Buprenorphine in Primary Care

Buprenorphine

in

Primary CareEric Olson, MD, FAAFP

Board-Certified Family Medicine and Addiction Medicine

March 26, 2021

Disclosures

No financial disclosures

I am addicted to fishing. I have no desire to Cut down, I do get Annoyed

when criticized for this, I do not feel Guilty for this, I frequently have an Eye-

opener fishing trip.

Acknowledgements

I appreciate assistance from:

PCSS-MAT for borrowed slides (from Half-and Half Buprenorphine waiver

course)

James Walsh at Swedish Addiction Recovery Services in Ballard for slides and

expert knowledge

Steve Aguilu for assistance with PowerPoint and Zoom

Objectives

Understand buprenorphine pharmacology

Understand how buprenorphine can be useful in chronic pain

Review legal issues in prescribing buprenorphine

Brief review of recent trends in Addiction Medicine

Medications for alcohol use disorder (if time allows)

Buprenorphine Pharmacotherapy

Partial agonist at mu opioid receptor

High affinity at mu receptor

Antagonist at kappa opioid receptor

Poor oral availability (first pass metabolism)

Major Features of Buprenorphine

Partial agonist at mu receptor

▪ Comparatively minimal respiratory

suppression and no respiratory arrest

when used as prescribed

Long acting

▪ Half-life ~ 24-36 Hours

High affinity for mu receptor

▪ Blocks other opioids

▪ Displaces other opioids

• Can precipitate withdrawal

Slow dissociation from mu receptor

▪ Stays on receptor for a long time

SAMHSA, 2018

Orman & Keating, 2009

full agonist(e.g. morphine,

methadone)

partial agonist(buprenorphine)

antagonist(naloxone,

naltrexone)

dose

mu o

pio

id e

ffects

Major Features of Naltrexone

Full Antagonist at mu receptor

▪ Competitive binding at mu receptor

Long acting

▪ Half-life:

• Oral ~ 4 Hours

• IM ~ 5-10 days

High affinity for mu receptor

▪ Blocks other opioids

▪ Displaces other opioids

• Can precipitate withdrawal

Formulations

▪ Tablets: Revia®: FDA approved in 1984

▪ Extended-Release intramuscular

injection: Vivitrol®: FDA approved in

2010

SAMHSA, 2018

full agonist(e.g. morphine,

methadone)

partial agonist(buprenorphine)

antagonist(naloxone,

naltrexone)

dose

mu o

pio

id e

ffects

Buprenorphine

▪ Semi-synthetic analogue of thebaine

▪ Approved by the FDA in 2002 as a Schedule III

medication for the treatment of opioid use disorder

▪ Metabolized in the liver, mainly by cytochrome

P450 3A4 (CYP3A4), and has a less-active

metabolite, norbuprenorphine

▪ Most buprenorphine is ultimately excreted into the biliary tract,

but small fractions enter the urine and are detectable in urine

drug tests

▪ Because of extensive first-pass metabolism, buprenorphine has

poor oral bioavailability when swallowed (<5%), and all therapeutic

formulations use other routes

▪ Sublingual administration bypasses first-pass metabolism and

allows bioavailability around 30%Mendelson et al., 1997

SAMHSA, 2016, 2016

SAMHSA, 2018

How Does Buprenorphine Work?

AFFINITY is the strength with which a drug physically binds to a receptor

Buprenorphine has strong affinity; will displace full mu receptor agonists like heroin and methadone

Receptor binding strength, is NOT the same asreceptor activation

DISSOCIATION is the speed (slow or fast) of disengagement or uncoupling of a drug from the receptor

Buprenorphine dissociates slowly

Buprenorphine stays on the receptor a long timeand blocks heroin, methadone and other opioidsfrom binding to those receptors

NOTE: It is unlikely to block all effects from an opioid taken after initiation of buprenorphine treatment. Because binding to mu receptors is a dynamic process; while effects may be less, they are not likely to be completely eliminated.

Common Adverse Effects

of Buprenorphine

▪ Headaches

Management: aspirin, ibuprofen, acetaminophen (if there are no contra-indications)

▪ Nausea

Management: Consider spitting the saliva out after adequate absorption instead of swallowing.

▪ Constipation

Management: Stay well-hydrated, Consume high-fiber diet, Consider stool softeners, laxatives, naloxegol

▪ Xerostomia (Dry mouth) – side effect of ALL opioids

Complications: Gingivitis, Periodontitis

Management: Stay well-hydrated, Maintain good oral hygiene

SAMHSA, 2018

Wald, 2016

Buprenorphine Dosing: Safety

▪ Nearly all fatal poisonings involve multiple substances

Buprenorphine dose (mg)

Resp

irato

ry r

ate

(bre

ath

s/m

in)

Buprenorphine dose (mg)

Oxygen s

atu

rati

on (

%)

Hakkinen et al., 2012

Walsh et al., 1994

▪ Cognitive and psychomotor effects appear to be negligible.

▪ Respiratory rate slowed but has as a plateau effect in adults.

Buprenorphine and Benzodiazepines

▪ Benzodiazepines are present in most fatal poisonings involving buprenorphine

▪ Used as prescribed benzodiazepines in combination with buprenorphine have

been associated with more accidental injuries, but not with other safety or

treatment outcomes

Bardy et al., 2015

Jones et al., 2012

Nielsen & Taylor, 2005

Schuman-Olivier et al., 2013

Buprenorphine for Opiate Dependence

Beyond the Scope of this lecture, but briefly:

MOUD (Medication for Opiate Use Disorder) is life-saving and life-changing

I strongly encourage ALL PCPs to take a buprenorphine waiver course

Using medication to treat substance use disorders is a critical part of primary

care.

You must complete a buprenorphine training course and receive a new DEA#

before prescribing buprenorphine FOR OPIOID DEPENDENCE

Poll Question

Do you have your Buprenorphine Prescribing Waiver?

A. Yes, and I am prescribing buprenorphine.

B. Yes, but I am not yet prescribing buprenorphine.

C. No, but I am thinking about taking the training.

D. What is a buprenorphine waiver?

Buprenorphine in Chronic pain

Only patches and liquid are approved for pain management

Use of other formulations is Off-Label

Keep in mind how pharmacology impacts medication effects

All forms may relieve pain

Buprenorphine Waiver is required to prescribe buprenorphine if OUD is

present

Buprenorphine Formulations

▪ Choice of formulations is based on: Insurance/Third party payer considerations

Patient preferences

Safety

Decreased Diversion potential

▪ Formulations: Buccal film; Sublingual films

Tablets

Subdermal implants

Depot formulation given as a subcutaneous injection

▪ All of the approved forms have demonstrated similar efficacy for

treating opioid use disorder

▪ Buprenorphine for transdermal (via patch) and intravenous (via

injection) use are available for analgesic use. They were tested but

not approved for treating opioid use disorder

SAMHSA, 2016, 2016

Buprenorphine Formulations for

Opioid Use Disorder

Acute Pain Management in

Buprenorphine Maintained Patients▪ Different Approaches:

• Initially try non-opioid

analgesics (ketorolac or

NSAIDs)

• Continue Same buprenorphine maintenance dose but add non-opioid analgesics

• Use split dose for concurrent pain and dependence

• Buprenorphine’s analgesic duration is only a few

hours

• Stop buprenorphine and initiate full agonist therapy

Perioperative Management

▪ General:

Patients fear mistreatment,

Providers fear deception

Lack of consensus in the field

– often based on the preference of the

surgical/anesthesia teams

▪ Pre-Op:

Confirm Multi-Party Consent and Coordination of care with

providers

If patient is already on Partial Agonist:

Take last Buprenorphine maintenance dose 24-hours prior to surgery

Higher dosing of short-acting opioids may be required post-surgical

Merrill et al., 2002

Wenzel et al., 2016

Post Op Options for Patients already on

Buprenorphine

Merrill et al., 2002

Wenzel et al., 2016

Chronic Pain Patients

▪ Consider consulting a

pain medicine

specialist

▪ Consider Multidisciplinary

Team Approach

▪ Try non-opioid and

adjuvant analgesics

▪ Consider non-pharmacologic therapies

Legal Aspects of Prescribing

Buprenorphine

FDA has approved only patches and injectable liquid for treating pain

Use of other formulations for pain is considered Off-Label

If prescribing for a patient with Opioid Use Disorder then waiver is required

When in doubt, do not prescribe without the waiver

DSM V Criteria Loss of Control

Larger amounts, longer time

Inability to cutback

More time spent, getting, using,

recovering

Activities given up to use.

Craving

Physiologic

Tolerance

Withdrawal

Consequences

Hazardous use

Social or interpersonal problems related

to use

Neglected major roles to use

Continued use after significant problems.

• A substance use disorder is

defined as having 2 or

more of these symptoms in

the past year

• Tolerance and withdrawal

alone don’t necessarily

imply a disorder.

• Severity is related by the

number of symptoms.

2-3 = mild

4-5 = moderate

6+ = severe

Pivotal Milestones in Treatment

DATA 2000 – Practitioners Requirements

▪ Licensed provider with DEA Registration

▪ Subspecialty training in addictions or completion

of an 8-hour course

▪ Registration with SAMHSA and DEA

▪ Must affirm the capacity to refer patients for appropriate counseling and

ancillary services

▪ Must adhere to patient panel size limits

30 during the first year

Eligible to apply for increase to 100 after the first year

May apply to increase to 275 after being at 100 for a year and meeting specific

criteria.

Drug Addiction Treatment Act

(DATA 2000)Permitted physicians who met certain

qualifications to treat opioid addiction

with:

Schedule III, IV, and V narcotic medications that had

been specifically approved by the FDA or combination

of such drugs for the treatment of opioid dependence

In treatment settings other than the traditional Opioid

Treatment Program ("methadone clinic") settings

DATA, 2000

Urine Drug Testing

Rapid Testing

Convenient

Inexpensive

Less Accurate

Gas Chromatography (Reference Lab)

Delayed Results

Expensive

More Accurate

General Goals of Drug Testing in

Office-Based Treatment

Important and routine component of treatment

Urine testing can be viewed as

a means for helping the provider

to help the patient

Testing is not meant to "catch" the

patient, and a positive test result should

not simply lead to discharge from treatment, but an opportunity for reviewing the

patient’s Recovery Management

Screening and Confirmatory Tests

▪ A common clinical approach:

Test for a panel of commonly-used substances using screening

tests

Then to perform confirmatory tests for:

Positive results whose accuracy is important for treatment planning

Periodic general screening assessing commonly used substances that are not evident

on POCT

Identification of prescribed medications or metabolites

▪ Confirmatory testing is not necessary at every visit

DuPont et al., 2013

Moeller et al., 2017

SAMHSA, 2012

Common Tests

▪ Some commonly-used screening tests include:

Benzodiazepines

Cannabinoids

Amphetamines

Cocaine metabolite (benzoylecgonine)

Opiates (detects morphine, codeine, and metabolites)

Less commonly-used screening tests include:

Alcohol metabolite (ethyl glucuronide or ethyl sulfite)

Buprenorphine

Fentanyl

Oxycodone

Methadone

Moeller et al., 2017

these and other synthetic opioids

require specific tests—they are not

detected by the test for opiates

Testing for Buprenorphine

▪ Confirmatory testing will distinguish buprenorphine and its metabolite,

norbuprenorphine, which is usually present in greater concentrations

▪ Individuals vary in the ratio of buprenorphine to norbuprenorphine due to

individual metabolism and co-administered inducers or inhibitors of CYP3A4

▪ Buprenorphine with little or no metabolite (i.e. a ratio of

norbuprenorphine:buprenorphine: < 0.02) suggests that buprenorphine was

added to the urine

▪ Testing for buprenorphine during MAT can be useful to monitor adherence and

detect possible diversion

Sethi & Petrakis, 2013

Hull et al., 2008

Recent Trends in Substance Misuse

Methamphetamine overdose deaths are up 400%

Counterfeit oxycodone tablets (M 30) contain no oxycodone

(100% contain fentanyl)

Recent Trends in Addiction Treatment

We don’t call it “Addiction” anymore

DSM-5 identifies Substance Use Disorder

Our words matter

Instead of “dirty urine” try ..

Positive urine drug screen.

Instead of “drug addict” try …

Person struggling with substance disorder


MAT is giving way to MOUD

MAT = Medication Assisted Treatment

MOUD = Medication for Opioid Use Disorder

MOUD recognizes that medication is the primary treatment for OUD

Very high risk of death when patients discontinue MOUD or when they are

released or discharged from structured environment.

MAT⇒ MOUD

Impact of treatment for opioid dependence on fatal drug related poisoning: a national cohort study in England

Matthias Pierce et al. Addiction 2015, 111, 298–308

Audience Response

True or False:

Fentanyl has a shorter half-life than morphine

True

False

Pharmacokinetics of fentanyl after subcutaneous administration in volunteers

Capper, Sarah Ja et al European Journal of Anaesthesiology: March 2010 - Volume 27 - Issue 3 - p 241-246

Audience Response

True or False:

Fentanyl has a shorter half-life than morphine

False



Audience Response Answer

Which drug has the shorter half life?

A. Fentanyl –

10 hours, 13.5 h, 7.9 h

B. Morphine –

2.1 hours, 1.6h




Buprenorphine Microdosing


Buprenorphine given concurrently

with full opioid agonists.

Initial very low dose with titration upward

over 5-10 days.

Full opioid agonists tapered after patient is on effective doses of

buprenorphine.


Buprenex

0.15 mg SL QID x 1 day



then Suboxone

2 mg QID x 2 days

4 mg QID x 2 days

8 mg TID

Suboxone

0.5 mg qD x 1 day

0.5 mg BID x 1 day

1 mg BID x 1 day

2 mg BID x 1 day

4 mg BID x 1 day

4 mg TID

Transitioning Hospitalized Patients with Opioid Use Disorder from Methadone to Buprenorphine without a Period of Opioid

Abstinence Using a Microdosing Protocol. Terasaki D et al Pharmacotherapy. 2019 Oct;39(10):1023-1029

Case report: Successful induction of buprenorphine/naloxone using a microdosing schedule and assertive outreach.

Rozylo J et al. Addict Sci Clin Pract. 2020 Jan 15;15(1):2

Would you prescribe or encourage him to take:

A. Disulfiram

B. Acamprosate

C. Naltrexone

D. Gabapentin

Audi Poll Question

▪ A 48 year old man was just completed a home alcohol detox with a 3 day

prescription of chlordiazepoxide after he was brought to his PCP by his wife.

▪ He was drinking 1 bottle of wine nightly.

▪ Still a little anxious and not sleeping great.

▪ He is confident that he won’t drink again.

Medications for Alcohol Use Disorder

Three FDA-Approved Medicines:

Disulfiram (Antabuse)

Acamprosate (Campral)

Naltrexone (Revia, Vivitrol)

Additional Medicines showing Promise:

Gabapentin

Topiramate

Ondansetron


Three FDA-Approved Medicines:





Aversive therapy

Blocks the Enzyme Aldehyde dehydrogenase (ALDH1A1)

Leads to rapid rise of acetaldehyde

Symptoms include flushing of the face, headache, nausea, vomiting, chest

pain, weakness, blurred vision, mental confusion, sweating, choking,

breathing difficulty, and anxiety.

Risk of liver toxicity

Mixed data on effectiveness, no longer commonly used


Inhibits Negative Reinforcement from alcohol

(Patient does not miss the alcohol as much)

333 mg, 2 tablets TID, do the math …..

666 mg three times daily

Really??

Decreases glutamate, increases beta-endorphins

Probably decreases craving for alcohol

NNT = 12 (abstinence), NNT = 9 (decreased drinking)


Inhibits positive reinforcement from alcohol

Opiate Antagonist (risk of precipitated withdrawal if using opiates)

50-100 mg po daily (compliance is often poor)

“Sinclair Method” (Take only on drinking days)

380 mg IM monthly ($$, improved compliance)


Additional Medicines showing Promise:

Gabapentin

Topiramate

Ondansetron

In patients with concurrent depression and AUD, sertraline and fluoxetine

have led to decreased alcohol use

Gabapentin

300 mg BID starting dose

May titrate up to 1800 mg daily

Be aware of abuse potential

Gabapentin

Abstinence 4.1% placebo, 11.1% 300 mg TID, 17% 600 mg TID

(NNT = 8 for 1800 mg).

No heavy drinking rate 22.5% placebo, 29.6% 900 mg, and 44.7% 1800 mg

(NNT = 5 for 1800 mg).

-----------------

No heavy drinking days 27% gabapentin vs 9% placebo NNT 5.4

Abstinence 18% gabapentin vs 4% placebo NNT 6.2

Worked mainly in pts who had withdrawal symptoms

Gabapentin Treatment for Alcohol Dependence: A Randomized Controlled Trial Barbara J. Mason et al JAMA Intern Med. 2014 Jan 1; 174(1): 70–77

Efficacy of Gabapentin for the Treatment of Alcohol Use Disorder in Patients With Alcohol Withdrawal Symptoms A Randomized Clinical Trial

Raymond F. Anton et al JAMA Intern Med. 2020;180(5):728-736.

Topiramate

Start at 25 mg daily

Titrate up to 300 mg BID

Decrease by 50% for creatinine clearance <60

Ondansetron

4 mcg/kg BID

May go to higher doses

Available in 4, 8, 16 and 24 mg doses

Thank You

Questions?

Documents

Buprenorphine in Primary Care