S20 Seminars in Oncology Nursing, Vol 25, No 2, Suppl 1 (May), 2009: pp S20-S28

CLINICAL APPROACHES TO

SPECIAL ISSUES RELATED

TO OPIOID THERAPY

PERRY G. FINE

Perry G. FiResearch Ce

Utah, Salt La

Based on a

Nursing Soci

Address co

Research Cen

Suite 200, 6

84108; e-mai

� 2009 Els

0749-2081/09

doi:10.1016/j

OBJECTIVES: To summarize the unique characteristics of methadone and the

putative mechanisms of rapid-onset opioid formulations for breakthrough

pain; to outline the principles underlying opioid rotation; and to describe

elements of risk assessment in opioid therapy.

DATA SOURCES: Published research articles and clinical experience.

CONCLUSION: Risk management for opioid therapy should involve multiple

approaches, tools, and regular patient interactions; urine toxicology can be

used to confirm suspicion of aberrant behavior. Yet, some aberrant drug-

related behaviors can reflect opioid efficacy failure or a deterioration of the

underlying condition. Opioid rotation can be an effective tool to manage

cases where opioids have not effectively controlled pain or were associated

with intolerable side effects. However, dose conversion requires careful

calculation and continuing follow-up care. Treatment of both baseline pain

and breakthrough pain is essential as both can erode an individual’s quality

of life.

IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses can better address

challenging clinical scenarios associated with opioid therapy.

KEY WORDS: Pain, opioids, methadone, opioid rotation, breakthrough pain.

ne, MD: Professor of Anesthesiology, Pain

nter, School of Medicine, University of

ke City, UT.

symposium held at the 2008 Oncology

ety Congress.

rrespondence to Perry G. Fine, MD, Pain

ter, School of Medicine, University of Utah,

15 Arapeen Drive, Salt Lake City, UT.

l: perry.fine@hsc.utah.edu

evier Inc. All rights reserved.

/2502, Suppl 1-$32.00/0.

.soncn.2009.03.011

OPIOIDS AND RISK MANAGEMENT APPROACHES

OPIOIDS are an indispensable andcurrently irreplaceable pharmaco-logic class of drugs for the treatmentof most causes of moderate to severe

cancer-related pain. While the side-effect profileand potential drug abuse liability can be limitingand problematic, opioid efficacy, potency, andversatility are incomparable. Clinicians managethe limitations of opioids by prophylaxis or treat-ment of common side effects and implementationof risk management approaches.

SPECIAL ISSUES RELATED TO OPIOID THERAPY S21

Pain medicine has borrowed the universalprecautions approach from infectious diseasemedicine. The potential for opioid misuse is identi-fied through risk stratification strategies, whereinpatients considered for opioid therapy undergoassessments that can predict their likelihood ofmisuse. In addition to protecting the patient,both the clinician and society are protected fromthe consequences of drug misuse, including abuseand diversion. Disease progression, increasedpain, and under-effective or ineffective treatmentall increase the risk for aberrant drug-relatedbehavior, as patients become desperate in theirattempts to control pain (eg, taking more medica-tion than directed, using other drugs or alcohol,or ‘‘borrowing’’ other opioid medications thatwere not prescribed). Adherence to drug regimensis generally imperfect, so a judgment must be maderegarding whether straying from a given treatmentplan imposes serious risks to that individual, theirfamily, and/or society. In any case, a urine toxi-cology screen should be conducted when aberrantdrug-related behavior is suspected, even when it islikely to be a case of pseudoaddiction (behaviorssuggestive of addiction, but resulting instead frominadequately controlled pain).

The Screener and Opioid Assessment for Patientswith Pain (SOAPP) tool is a quick method to eval-uate and document a patient’s risk for aberrantbehavior associated with opioid therapy (Fig 1).Along with a patient’s presentation and history,a risk assessment tool, such as SOAPP, the OpioidRisk Tool, or the Pain Assessment and Documen-tation Tool, can help clinicians determine ifopioids are an appropriate option for a patientwith moderate to severe uncontrolled pain. TheSOAPP V.1–short form consists of five questionsidentified empirically as predictive of aberrantmedication-related behavior; the shortened toolalso retains most of the predictive validity andsensitivity of the standard SOAPP version.1 ASOAPP V.1–short form score of 4 or 5 has beenpredicted to identify 86% of those who actuallyare at high risk of drug misuse or abuse (comparedwith 91% for the 14-item version).1 The negativepredictive value for a cutoff score of 4 is 0.85,which indicates that most people who have a nega-tive SOAPP score are likely at low risk of drugmisuse or abuse. Meanwhile, the positive likeli-hood ratio suggests that a positive SOAPP score(at a cutoff of 4) is more than two and one-halftimes as likely to come from an individual who isactually at high risk. Still, even for patients who

have a low risk for opioid misuse, and especiallythose for whom there is no established relation-ship, there must be regular ongoing follow-upcare. The cardinal underlying principle for allpatients is that there is no substitute for continuityof care and regular visits in pain management,particularly when opioids are being prescribed.

For ongoing evaluation, a comprehensive butefficient approach to documentation includes the‘‘4 A’s of reassessment.’’ This mnemonic strategyensures that the key clinical aspects of the caseare captured, such as the level of analgesia ob-tained, including average pain intensity by visualanalog scale; the presence of adverse effects; andthe functional effects of pain as noted by changesto activities of daily living. Adverse effects such assedation, bowel dysfunction, and nausea shouldbe assessed, documented, and treated. Also, anyapparent aberrant drug-taking behaviors shouldbe noted, such as requests for early refills, ‘‘lost orstolen’’ drugs, missed appointments, or either signsof excessive medication use (nodding off, poorattention span, pinpoint pupils) or acute with-drawal (yawning, rhinorrhea, abdominal cramp-ing, mood lability/irritability). For completeness,two additional ‘‘A’s’’ serve as a helpful reminder:an overall assessment impression should be notedand then an action plan should be detailed andimplemented as well.

SPECIAL CONCERNS WITH OPIOID THERAPY

Methadone and Opioid-related Sleep Problems

When optimizing a pain regimen, the cardinalelements of the presentation and history are consid-ered. In a situation where one opioid is notadequately reducing the level of pain, rotation (ie,switching) to a different opioid should be consid-ered. Many different long-acting opioids are avail-able in the clinical armamentarium, includingones with varying potencies, unique pharmacoki-neticparameters,metabolism bydifferent enzymes,and with particular side effect profiles. For example,methadone is inexpensive, very potent, and versa-tile. Methadone can be a good alternative forcontrolling pain, especially when other opioidshave failed to provide adequate relief, such as inpatients who are genetically predisposed to havepoor responsiveness to certain other opioids(eg, slow metabolizers of prodrugs such as codeineor oxycodone). It is available in tablet, liquid, and

FIGURE 1. SOAPP Short Form. A tool to assess an individual’s level of risk associated with opioid use.

S22 P.G. FINE

injectable formulations for patients with specialneeds and limitations such as swallowing difficul-ties, feeding tubes, etc. Methadone has no knownactivemetabolites (and therefore no risk of accumu-lation of toxic metabolites), thereby obviating theneed for dose adjustments in patients who haverenal insufficiency.2 This is an important consi-deration because renal insufficiency is a commonproblem in patients with advanced medicalillnesses, including cancer, as well as in olderpatients (creatinine clearance declines appreciablyin the geriatric population). Also, animal studies ofthis agent have suggested that methadone may have

clinically relevant NMDA (N-methyl-D-aspartate)receptor antagonist activity, which may make theanalgesic particularly useful for treating neuro-pathic pain and could also be advantageous forpatients who develop opioid tolerance or opioid-mediated hyperalgesia.

However, the advantages associated with meth-adone can be offset by some distinct clinical disad-vantages. Recently, the increased popularity ofmethadone has led to a spike in the number ofcases of associated morbidity and mortality amongthe population of patients prescribed methadone,as well as within individuals who inappropriately

SPECIAL ISSUES RELATED TO OPIOID THERAPY S23

use it.3,4 In fact, methadone has been associatedwith sudden death, even at presumably thera-peutic levels.4 It has adverse reactions with tricy-clic antidepressants, cardiac toxicity with highdoses (QTc prolongation [‘‘torsades de pointe’’]that can lead to sudden death), and has been asso-ciated with multiple overdose deaths (US Foodand Drug Administration black-box warning advi-sory, November 2006).3

Methadone has complex pharmacokinetics. Ithas a highly variable and potentially very longelimination half-life (up to 130 hours) that canlead to accumulation, despite limited concurrentanalgesic effects.2,5 Because it is potentially fatal,unintentional overdoses can occur because ofthis phenomenon; methadone should be adminis-tered with caution in an unmonitored setting, withlong intervals between dose adjustments (at least5 to 7 days) until a patient has reached a steadystate (which takes approximately 4 to 6 half-livesof methadone; ie, for a 20-hour half-life, it maytake 4 to 5 days to reach equilibrium). An extradose taken before the steady state has beenreached will lead to the accumulation of metha-done, and with higher drug concentrations therewill be more drug crossing the blood-brain barrier.This is associated with increased central effects,which may be toxic; thus, the timing of the dosebefore a patient is at steady state is criticallyimportant. Older adults and those patients whoundergo rapid dose adjustments of methadonehave a greater risk for sedation and respiratorydepression.2 It must be impressed upon patientsthat all drugs, but especially methadone, must betaken exactly as directed to avoid potentiallydangerous side effects. Furthermore, opioidconversion tables underestimate the potency ofmethadone, especially when switching fromanother opioid to methadone. Also, serum levelsof methadone are increased by CYP3A4 inhibitors,including verapamil, cimetidine, and grapefruitjuice. If unfamiliar with the use of methadone, itis advisable to seek consultation with a painspecialist, especially when considering prescribingmore than low-dose methadone (5 mg three timesdaily) or when switching from another opioid tomethadone.6

Sleep disturbance is commonly associated withchronic pain. But opioids themselves have alsobeen shown to have detrimental effects on sleepphysiology. Thirty percent of patients stabilizedon a methadone maintenance program were re-ported to have central sleep apnea compared

with matched controls in a small but well-designedstudy.7 These results were a confirmation of anearlier, similarly designed study in which patientswho were on a stable methadone maintenanceprogram had more sleep architecture abnormali-ties and a higher prevalence of central sleep apneathan the control cohort.8

In another study, patients who were takingopioids for pain control developed disordered sleeppatterns. A direct relationship was shown betweencentral apnea index and daily dose of metha-done (P ¼ .008) and benzodiazepines (P ¼ .004).9

Furthermore, a double-blind, placebo-controlledpolysomnography study of healthy individualsfound that both extended-release morphine (15mg) and methadone (5 mg) significantly reduceddeep sleep and increased Stage 2 sleep (P <.01 forboth).10 Finally, further evidence on disruptedsleep associated with opioid use was accumulatedfrom a retrospective cohort case-control polys-omnography study comparing 60 patients takingopioids to 60 patients who were not takingopioids.11 Individuals taking morphine for anextended period at doses of 200 mg or higher hada dose-dependent increase in sleep apnea andataxic breathing. Sleep architecture issues can beassessed by a polysomnography work-up (a diag-nostic test during which a number of physiologicvariables are measured and recorded during sleep).The need for this assessment can be suggested bycomplaints such as daytime fatigue, sleepiness,and other possible indications of interrupted sleep.Sleep partners of patients should be asked if thepatient snores during the night or has periods ofapnea. Disrupted sleep can lead to other issues,such as mood disturbances, depression, andreduced function and activity levels, similar tothe sequela associated with uncontrolled pain.

Opioid Rotation

Opioid responsiveness is a highly individualizedphenomenon and depends upon many factors,including pain etiology, prior exposure to opioids,pharmacogenetics, and other psychophysiologicaldeterminants. Therefore, when a patient hasundergone analgesic titration and has had undesir-able opioid effects (such as constipation or nausea)prevented and treated as best possible, but painremains poorly controlledor intolerable side effectsprevent upward titration, these various factorsmust be considered. In these circumstances,absent a well-defined contraindication to opioids,

S24 P.G. FINE

opioid rotation may be a suitable option for betteroptimizing analgesic therapy.12

Opioid rotation is the practice of switching toa different opioid analgesic when adequate effec-tiveness is not achieved during a trial of reasonableduration or when side effects become intolerable.This approach to managing lack of efficacy or intol-erable side effects is supported both by empiricalclinical evidence as well as current research. Clin-ically, significant interpatient variability inresponses to opioids has been observed fordecades, in terms of both efficacy and side effects.13

In a trial of opioids for chronic rheumatologic pain,Grilo and colleagues14 enrolled 67 patients inwhom other analgesics had failed. In most cases,the patients were switched from morphine to eitheroral hydromorphone or transdermal fentanyl.The mean improvement in pain observed was 30mm by visual analog scale (P <.001). The authorsconcluded that opioid rotation could alleviatepreviously uncontrolled pain in most cases.14

Also, Quang-Cantagrel et al15 considered opioidrotation for a population with chronic noncancerpain by a retrospective chart review. They foundthat the first opioid prescribed was effective for36% of patients, stopped due to side effects for30%, and stopped for ineffectiveness for another34%. The remaining patients who still had uncon-trolled pain or side effects were given a differentopioid, and the second opioid prescribed was effec-tive in 31%. Further rotation led to effectiveness ofthe third opioid tried in 40%, the fourth in 56%, andthe fifth in 14%.15 One case of addiction and no

Level o

f A

ctivatio

n

MOR-1Variant 1

Drug 1

Drug 2

Receptor

Mu-Opioid Receptor Activation and Inc

Cross Tolerance

Adapted from Pasternak GW.Trends PharmacolSci. 2001;22:67-70.

MOR-1Variant 2

MOR-1Variant 3

MOR-1Variant 4

Receptor Variation for Same Patient With Different D

cases of tolerance were noted. For patients inwhom it is necessary to change the opioid prescrip-tion because of intolerable side effects or ineffec-tiveness, the cumulative percentage of efficacywithin the population increased with each newopioid tested.15 These and other studies suggestthat the failure of one opioid does not predict thepatient’s response to another opioid analgesic.16

Indeed, animal studies have documented incom-plete cross-tolerance between opioids, whereinpotency to select opioids is retained in the face ofinsensitivity to other opioids (eg, mice unresponsiveto morphine, yet able to derive normal levels ofanalgesia from fentanyl and methadone; Fig 2).13

Meanwhile, evidence gathered over the last severaldecades has identified multiple m-opioid receptorsubtypes (so-called ‘‘splice variants’’) with distinctproperties that influence the pharmacodynamics ofindividual opioids.17 Although the opioid analgesicstypically bind to all of the m-opioid receptor variants,their ability to activate the receptors can vary.Research on the pharmacogenetics of the OPRM-1opioid receptor has also indicated that specificsingle-nucleotide changes, called polymorphisms,further increase the variability in patient responsesto opioid analgesics.18

The range of the expression of the genes thatcode for m-opioid receptors, the enzymes involvedin metabolizing opioids, and the proteins thattransport opioids vary considerably, leading toextraordinary variation in analgesic responsesacross individuals.18 Furthermore, the expressionpattern of these genes, based on other influences,

omplete

MOR-1Variant 5

rug

Figure 2. Incomplete cross-toleranceamong drugs.17 Although the m-opioids typically bind to all of thereceptor splice variants, their abilityto activate them can vary. Picturedis a hypothetical example of twodrugs with unique activation profilesfor different m-opioid receptorsubtypes.

SPECIAL ISSUES RELATED TO OPIOID THERAPY S25

such as disease states and varying degrees or typesof physiological or emotional stress, may changeover time and can even be divergent across organsystems and tissues within the same individual.

Guidelines have been formed to help clinicianssafely and effectively switch opioids and adjustthe dose accordingly.19 The basics include calcu-lating a new opioid dose based on the equianalge-sic table equivalency chart (Table 1), then makingan adjustment to determine a safe starting dose.Important principles are that one-to-one conver-sions often yield too-high doses for most patientsbecause of incomplete cross-tolerance, so thatthe equianalgesic dose for most opioids, exceptmethadone and transdermal fentanyl, must bedecreased by 25% to 50%. For methadone, theequianalgesic dose should be reduced by 75% to90%, but there is no equianalgesic dose reductionneeded when switching to transdermal fentanylbecause this safety calculation has been builtinto the conversion charts found in the packageinsert for this delivery system.20 An example ofopioid conversion calculations is given in Table 2.

TABLEEquianalgesic Opioid Doses

Opioid Analgesic

Equianalgesic

Dosesa,b (mg)

Morphine 10 IM/IV/SQ

20–30 PO

Controlled-release morphine 20–30 PO

Extended-release morphine 20–30 PO

Hydromorphone 1.5 IM/IV/SQ

7.5 PO

Oxycodone 20–30 PO

Controlled-release oxycodone 20–30 PO

Oxymorphone 1 IM/IV/SQ

Immediate-release oxymorphone 10–15 PO

Extended-release oxymorphone 10–15 PO

Levorphanol 2 IM/IV/SQ

4 PO

Methadone Variable

Hydrocodone 30 PO

Fentanyl 50–100 mg IV/SQ

Fentanyl transdermal system NA

Oral transmucosal fentanyl citrate NA

Fentanyl buccal tablet NA

Abbreviations: IM, intramuscular; IV, intravenous; NA, not applicab

Adapted from Fine PG, and Portenoy RK.19

aDose provides analgesia equivalent to 10 mg of morphine given i

drugs or routes of administration. In clinical practice, the potency obWhen switching from one opioid to another, incomplete cross-tole

a reduction in the dose of the new drug by at least 25% to 50% to pre

during the conversion period (a few days) prevent breakthroug

Additional dose reduction adjustments may benecessary based on a patient’s medical condition,age, and pain severity. In fact, dose ratios found inequianalgesic tables should be considered a roughguide only. In particular, deviations from predicteddoses may arise from incomplete cross-tolerance;however, this phenomenon is not possible topredict and likely depends on duration and doseof opioid use, genetic factors, disease states, andconcomitant medications. Although analgesicdose tables reflect the best science and are usefulto estimate a ‘‘first best guess’’ in cases where opioidtype or route of administration requires changing,the tables are largely derived from single-dosecrossover studies that do not necessarily reflectthe clinical circumstances of most patients experi-encing chronic pain who have been exposed toopioids. Therefore, careful and frequent reassess-ment of the patient’s response to a new opioidshould be conducted, and upward or downwarddose adjustments should be made according toeach individual patient’s response, optimizing ther-apeutic goals against adverse effects.

1.and Timing of Effects19

Peak Effect (h) Duration(h)

0.5–1 IV

1–2 PO

3–4 IV

3–6 PO

NA 8–12

NA 12–24

0.5–1 IV

1–2 PO

3–4 IV

3–6 PO

1–2 3–6

3–4 8–12

0.5–1 3–6

1–2 6–8

2.5–4 12

0.5–1 IV

1–2 PO

3–6 IV

3–6 PO

1–2 6–8

1–2 3–6

<10 min 1–2

12–24 48–72 per patch

15–30 min 1–2

15 min 1–2

le; PO, by mouth; SQ, subcutaneous.

ntramuscularly. These ratios are useful guides when switching

f the IM route is considered to be identical to IV and SQ routes.

rance and other mitigating medical circumstances may require

vent excessive opioid effects. Provisions of ‘‘rescue’’ medication

h pain that might result from relative underdosing.

TABLE 2.A Case Example of Opioid Rotation: Converting From

a Methadone Prescribed Dose to an Oxymorphone

Extended-release Dose

Calculate the total methadone 24-h dosage

20 mg 3 times daily ¼ 60 mg/24 h

Look up the oxymorphone dose equivalency to methadone

on the equivalency chart

1 mg methadone ¼ 6 mg morphine ¼ 2 mg oxymorphone

Convert 24-h methadone dosage to oxymorphone dosage

60 mg methadone ¼ 120 mg oxymorphone

Split 50% total calculated oxymorphone dosage to twice-

daily dose, reduce by 50% for incomplete

cross-tolerance, and add prn rescue analgesic (10%–20%

of 24-h opioid dose)

Prescribe oxymorphone extended-release 30 mg orally

every 12h

Prescribe oxymorphone IR 10 mg orally every 6 hours prn for

rescue analgesia

S26 P.G. FINE

For decades, the formulary of pure m-opioidagonists has included morphine, oxycodone, fen-tanyl, levorphanol, hydromorphone, codeine,and methadone. Oxymorphone, which has beenavailable in rectal suppository form, has recentlybeen made available in oral form, adding tothe armamentarium of immediate-release andextended-release opioids for the management ofacute pain and persistent pain. Oxymorphone wasdemonstrated to be effective and well toleratedin opioid-experienced patients with chronic lowback pain in a 3-month, randomized, placebo-controlled study,21 as well as in studies of postsur-gicalpain,22-25 cancerpain,26 andmoderate to severepain from osteoarthritis.27-29 This opioid analgesichas low peak-to-trough fluctuation,30 and is notsignificantly metabolized by the cytochrome P450enzymes CYP2C9 or CYP3A4.31 Therefore, oxymor-phone does not interact with cimetidine andverapamil and has a low likelihood of drug-druginteractions affecting drug plasma concentration.

Addressing Breakthrough Pain

A consideration of an individual’s temporalpattern of pain and pain quality provides insightboth into the type of pain affecting an individualand treatment strategies. When a patient’s base-line or persistent pain is well controlled, but there

are recurring episodes of sharp spikes of moresevere pain, then quality of life, sleep, function-ality, and mood may be seriously affected. Thesetemporal patterns of episodic severe pain, calledbreakthrough pain, were most formally describedin patients with cancer pain approximately 20years ago.32

Breakthrough pain is a discrete, transitory exac-erbation, or flare, of moderate to severe pain33,34

characterized by rapid onset and escalation ofpain, often reaching its peak in minutes. It maybe precipitated by movement or action; however,breakthrough pain is not always that predictable.33

Because breakthrough pain can have a negativeeffect on an individual’s daily functioning andquality of life,19 this type of pain requires indepen-dent assessment and targeted treatment.33,34 Witha background of well-controlled pain, increasingthe basal dose of long-acting analgesia to addressthe episodes of severe pain risks an effective over-dose during periods when there is no breakthroughpain. This could lead to an increased potential foradverse effects, especially central nervous systemeffects, such as mental clouding or sedation.Rather, breakthrough pain may be better ad-dressed through administration of an adjuvantanalgesic, especially for neuropathic pain, or byan immediate-release or rapid-onset opioid formu-lation. The consequences of not treating break-through pain are as significant as not treatingbaseline pain. Breakthrough pain can havea substantial negative impact on a patient’s qualityof life by affecting mood, work, sleep, social rela-tions, and enjoyment of life.33

CONCLUSION

Opioid analgesics constitute an importantcomponent of pharmacological management ofpain in patients with cancer. To optimize thera-peutic goals and minimize risks and adverseeffects, clinicians caring for these patients needto have a thorough understanding of the principlesof prescribing and practice for this class of drugs.Critical principles include:

C Knowledge of the clinical pharmacology andformulations of available opioids.

C Determination of indications based on appro-priate assessment, including risk assessmentand stratification.

C A safe and effective approach to initiation andtitration of various opioids.

SPECIAL ISSUES RELATED TO OPIOID THERAPY S27

C The ability to manage side effects and recog-nize toxicity.

C Comprehension of the need to conduct on-going reassessment of therapeutic outcomes,adverse effects, and problematic behaviors.

C An understanding of implementing opioidrotation.

C Recognition and treatment of breakthroughpain.

C A safe and effective means to discontinueopioid therapy if indicated.

C Knowledge of when to seek consultation froma pain medicine specialist.

This monograph has attempted to review some,but not all, of these principles. Readers areencouraged to further their knowledge throughadditional reading.

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