureof morphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients Embeda 100 mg/4 mg capsule is for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Exalgo Hydromorphone HydrochlorideExtended-Release Tablets, 8 mg, 12 mg, 16 mg or 32 mg

Dosing Interval Once a day

Key Instructions • Use the conversion ratios in the individual product information.• Start patients wit hmoderate hepatic impairment on 25% dose that

would be prescribed for a patient with normal hepatic function.• Start patients with moderate renal impairment on 50%, and patients

with severe renal impairment on 25% of the dose that would be prescribed for a patient with normal renal function.• Titrate in increments of 4 to 8 mg using a minimum of 3 to 4 day intervals• Swallow tablets whole (do not chew, crush, or dissolve).• Do not use in patients with sulfite allergy—contains sodium metabisulfite.

Specific Drug Interactions None

Use in Opioid-Tolerant Patients All doses of Exalgo are indicated for opioid-tolerant patients only.

Drug-Specific Adverse Reactions Allergic manifestations to sulfite component.

Relative Potency To Oral Morphine Approximately 5:1 oral morphine to hydromorphone oral dose ratio, use conversion recommendations in the individual product information.

Hysingla ER Hydrocodone bitartrateExtended-Release Tablets, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg

Dosing Interval Every 24 hours (once-daily)

110

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)Key Instructions • Opioid-naïve patients: initiate treatment with 20 mg orally once daily.

During titration, adjust the dose in increments of 10 mg to 20 mg every 3 to 5 days until adequate analgesia is achieved.

• Swallow tablets whole (do not chew, crush, or dissolve).• Consider use of an alternative analgesic in patients who have difficulty

swallowing or have underlying gastrointestinal disorders that may predispose them to obstruction.

• Take one tablet at a time, with enough water to ensure complete swal-lowing immediately after placing in the mouth.

• Use 1/2 of the initial dose and monitor closely for adverse events, such as respiratory depression and sedation, when administering Hysingla ER to patients with severe hepatic impairment or patients with moderate to severe renal impairment.

Specific Drug Interactions • CYP3A4 inhibitors may increase hydrocodone exposure.• CYP3A4 inducers may decrease hydrocodone exposure• Concomitant use of Hysingla ER with strong laxatives (e.g., Lactulose)

that rapidly increase GI motility may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels.

• The use of MAO inhibitors or tricyclic antidepressants with Hysingla ER may increase the effect of either the antidepressant or Hysingla ER.

Use in Opioid-Tolerant Patients A single dose of Hysingla ER greater than or equal to 80 mg is only for use in opioid tolerant patients.

Product-Specific Safety Concerns • Use with caution in patients with difficulty swallowing the tablet or underlying gastrointestinal disorders that may predispose patients to obstruction.

• Esophageal obstruction, dysphagia, and choking have been reported with Hysingla ER.

• In nursing mothers, discontinue nursing or discontinue drug.• QTc prolongation has been observed with Hysingla ER following daily

doses of 160 mg. Avoid use in patients with congenital long QTc syndrome. This observation should be considered in making clinical decisions regarding patient monitoring when prescribing Hysingla ER in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QTc interval. In patients who develop QTc prolongation, consider reducing the dose.

Relative Potency To Oral Morphine See individual product information for conversion recommendations from prior opioid

Kadian Morphine SulfateExtended-Release Capsules, 10 mg, 20mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 130 mg, 150 mg, and 200 mg

Dosing Interval Once a day or every 12 hours

Key Instructions • Product information recommends not using as firs opioid.• Titrate using a minimum of 2-day intervals.• Swallow capsules whole (do not chew, crush, ordissolve).• May open capsule and sprinkle pellets on applesauce for patients who

can reliably swallow without chewing, use immediately.

111

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result in the

rapid release and absorption of a potentially fatal dose of morphine.• P-gp inhibitors(e.g. quinidine)may increase the absorption/exposure of

morphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients Kadian 100 mg, 130 mg, 150 mg, and 200 mg capsules are for use in opioid- tolerant-patients only

Product-Specific Safety Concerns None

MorphaBond Morphine SulfateExtended-release Tablets, 15 mg, 30 mg, 60 mg, 100 mg

Dosing Interval Every 8 hours or every 12 hours

Key Instructions For opioid-naïve and opioid non-tolerant patients, initiate treatment with 15mg tablets orally every 12 hours. Swallow tablets whole (do not cut, break, chew, crush, or dissolve).

Specific Drug Interactions P-gp inhibitors (e.g. quinidine) may increase the absorption/exposure of morphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients MorphaBond ER 100 mg tablets, as single dose greater than 60mg, or a totaldaily dose greater than 120mg, are only for use in patients in whom toleranceto an opioid of comparable potency has been established.

Product-Specific Safety Concerns None

MS Contin Morphine SulfateExtended-release Tablets, 15 mg, 30 mg, 60 mg, 100 mg, and 200 mg

Dosing Interval Every 8 hours or every 12 hours

Key Instructions • Product information recommends not using as first opioid. • Titrate using a minimum of 1 to 2-day intervals.• Swallow tablets whole (do not chew, crush, or dissolve).

Specific Drug Interactions P-gp inhibitors (e.g. quinidine) may increase the absorption/exposure of morphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients MS Contin 100 mg and 200 mg tablet strengths are for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Nucynta ER TapentadolExtended-Release Tablets, 50 mg, 100mg, 150 mg, 200 mg, and 250 mg

Dosing Interval Every 12 hours

Key Instructions • Use 50 mg every 12 hours as initial dose in opioid nontolerant patients• Titrate by 50 mg increments using a minimum of 3-day intervals.• Maximum total daily dose is 500 mg• Swallow tablets whole (do no tchew, crush, ordissolve).• Take one tablet at a time and with enough water to ensure complete

swallowing immediately after placing in the mouth.• Dose once daily in moderate hepatic impairment with100 mg per day

maximum• Avoid use in severe hepatic and renal impairment.

112

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may resultinthe

rapid release and absorption of a potentially fatal dose of tapentadol.• Contraindicated in patients taking MAOIs.

Use in Opioid-Tolerant Patients No product-specific considerations.

Product-Specific Safety Concerns • Risk of serotonin syndrome • Angioedema

Relative Potency To Oral Morphine Equipotency to oral morphine has not been established.

Opana ER Oxymorphone HydrochlorideER Tablets, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg

Dosing Interval Every 12h dosing, some may benefit from asymmetric (different dose given in AM than in PM) dosing.

Key Instructions • Use 5 mg every 12 hours as initial dose in opioid non-tolerant patients and patients with mild hepatic impairment and renal impairment (creati-nine clearance < 50 mL/min) and patients over 65 years of age

• Swallow tablets whole (do not chew, crush, or dissolve).• Take one tablet at a time, with enough water to ensurecomplete• swallowing immediately after placing in the mouth.• Titrate in increments of 5 to 10 mg using a minimum of 3 to 7-day

intervals.• Contraindicated in moderate and sever ehepatic impairment.

Specific Drug Interactions Alcoholic beverages or medications containing alcohol may resultinthe ab-sorption of a potentially fatal dose of oxymorphone.

Use in Opioid-Tolerant Patients No product specific considerations.

Product-Specific Safety Concerns Use with caution in patients who have difficulty in swallowing or have under-lying GI disorders that may predispose them to obstruction, such as a small gastrointestinal lumen.

Relative Potency To Oral Morphine Approximately 3:1 oral morphine to oxymorphone oral dose ratio

OxyContin Oxycodone HydrochlorideExtended-release Tablets, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg

Dosing Interval Every 12 hours

113

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)Key Instructions ◊ For Adults:

• Initial dose in opioid-naïve and opioid non-tolerant patients is 10 mg every 12 hours.• If needed, adult dosage may be adjusted in 1 to 2 day intervals.• When a dose increase is clinically indicated, the total daily oxycodone dose usually can be increased by 25% to 50% of the current dose.◊ For Pediatric patients (11 years and older): Use only in opioid-tol-

erant patients (see below, Use in Opioid-Tolerant Patients for dosing information).

◊ For all patients:• Hepatic impairment: start with one third to one half the usual dosage• Renal impairment (creatinine clearance <60 mL/min): start with one

half the usual dosage.• Consider use of other analgesics in patients who have difficulty swallow-

ing or have underlying GI disorders that may predispose them obstrucu-tion. Swallow tablets whole (do not chew, crush, or dissolve).

• Takeonetabletatatime,withenoughwatertoensurecomplete swallowing immediately after placing in the mouth.

Specific Drug Interactions • CYP3A4 inhibitors may increase oxycodone exposure. • CYP3A4 inducers may decrease oxycodone exposure.

Use in Opioid-Tolerant Patients ◊ For Adults:• Single dose greater than 40 mg or total daily dose greater than 80 mg• are for use in adult patients in whom tolerance to an opioid of compara-

ble potency has been established.◊ For Pediatric patients (11 years and older):• For use only in opioid-tolerant pediatric patients already receiving and• tolerating opioids for at least 5 consecutive days with a minimum of 20

mg per day of oxycodone or its equivalent for at least two days immedi-ately preceding dosing with OxyContin.

• If needed, pediatric dosage may be adjusted in 1 to 2 day intervals.• When a dose increase is clinically indicated, the total daily oxycodone

dose usually can be increased by 25% of the current total daily dose.

Product-Specific Safety Concerns • Choking, gagging, regurgitation, tablets stuck in the throat, difficulty swallowing the tablet.

• Contrain dicated in patients with gastrointestinal obstruction.

Relative Potency To Oral Morphine Approximately 2:1 oral morphine to oxycodone oral dose ratio.

Targiniq ER Oxycodone Hydrochloride / Naloxone HydrochlorideExtended-release tablets, 10 mg/5 mg, 20 mg/10 mg, and 40 mg/20 mg

Dosing Interval Every 12 hours

114

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)Specific Drug Interactions ◊ Pharmacokinetic drug-druginteractions with methadone are complex.

• CYP450 inducers may decrease methadone levels.• CYP450 inhibitors may increase methadone levels.• Anti-retroviral agents have mixed effects on methadone levels.◊ Potentially arrhythmogenic agents may increase risk for QTc prolonga-

tion and torsade de pointe.◊ Benzodiazepines may increase respiratory depression

Use in Opioid-Tolerant Patients Refer to full prescribing information.

Product-Specific Safety Concerns • QTc prolongation and torsade de pointe.• Peak respiratory depression occurs later and persists longer than

analgesic• effect.• Clear ance may increase during pregnancy.• False positive urine drug screens possible.

Relative Potency To Oral Morphine Varies depending on patient’s prior opioid experience.

Duragesic FentanylTransdermal System, 12, 25, 37.5*, 50, 62.5*, 75, 87.5*, and 100 mcg/hr (*These strengths are available only in generic form)

Dosing Interval Every 72 hours (3 days)

Key Instructions ◊ Use product specific information for dose conversion from prior opioid◊ Use 50% of the dose in mild or moderate hepaticorrenal impairment,

avoid use in severe hepatic or renal impairment◊ Application• Apply to intact/non-irritated/non-irradiated skin on a flat surface.• Skin may be prepped by clipping hair, washing site with water only• Rotate site of application.• Titrate using a minimum of 72 hour intervals between dose adjustments.• Do not cut.◊ Avoid exposure to heat.◊ Avoid accidental contact when holding or caring for children.◊ Dispose of used/unused patches by folding the adhesive side together

and flushing down the toilet.Specific contraindications:• Patients who are not opioid-tolerant.• Management of acute or intermittent pain, or in patients who require opioid analgesia for a short period of time.• Management of post-operative pain, including use after out-patient or day surgery.• Management of mild pain.

Specific Drug Interactions • CYP3A4 inhibitors may increase fentanyl exposure.• CYP3A4 inducers may decrease fentanyl exposure.• Discontinuation of a concomitantly used cytochrome P450 3A4 inducer• may result in an increase in fentanyl plasma concentration.

Use in Opioid-Tolerant Patients All doses of Duragesic are indicated for use in opioid-tolerant patients only.

Product-Specific Safety Concerns • Accidental exposure due to secondary exposure to unwashed/unclothed application site.

• Increased drug exposure with increased core body temper atureor fever.• Bradycardia• Application site skin reactions

115

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)Relative Potency To Oral Morphine See individual product information for conversion recommendations from

prior opioid

Embeda Morphine Sulfate ER-NaltrexoneCapsules, 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, 100 mg/4 mg

Dosing Interval Once a day or every 12 hours

Key Instructions • Initial dose as first opioid: 20mg/0.8mg.• Titrate using a minimum of 1 to 2 day intervals.• Swallow capsules whole(do not chew, crush, or dissolve)• Crushing or chewing will release morphine, possibly resulting in fatal overdose, and naltrexone, possibly resulting in withdrawal symptoms.• May open capsule and sprinkle pellets on applesauce for patients who

can reliably swallow without chewing, use immediately.

Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result in the rapid release and absorption of a potentially fatal dose of morphine.

• P-gpinhibitors(e.g.quinidine)mayincreasetheabsorption/exposureof morphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients Embeda 100 mg/4 mg capsule is for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Exalgo Hydromorphone HydrochlorideExtended-Release Tablets, 8 mg, 12 mg, 16 mg or 32 mg

Dosing Interval Once a day

Key Instructions • Use the conversion ratios in the individual product information.• Start patients wit hmoderate hepatic impairment on 25% dose that

would be prescribed for a patient with normal hepatic function.• Start patients with moderate renal impairment on 50%, and patients

with severe renal impairment on 25% of the dose that would be prescribed for a patient with normal renal function.• Titrate in increments of 4 to 8 mg using a minimum of 3 to 4 day intervals• Swallow tablets whole (do not chew, crush, or dissolve).• Do not use in patients with sulfite allergy—contains sodium metabisulfite.

Specific Drug Interactions None

Use in Opioid-Tolerant Patients All doses of Exalgo are indicated for opioid-tolerant patients only.

Drug-Specific Adverse Reactions Allergic manifestations to sulfite component.

Relative Potency To Oral Morphine Approximately 5:1 oral morphine to hydromorphone oral dose ratio, use conversion recommendations in the individual product information.

Hysingla ER Hydrocodone bitartrateExtended-Release Tablets, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg

Dosing Interval Every 24 hours (once-daily)

116

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics

(ER/LA opioid analgesics)

Source: FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. May, 2017.https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM515636.pdf. Last Accessed January, 2018.

Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result in the rapid release and absorption of a potentially fatal dose of hydrocodone.

• CYP3A4 inhibitors may increase hydrocodone exposure. • CYP3A4 inducers may decrease hydrocodone exposure.

Use in Opioid-Tolerant Patients Single dose greater than 40 mg or total daily dose greater than 80 mg are for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Relative Potency To Oral Morphine Approximately 1.5:1 oral morphine to hydrocodone oral dose ratio.

TABLE 11. PATIENT COUNSELING DOCUMENT ON EXTENDED-RELEASE / LONG-ACTING OPIOID ANALGESICS

Patient Name:

The DOs and DON’Ts ofExtended-Release / Long-Acting Opioid Analgesics

DO: • Read the Medication Guide • Take your medicine exactly as prescribed • Store your medicine away from children and in a safe place • Flush unused medicine down the toilet • Call your healthcare provider for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088.

Call 911 or your local emergency service right away if: • You take too much medicine • You have trouble breathing, or shortness of breath • A child has taken this medicine

Talk to your healthcare provider: • If the dose you are taking does not control your pain • About any side effects you may be having • About all the medicines you take, including over-the-counter medi-

cines, vitamins, and dietary supplements

DON’T: • Do not give your medicine to others • Do not take medicine unless it was prescribed for you • Do not stop taking your medicine without talking to your healthcare

provider • Do not break, chew, crush, dissolve, or inject your medicine. If you

cannot swallow your medicine whole, talk to your healthcare provider. • Do not drink alcohol while taking this medicine

For additional information on your medicine go to:dailymed.nlm.nih.gov

Patient Name:

Patient Specific Information

Take this card with you every time you see your healthcare provider and tell him/her:

• Your complete medical and family history, including any history of substance abuse or mental illness

• If you are pregnant or are planning to become pregnant• The cause, severity, nature of your pain• Your treatment goals• All the medicines you take, including over-the-counter (non-prescrip-

tion) medicines, vitamins, and dietary supplements• Any side effects you may br having• Take your opiod pain medicine exactly as prescribed by your health-

care provider.

117

RESOURCESAmerican Academy of Pain Medicinewww.painmed.org

Drug Enforcement Administration Diversion Control Programwww.DEAdiversion.usdoj.gov

FDA Blueprint for Prescriber Educationhttp://www.er-la-opioidrems.com

National Institute on Drug AbuseShort and longer-form validate questionnaireshttp://www.drugabuse.gov/sites/default/files/pdf/nmassist.pdf

National Association of Drug Diversion Investiga-torswww.naddi.org

The National Association of State Controlled Sub-stances Authorities (NASCSA)www.nascsa.org

Opioids911-Safety www.opioids911.org

Pain Treatment Topics www.Pain-Topics.org

Patient Health Questionnaire www.phqscreeners.com

PainLaw.orgwww.painlaw.org

University of Wisconsin Pain & Policy Studies Groupwww.medsch.wisc.edu/painpolicy

Veterans Administration opioid clinical practice guidelines http://www.healthquality.va.gov/guidelines/Pain/cot/

REFERENCES1. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49.2. Food and Drug Administration. Califf, FDA top officials call for sweeping review of agency opioids policies. FDA News Release February 4, 2016; http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm484765.htm.3. Califf RM, Woodcock J, Ostroff S. A Proactive Response to Prescription Opioid Abuse. N Engl J Med. 2016.4. Centers for Disease Control & Preven-tion. Vital signs: overdoses of prescription opioid pain relievers---United States, 1999--2008. MMWR. Morbidity and mortality weekly report. 2011;60(43):1487-1492.

5. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opi-oid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130.6. Von Korff M, Kolodny A, Deyo RA, Chou R. Long-term opioid therapy reconsidered. Annals of internal medicine. 2011;155(5):325-328.7. Goodnough A. Opioid prescriptions drop for first time in two decades. New York Times. May 20, 2016.8. Sites BD, Beach ML, Davis MA. Increases in the use of prescription opioid analgesics and the lack of improvement in disability metrics among users. Regional anesthesia and pain medicine. 2014;39(1):6-12.9. Fox CD, Berger D, Fine P, et al. Pain assessment and treatment in the managed care environment: a position statement from the American Pain Society. Glenview, IL: American Pain Society;2000.10. NCHS. Health, United States, 2006 with Chartbook on trends in the health of Americans. Hyattsville, MD: U.S. Department of Health and Human Services;2006.11. American Cancer Society. Cancer Facts and Figures, 2012. Atlanta, GA: American Cancer Society;2012.12. Becker N, Bondegaard Thomsen A, Olsen AK, Sjogren P, Bech P, Eriksen J. Pain epidemiology and health related quality of life in chronic non-malignant pain patients referred to a Danish multidisciplinary pain center. Pain. 1997;73(3):393-400.13. Food and Drug Administration. FDA Blueprint for Prescriber Education for Extend-ed-Release and Long-Acting Opioid Analgesics. April 2016.14. Classification of chronic pain. Descrip-tions of chronic pain syndromes and definitions of pain terms. Prepared by the International Association for the Study of Pain, Subcommittee on Taxonomy. Pain. Supplement. 1986;3:S1-226.15. Alexander J, Black A. Pain mecha-nisms and the management of neuropathic pain. Current opinion in neurology and neurosurgery. 1992;5(2):228-234.16. Neumann S, Doubell TP, Leslie T, Woolf CJ. Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature. 1996;384(6607):360-364.17. Arner S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain. 1988;33(1):11-23.18. Covington EC. Anticonvulsants for neuropathic pain and detoxification. Cleveland Clinic journal of medicine. 1998;65 Suppl 1:SI21-29; discussion SI45-27.19. American Society of Addiction Medicine. Definitions related to the use of opioids for the treatment of pain. Consensus document from the

American Academy of Pain Medicine, the American Pain Society, and the American society of Addiction Medicine. 2001.20. Morone NE, Greco CM, Moore CG, et al. A Mind-Body Program for Older Adults With Chronic Low Back Pain: A Randomized Clinical Trial. JAMA internal medicine. 2016;176(3):329-337.21. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for os-teoarthritis. The Cochrane database of systematic reviews. 2006(1):CD004257.22. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42(6):1364-1372.23. Food and Drug Administration. Pre-scription drug products containing acetaminophen; actions to reduce liver injury from unintentional overdose. Federal Register. 2011;76(10):2691-2697. http://www.gpo.gov/fdsys/pkg/FR-2011-01-14/html/2011-709.htm. 2011.24. Abraham NS, Davila JA, Rabeneck L, Berger DH, El-Serag HB. Increased use of low anterior resection for veterans with rectal cancer. Aliment Pharmacol Ther. 2005;21(1):35-41.25. Shaheen NJ. The rise and fall (and rise?) of endoscopic anti-reflux procedures. Gastroenter-ology. 2006;131(3):952-954.26. Garner S, Fidan D, Frankish R, et al. Ce-lecoxib for rheumatoid arthritis. The Cochrane da-tabase of systematic reviews. 2002(4):CD003831.27. Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW. Non-steroidal anti-inflammatory drugs for low back pain. The Cochrane database of systematic reviews. 2008(1):CD000396.28. Hawkey CJ, Svedberg LE, Naesdal J, Byrne C. Esomeprazole for the management of upper gastrointestinal symptoms in patients who require NSAIDs: a review of the NASA and SPACE double-blind, placebo-controlled studies. Clinical drug investigation. 2009;29(10):677-687.29. Desai JC, Sanyal SM, Goo T, et al. Primary prevention of adverse gastroduodenal effects from short-term use of non-steroidal anti-inflammatory drugs by omeprazole 20 mg in healthy subjects: a randomized, double-blind, placebo-controlled study. Digestive diseases and sciences. 2008;53(8):2059-2065.30. Paice JA, Ferrans CE, Lashley FR, Shott S, Vizgirda V, Pitrak D. Topical capsaicin in the man-agement of HIV-associated peripheral neuropathy. J Pain Symptom Manage. 2000;19(1):45-52.31. Low PA, Opfer-Gehrking TL, Dyck PJ, Litchy WJ, O’Brien PC. Double-blind, placebo-con-trolled study of the application of capsaicin cream in chronic distal painful polyneuropathy. Pain. 1995;62(2):163-168.32. Max MB PR, Edwards WT, et al.,. Prin-ciples of analgesic use in the treatment of acute pain and cancer pain. 4th Edition. Glenview, IL:

118

American Pain Society; 1999.33. Portenoy RK MM. Adjuvant analgesics. In: McCaffery M PC, ed. Pain Clinical Manual, 2nd Edition. St. Louis, MO: Mosby Inc.; 1999.34. Kishore-Kumar R, Max MB, Schafer SC, et al. Desipramine relieves postherpetic neu-ralgia. Clinical pharmacology and therapeutics. 1990;47(3):305-312.35. Lunn MP, Hughes RA, Wiffen PJ. Duloxe-tine for treating painful neuropathy, chronic pain or fibromyalgia. The Cochrane database of systematic reviews. 2014;1:CD007115.36. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, place-bo-controlled study. Pain. 2004;110(3):697-706.37. Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y. Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clinical therapeutics. 2008;30(11):1988-2004.38. Mease PJ, Clauw DJ, Gendreau RM, et al. The efficacy and safety of milnacipran for treatment of fibromyalgia. a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009;36(2):398-409.39. Mendell JR, Sahenk Z. Clinical prac-tice. Painful sensory neuropathy. N Engl J Med. 2003;348(13):1243-1255.40. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326(19):1250-1256.41. Macdonald RL, Kelly KM. Mechanisms of action of currently prescribed and newly developed antiepileptic drugs. Epilepsia. 1994;35 Suppl 4:S41-50.42. Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. The Cochrane database of systematic reviews. 2009(3):CD007076.43. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. Jama. 1998;280(21):1831-1836.44. Wiffen PJ, McQuay HJ, Moore RA. Carbamazepine for acute and chronic pain. The Cochrane database of systematic reviews. 2005(3):CD005451.45. Tanda G, Pontieri FE, Di Chiara G. Cannabinoid and heroin activation of meso-limbic dopamine transmission by a common mu1 opioid receptor mechanism. Science. 1997;276(5321):2048-2050.46. Martin-Sanchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain medi-

cine. 2009;10(8):1353-1368.47. Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. British journal of clinical pharmacology. 2011;72(5):735-744.48. Scavone JL, Sterling RC, Weinstein SP, Van Bockstaele EJ. Impact of cannabis use during stabilization on methadone maintenance treatment. The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addic-tions. 2013;22(4):344-351.49. Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010. JAMA internal medicine. 2014.50. Gruber AJ, Pope HG, Hudson JI, Yurgelun-Todd D. Attributes of long-term heavy cannabis users: a case-control study. Psychological medicine. 2003;33(8):1415-1422.51. Lipman AG, Jackson K. Opioid pharma-cotherapy. In: Warfield CA BZ, ed. Principles and practice of pain medicine, 2nd Edition. New York, NY: McGraw-Hill Companies, Inc.; 2004.52. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med. 2003;349(20):1943-1953.53. Young SS, Ballantyne JC, Domino FJ, Wet-terau NW. Balancing clinical and risk management considerations for chronic pain patients on opioid therapy: CME monograph. American Academy of Family Physicians;2008.54. Ballantyne JC, LaForge KS. Opioid dependence and addiction during opioid treatment of chronic pain. Pain. 2007;129(3):235-255.55. Goertz M, Thorson D, Bonsell J, et al. Adult acute and subacute low back pain. Blooming-ton, MN: Institute for Clinical Systems Improvement; November 2012 2012.56. Rodgers J, Cunningham K, Fitzgerald K, Finnerty E. Opioid consumption following outpa-tient upper extremity surgery. The Journal of hand surgery. 2012;37(4):645-650.57. Centers for Disease Control & Preven-tion. Adult use of prescription opioid pain medica-tions - Utah, 2008. MMWR. Morbidity and mortality weekly report. 2010;59(6):153-157.58. Braden JB, Fan MY, Edlund MJ, Martin BC, DeVries A, Sullivan MD. Trends in use of opioids by noncancer pain type 2000-2005 among Arkansas Medicaid and HealthCore enrollees: results from the TROUP study. J Pain. 2008;9(11):1026-1035.59. Von Korff M, Saunders K, Thomas Ray G, et al. De facto long-term opioid therapy for noncancer pain. The Clinical journal of pain. 2008;24(6):521-527.60. Martin BC, Fan MY, Edlund MJ, Devries A, Braden JB, Sullivan MD. Long-term chronic opioid therapy discontinuation rates from the TROUP study. Journal of general internal medicine.

2011;26(12):1450-1457.61. Volinn E, Fargo JD, Fine PG. Opioid ther-apy for nonspecific low back pain and the outcome of chronic work loss. Pain. 2009;142(3):194-201.62. California Medical Association. Prescrib-ing Opioids: Care amid Controversy. Recommen-dations from the California Medical Association’s Council on Scientific Affairs. March, 2014.63. Fishman SM. Responsible Opioid Pre-scribing: A Clinician’s Guide, 2nd Ed. Washington, DC: Waterford Life Sciences; 2012.64. Washington State Department of Labor & Industries. Guideline for prescribing opioids to treat pain in injured workers. Office of the Medical Director;2013.65. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic non-cancer pain. The Cochrane database of systematic reviews. (1):CD006605.66. Agency for Healthcare Research and Quality. The effectiveness and risks of long-term opioid treatment of chronic pain. 2014.67. Martell BA, O’Connor PG, Kerns RD, et al. Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Annals of internal medicine. 2007;146(2):116-127.68. Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DD. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain. 2007;8(7):573-582.69. Banta-Green CJ, Merrill JO, Doyle SR, Boudreau DM, Calsyn DA. Opioid use behaviors, mental health and pain--development of a typology of chronic pain patients. Drug and alcohol depen-dence. 2009;104(1-2):34-42.70. Fishbain DA, Cole B, Lewis J, Rosomoff HL, Rosomoff RS. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addic-tion and/or aberrant drug-related behaviors? A structured evidence-based review. Pain medicine. 2008;9(4):444-459.71. Edlund MJ, Martin BC, Russo JE, DeVries A, Braden JB, Sullivan MD. The role of opioid pre-scription in incident opioid abuse and dependence among individuals with chronic noncancer pain: the role of opioid prescription. The Clinical journal of pain. 2014;30(7):557-564.72. Boscarino JA, Rukstalis MR, Hoffman SN, et al. Prevalence of prescription opioid-use disorder among chronic pain patients: comparison of the DSM-5 vs. DSM-4 diagnostic criteria. Journal of addictive diseases. 2011;30(3):185-194.73. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Annals of internal medicine. 2010;152(2):85-92.74. American Pain Society. Guideline for the use of chroni opioid therapy in chronic noncancer

119

pain. 2009.75. Moore RA, McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids. Arthritis Res Ther. 2005;7(5):R1046-1051.76. Takkouche B, Montes-Martinez A, Gill SS, Etminan M. Psychotropic medications and the risk of fracture: a meta-analysis. Drug Saf. 2007;30(2):171-184.77. Miller M, Sturmer T, Azrael D, Levin R, Solomon DH. Opioid analgesics and the risk of fractures in older adults with arthritis. J Am Geriatr Soc. 2011;59(3):430-438.78. Brack A, Rittner HL, Stein C. Immuno-suppressive effects of opioids--clinical relevance. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharma-cology. 2011;6(4):490-502.79. Dublin S, Walker RL, Jackson ML, et al. Use of opioids or benzodiazepines and risk of pneumonia in older adults: a popula-tion-based case-control study. J Am Geriatr Soc. 2011;59(10):1899-1907.80. McCaffery M, Pasero C. Assessment: underlying complexities, misconceptions, and practical tools. In: McCaffery M, Pasero C, eds. Pain Clinical Manual, 2nd Ed. St. Louis, MO: Mosby Inc.; 1999:35-102.81. Daut RL, Cleeland CS, Flanery RC. Devel-opment of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain. 1983;17(2):197-210.82. Melzack R. The short-form McGill Pain Questionnaire. Pain. 1987;30(2):191-197.83. Krebs EE, Lorenz KA, Bair MJ, et al. Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference. Journal of general internal medicine. 2009;24(6):733-738.84. Gourlay D, Heit H. Universal precautions: a matter of mutual trust and responsibility. Pain medicine. 2006;7(2):210-211; author reply 212.85. Tang NK, Crane C. Suicidality in chronic pain: a review of the prevalence, risk factors and psychological links. Psychological medicine. 2006;36(5):575-586.86. Roskos SE, Keenum AJ, Newman LM, Wallace LS. Literacy demands and formatting char-acteristics of opioid contracts in chronic nonmalig-nant pain management. J Pain. 2007;8(10):753-758.87. Fishman SM, Mahajan G, Wilsey B. Author response to: The trilateral opioid contract: bridging the pain clinic and the primary care phy-sician through the opioid contract. J Pain Symptom Manage. 2003;25(5):403.88. Cleeland CS, Ryan KM. Pain assess-ment: global use of the Brief Pain Inventory. Annals of the Academy of Medicine, Singapore.

1994;23(2):129-138.89. Payne R, Anderson E, Arnold R, et al. A rose by any other name: pain contracts/agree-ments. The American journal of bioethics : AJOB. 2010;10(11):5-12.90. Centers for Disease Control & Preven-tion. Increases in poisoning and methadone-relat-ed deaths: United States, 1999-2005. NCHS Health & Stats. 2008.91. Levine DA. “Pharming”: the abuse of prescription and over-the-counter drugs in teens. Current opinion in pediatrics. 2007;19(3):270-274.92. Webster LR, Fine PG. Overdose deaths demand a new paradigm for opioid rotation. Pain medicine. 2012;13(4):571-574.93. Fishman SM, Wilsey B, Mahajan G, Molina P. Methadone reincarnated: novel clinical applications with related concerns. Pain medicine. 2002;3(4):339-348.94. Knotkova H, Fine PG, Portenoy RK. Opi-oid rotation: the science and the limitations of the equianalgesic dose table. J Pain Symptom Manage. 2009;38(3):426-439.95. Food and Drug Administration. Public Health Advisory: Methadone Use for Pain Control May Result in Death and Life-Threatening Changes in Breathing and Heart Beat. November 27.96. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in meth-adone treatment. Annals of internal medicine. 2009;150(6):387-395.97. Goodnough A, Zezima K. When children’s scribbles hide a prison drug. New York Times. May 26, 2011.98. Franklin GM, Rahman EA, Turner JA, Daniell WE, Fulton-Kehoe D. Opioid use for chronic low back pain: A prospective, population-based study among injured workers in Washington state, 2002-2005. The Clinical journal of pain. 2009;25(9):743-751.99. Webster LR, Dove B. Avoiding opioid abuse while managing pain. North Branch, MN: Sunrise River Press; 2007.100. VA/DoD. The management of opioid therapy for chronic pain working group. VA/DoD clinical practice guidelines for the management of opiod therapy for chronic pain. 2003(contract number: V101 (93)).101. Blondell RD, Ashrafioun L, Dambra CM, Foschio EM, Zielinski AL, Salcedo DM. A Clinical Trial Comparing Tapering Doses of Buprenorphine with Steady Doses for Chronic Pain and Co-existent Opioid Addiction. Journal of addiction medicine. 2010;4(3):140-146.102. Swedlow A, Gardner, L., Ireland, J., Genovese, E. “Pain Management and the Use of Opioids in the Treatment of Back Conditions in the California Workers’ Compensation System.” Report to the Industry. CWCI. June 2008. http://www.

pdmpexcellence.org/sites/all/pdfs/Swedlow%20CWCI_PainMgt_0608.pdf.103. Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet. 1997;349(9052):599-603.104. Anand KJ, Anderson BJ, Holford NH, et al. Morphine pharmacokinetics and pharmacody-namics in preterm and term neonates: secondary results from the NEOPAIN trial. British journal of anaesthesia. 2008;101(5):680-689.105. American Academy of Pediatrics. Committee on Psychosocial Aspects of C, Family H, Task Force on Pain in Infants C, Adolescents. The assessment and management of acute pain in infants, children, and adolescents. Pediatrics. 2001;108(3):793-797.106. Centers for Disease Control and Preven-tion. Community-based opioid overdose prevention programs providing naloxone—United States, 2010. MMWR. Morbidity and mortality weekly report. 2010;61(6):101-105.107. Ferrell BA. Pain management in elderly people. J Am Geriatr Soc. 1991;39(1):64-73.108. Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastat-ic cancer. N Engl J Med. 1994;330(9):592-596.109. Cherny NI, Thaler HT, Friedlander-Klar H, et al. Opioid responsiveness of cancer pain syndromes caused by neuropathic or nociceptive mechanisms: a combined analysis of controlled, single-dose studies. Neurology. 1994;44(5):857-861.110. Bader P ED, Fonteyne V, et al. . Guide-lines on pain management. 2010.111. Forrow L SH. Pain management in end of life: palliative care. In: Warfield CA BZ, ed. Prin-ciples & Practice of Pain Medicine. 2nd ed. New York, NY: McGraw-Hill; 2004.112. Desbiens NA, Mueller-Rizner N. How well do surrogates assess the pain of seriously ill patients? Critical care medicine. 2000;28(5):1347-1352.113. Mercadante S. Intravenous morphine for management of cancer pain. The Lancet. Oncology. 2010;11(5):484-489.114. Morita T, Tsunoda J, Inoue S, Chihara S. Effects of high dose opioids and sedatives on survival in terminally ill cancer patients. J Pain Symptom Manage. 2001;21(4):282-289.

120

46. Extended-release (ER) and Long-acting (LA) formulations of opioids should typically not be used for which of the following?A. Treating cancer painB. Treating acute painC. Treating end-of-life painD. Treating nociceptive pain

47. If an organic pathology cannot be found to explain a patient’s pain, what should a clinician infer?A. The pain is real, though unexplainedB. The pain is psychosomaticC. The patient is seeking opioids for illegal useD. The pain is the result of a mental health condition

48. Which of the following is the appropriate use of “universal precautions” as it applies to patients with chronic pain?A. Exploring patients’ HIV statusB. Having all patients submit to a screening urine

toxicology testC. Being vigilant about the possibility of misuse or

abuse with all patientsD. Both B and C

49. The DIRE and the ORT are examples of which kind of assessment?A. Quantifying patients’ pain perceptionsB. Assessing patient risk of opioid misuse or abuseC. Evaluating risk of physical adverse reactions to

opioidsD. Determining a reason for opioid pain medications

50. All of the following need to be documented in writing as part of an overall therapeutic approach to managing chronic pain patients EXCEPT: A. Informed consentB. Patient/provider agreementsC. Treatment agreementsD. Expected cost of prescribed medications

51. All of the following are possible advantages of patient/provider agreements EXCEPT:A. Provides a foundation for subsequent decisions

about treatment terminationB. Can help clinicians identify a patient’s level of risk

for opioid abuseC. Can help avoid misunderstandings between

provider and patientD. Can document informed consent

52. All of the following are examples of functional goals EXCEPT:A. Reduced anxiety about painB. Walking around the blockC. Increased sexual activityD. Returning to work

53. A fundamental part of ethical treatment for patients with chronic pain is:A. Assessing a patient’s risk for opioid use disorderB. Obtaining informed consentC. Proper insurance coverageD. Avoiding high doses of opioids

54. When opioid treatment is initiated, both the patient and clinician should view the commitment as:A. Short-term trial of therapyB. A long-term use of opioid therapyC. A titration of the opioid to reach optimal pain reliefD. Continued therapy until adequate pain relief is

achieved

55. It can be particularly unsafe to combine opioids with which of the following other medicines?A. Stimulant medicationsB. SSRI antidepressantsC. Benzodiazepines or barbituratesD. Anti-hypertensive medications

PRESCRIBER EDUCATION FOR EXTENDED-RELEASE AND LONG-ACTING OPIOID ANALGESICSSelf-Assessment

Choose the best possible answer for each question and mark your answers on the Self-Assessment answer sheet at the end of this book. There is a required score of 70% or better to receive a Certificate of completion.

121

56. Which class of antidepressant medications has been shown to be effective in treating some neuropathic pain conditions?A. SNRIsB. SSRIsC. MAOIsD. DNSIs

57. Combination products are those that include an opioid with which of the following elements?A. Non-opioid coanalgesicB. Non-opioid narcotic medicationC. Opioid antagonist to prevent abuseD. Caffeine

58. In general, the amount of opioids prescribed for acute pain should be limited to a ____ day supply:A. 1B. 3C. 7D. 10

59. Uncomfortable or unpleasant side effects (aside from constipation) may potentially be reduced by which approach?A. Switching to another opioid B. Using adjunctive medications to treat symptomsC. Changing the route of administrationD. All of the above

60. All of the following are valid reasons to pursue opioid rotation EXCEPT:A. Lack of efficacyB. Bothersome or unacceptable side effectsC. Desire to prevent the patient from illegally diverting

opioidsD. Change in patient’s ability to absorb a medication

in its present formulation

61. One reason that methadone must be prescribed with particular caution is that:A. Methadone is only appropriate for opioid

maintenance therapy programsB. Methadone’s analgesic half-life is much shorter

than its elimination half-lifeC. Methadone has uniquely powerful respiratory

depressive effectsD. Methadone may produce visual disturbances

62. Which of the following is not a potential benefit of urine drug testing?A. May deter inappropriate useB. Provides objective evidence of abstinence from

drugs of abuseC. May demonstrate to regulatory authorities a

clinician’s dedication to patient monitoringD. Can differentiate between specific opioid products

that a patient may be using

63. All of the following are of particular concern when prescribing an ER/LA opioid pain medication EXCEPT:A. Abuse by breaking, chewing, or crushing tabletsB. Risk of overdose if long-duration drugs are

combined with short-acting medicationsC. ER/LA medications tend to be costlier than short-

acting formulationsD. Some opioids with ER/LA characteristics (i.e.,

methadone) may have atypical pharmacokinetics

64. In 2006, the FDA added a caution to the “black box” warning that methadone may cause which of the following serious adverse effects?A. Respiratory depressionB. Cardiac conduction disturbancesC. MyoclonusD. Renal failure

65. Which of the following is the APS-AAPM guideline regarding the prescription of opioids to pregnant women?A. Avoid prescribing opioids unless potential benefits

outweigh risksB. Completely avoid prescribing opioids to this

populationC. Prescribe ER/LA opioids rather than short-acting

opioids to avoid spike exposure to fetusD. Prescribe opioids as needed for maternal pain, but

monitor infant after delivery for possible neonatal abstinence syndrome

122

NOTES

123

NOTES

124

NOTES

125

NOTES

126

NOTES

127

Free Credit, Unlimited AccessLearn about Internet Point of Care Learning and how to earn CME Credits. Take advantage of the trial offer to receive the Directus application for the remainder of the calendar year & earn up to 100 AMA PRA Category 1 Credits™

CME Credit for Self-Directed, Structured LearningInternet Point of Care activities are intended to give licensed physicians and other healthcare professionals the opportunity to research a self-identified clinical question at the point of care and then apply that knowledge into either their practice or the systems of care in which they work. Individuals will review evidence-based sources relevant to their clinical practice and evaluate their application, or planned application, to their own practice. This structured, self-directed online learning is eligible for AMA PRA Category 1 Credit™.

Directus Internet Point of CareDirectus is an example of an application for turning your search into a self-directed CME activity for which you earn AMA PRA Category 1 Credit™. It provides the structure for this process by documenting the educational activity & planned outcome, capturing your search efforts & evaluating your actual outcome. Directus has a clearly defined list of approved databases for users to utilize during their research efforts.

Terms and ConditionsStart Earning CME Credits Today. Free Credits, Unlimited Access

Eligible individuals who complete one of our educational programs are able to take advantage of Directus Free Trial Offer. Directus is an application for turning clinical search into a structured, self-directed CME activity at the Point of Care. If you do not wish to register for Directus, you may choose to opt-out during the checkout process. Individuals that do register will receive

an e-mail to begin earning CME credits the next time you go online.

TERMSAvailable for new subscribers only. The subscription fee is waived for the remainder of the calendar year. Completing the application process through the checked box indicates your acceptance of this offer and will create your account with the Directus application. Username and registration link are sent via email upon completion. The annual subscription fee of

$95 is waived for this initial time period. Thereafter, you agree to pay for your annual subscription of $95.

If you do not wish to utilize the free trial for Directus, you may choose to opt-out during the checkout process. You may cancel your subscription any time for any reason. Please notify us of your request at 1-800-237-6999 or support@cme.edu. You are fully protected by our 100% No-Risk Double Guarantee. If you don’t like it, then we will happily refund 100% of your money. No questions asked.

You can view the full terms of service at [https://directus.cme.edu/#/terms].〉

HOW TO EARN AMA PRA CATEGORY 1 CREDITSTM

Step 1: Clinical QuestionTo earn AMA PRA Category 1 Credit™ for your research, you must document the clinical question or information you are researching. Before you decide to search for literature about a particular subject, establish & document the clinical question to

research.

Step 2: Identify Relevant Sources & Citations:

For each learning cycle, users must document the relevant sources & select professional, peer reviewed literature from sources & databases vetted by the CME provider. These commonly include databases such as

National Library of Medicine.

Step 3: Evaluate:Describe the application of your findings to clinical practice and/or how you can you apply this learning experience. Determine if the findings result in any change or improvement to your knowledge, competence, professional performance or patient

care.

128Phone: 1-800-237-6999 • Fax: 1-800-647-1356

VERIFIED CERTIFICATES AND LEARNER RECORDS

FIRST NAME:

EMAIL ADDRESS:

LICENSE TYPE/DEGREE:

MAILING ADDRESS:

SPECIALTY:

CITY: STATE: ZIP CODE:

LICENSE #: LICENSE EXPIRATION DATE:LICENSE STATE:

abbr.

abbr.

MD, DO and PA

PHONE NUMBER:

LAST NAME:

John

MD

1234 Cherry Street Sacramento CA 95814

Internal Medicine

CA

johndoe@e-mail.com

Doe

(916) 456-7890

6/30/2018MM / DD / YYYY

A65432

LICENSE NUMBER FORMATS:

Physicians (MDs) and Doctors of Osteopathy (DOs):• Three to Five numbers. (Ex: 432 or 13753)

• A capital “A” followed by four to six numbers. (Ex: A65432)• A capital “C” followed by four to six numbers. (Ex: C65432)

• A capital “G” followed by three to six numbers. (Ex: G65432)

RENEWING A LICENSERenewal Process Licenses are renewed every two years, at the end of your birth month. It’s very important that you notify the Board office via the website, or by fax when you change your mailing address as renewal notifications are not forwarded by the Post Office. The notification will give you information about renewing your license online, paying with a credit card, or the process to follow if you would rather renew with a paper form. The notification is mailed 3-4 months before your license expires.

CME for Renewal In order to renew your license, you must earn 50 AMA PRA Category 1 Credit(s) TM during the current licence period. All licensees, except pathologist and radiologists, must earn twelve credits in approved courses in the area of pain management and appropriate care for the terminally ill and dying patients. This is a one-time requirement that must be completed by your second license renewal date or within four years your of initial license date, whichever comes first.

Complete the self-assessment, survey (on the following page) & customer information Tear out the following page Mail the form in the self-addressed

envelope

1. Important: To ensure accurate record keeping and reporting, your personal information entered at the beginning of the assessment should match your license record.2. Why we collect this info: We use this information to uniquely identify each individual who successfully completes our activities and verify learner records for professional credentialing.

129Phone: 1-800-237-6999 • Fax: 1-800-647-1356

2018 CALIFORNIA MEDICAL LICENSURE PROGRAMSELF-ASSESSMENT ANSWER SHEET

To Receive Credit: Please ensure information entered matches your license record and all required fields are accurately completed. For help see the previous page.

See Terms & Conditions on pg 119

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

Program Price

BILLING ZIP CODE:

CONTROLLED SUBSTANCE EDUCATION FOR PRESCRIBERS (p 18-19 )

CDC GUIDELINES (p 58-60)

CARING FOR PATIENTS AT THE END OF LIFE (p 78)

PRESCRIBER EDUCATION FOR EXTENDED-RELEASE AND LONG-ACTING OPIOID ANALGESICS (p 120-121)

CA12CME

A B C D

$135

A B A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B

A B

A B

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

A B C D

130PROGRAM CODE: CA12CME

DCBA

DCBA

NoYes

ACTIVITY EVALUATION(S)For each of the objectives determine if the activity increased your: A Competence B Performance C Outcome D No Change

CONTROLLED SUBSTANCE EDUCATION FOR PRESCRIBERS: 1. Identify Controlled Substance Act (CSA) requirements. 2. Describe safe prescribing practices for controlled substances. 3. Recognize pharmacological treatment options for anxiety, insomnia, narcolepsy, ADHD and obesity4. Please identify a specific change, if any, you will make in your practice related to prescribing controlled substances

5. What do you see as a barrier to making these changes?

CDC OPIOID PRESCRIBING GUIDELINES FOR CHRONIC PAIN:6. Determining when to initiate or continue opioids for chronic Pain 7. Discussing known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy8. Clinical treatment when opioids are started, including selection, dosage, duration, follow-up, tapering and discontinuation9. Assessing Risk and Addressing Harms of Opioid Use10. Please identify a specific change, if any, you will make in your practice related to improving the safety and effectiveness of pain treatment

11. What do you see as a barrier to making these changes?

CARING FOR PATIENTS AT THE END OF LIFE:12. Formulating patient-centered goals and treatment for end-of-life care13. Incorporating communication strategies for discussing end-of-life care with patients and family members14. Assessing and managing pain as well as other physical symptoms in patients near the end of life15. Please identify a specific change, if any, you will make in your practice related caring for patients at the end-of-life?

16. What do you see as a barrier to making these changes?

PRESCRIBER EDUCATION FOR EXTENDED-RELEASE AND LONG-ACTING OPIOID ANALGESICS:17. Assessing Patients for Treatment with ER/LA Opioid Analgesic Therapy18. Initiating Therapy, Modifying Dosing, and Discontinuing Use of ER/LA Opioid Analgesics19. Managing Therapy with ER/LA Opioid Analgesics. 20. Counseling Patients and Caregivers about the Safe Use of ER/LA Opioid Analgesics 21. General Drug Information for ER/LA Opioid Analgesic Products22. Specific Drug Information for ER/LA Opioid Analgesic Products23. Have you presecribed ER/LA opioids in the past tweleve months ?24. Please identify a specific change, if any, you will make in your practice related to prescribing ER/LA opioid analgesics?

25. What do you see as a barrier to making these changes?

PROGRAM EVALUATION:26. The program was balanced, objective & scientifically valid. 27. Do you feel the program was scientifically sound & free of commercial bias or influence?28. How can this program be improved?

29. Based on your educational needs, please provide us with suggestions for future program topics & formats

DCBA

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . .. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . .

. . .. . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . .. . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .

DCBA

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

NY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .

CUSTOMER SERVICEWe maintain a fully-staffed educational service center that physicians and course participants can contact Monday through Friday, 8:30 AM to 5:30 PM (EST) by calling toll-free at 1-800-237-6999. Physicians can speak directly with our educational support personnel to request course materials, have tests graded, receive interactive training and interpretation of course materials, request duplicate certificates and resolve problems.

EMAIL MAIL PHONE/FAX1649 Atlantic Blvd. #100Jacksonville, FL 32207

support@cme.edu p: 1.800.237.6999f: 1.800.647.1356

OPEN ACCESSEnjoy free access to all course materials. Whether you’re at home or on the go, all course materials are readily available.

SELF-PACEDOur content is available on demand for your convenience and can be completed entirely at your own pace.

TARGETED SERIESOur CME is geared towards helping you advance your professional career while focusing on refining your practice.

VERIFIED CERTIFICATEClaim & Receive a verified certificate upon successful course completion.

OPEN CME EDUCATION FOR THE FUTURE

“I’ve been using InforMed to satisfy my CME for over 15 years. They provide first-

rate content at an unbeatable cost.”- Ashley Holmstead

“The course is 100% relevant to my practice. InforMed offers real life

scenarios that I can apply to my daily performance.”

- Christina Gomez

“Open access to all the course materials make it convenient and easy for me to

satisfy my CME requirements.”- Joseph Alasi

KEEP IN TOUCHWWW.CA.CME.EDUInforMed is Accredited With Commendation by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

C O N T I N U I N G M E D I C A L E D U C A T I O N

1649 Atlantic Blvd. #100 | Jacksonville, FL 32207

Presort StandardU.S. Postage

PAIDTallahassee, FLPermit No. 571

2018 C ALIFORNIA MEDIC AL L ICENSURE PROGRAMSATISFIES 12 CREDITS OF CME IN

PAIN MANAGEMENT AND THE APPROPRIATE TREATMENT OF THE TERMINALLY ILL