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Tapering Buprenorphine in Patients with Opioid Use Disorders

David Fiellin, M.D. Yale University School of Medicine

John Renner, M.D.

Boston University School of Medicine

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David Fiellin and John Renner Disclosures

• Dr. Fiellin has received honoraria from Pinney Associates for serving on an external advisory board monitoring the diversion and abuse of buprenorphine.

• Dr. Renner has no financial relationships relevant to the content of the presentation.

The contents of this activity may include discussion of off label or investigative drug uses. The faculty is aware that is their responsibility to disclose this information.

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Planning Committee, Disclosures

AAAP aims to provide educational information that is balanced, independent, objective and free of bias and based on evidence. In order to resolve any identified Conflicts of Interest, disclosure information from all planners, faculty and anyone in the position to control content is provided during the planning process to ensure resolution of any identified conflicts. This disclosure information is listed below:

The following developers and planning committee members have reported that they have no commercial relationships relevant to the content of this webinar to disclose: AAAP CME/CPD Committee Members Dean Krahn, MD, Kevin Sevarino, MD, PhD, Tim Fong, MD, Tom Kosten, MD, Joji Suzuki, MD; and AAAP Staff Kathryn Cates-Wessel, Miriam Giles, Sharon Joubert Frezza, and Justina Andonian.

All faculty have been advised that any recommendations involving clinical medicine must be based on evidence that is accepted within the profession of medicine as adequate justification for their indications and contraindications in the care of patients. All scientific research referred to, reported, or used in the presentation must conform to the generally accepted standards of experimental design, data collection, and analysis. The content of this CME activity has been reviewed and the committee determined the presentation is balanced, independent, and free of any commercial bias. Speakers must inform the learners if their presentation will include discussion of unlabeled/investigational use of commercial products.

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Target Audience

• The overarching goal of PCSS-O is to offer evidence-based trainings on the safe and effective prescribing of opioid medications in the treatment of pain and/or opioid addiction.

• Our focus is to reach providers and/or providers-in-training from diverse healthcare professions including physicians, nurses, dentists, physician assistants, pharmacists, and program administrators.

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Educational Objectives

• At the conclusion of this activity participants should be able to: Describe the natural history of opioid dependence. Describe the rationale for maintenance therapy. Describe the symptoms of opioid withdrawal. Describe the comparative effectiveness of opioid

agonist maintenance vs. taper treatment. Describe the relapse, overdose and psychiatric

considerations associated with buprenorphine taper.

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Overview

• Natural history of opioid use disorder • Neurobiology of opioid use disorder • Treatments for opioid use disorder • Taper vs. Maintenance • Taper duration • Taper considerations Patient selection Patient education Overdose education Withdrawal management Relapse prevention Psychiatric disorders

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Natural history of opioid use disorder

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The natural history of narcotics addiction among a male sample (N = 581). From: Yih-Ing, et. al., 2001. A 33-Year Follow-up of Narcotics Addicts. Archives of General Psychiatry, 58:503-508)

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NIDA

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Nestler et al. Science, 1997

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Neurobiology

• Mu receptor mediates opioid effects high affinity for enkephalins, beta endorphins, and opioids

• Dose dependent changes Repeated exposure to short acting opioids Neuronal cellular and receptor adaptations

− Mesolimbic dopamine system Mediate tolerance, withdrawal, craving, self-

administration Explain chronic and relapsing nature of opioid use

disorder Basis of pharmacotherapies to stabilize neuronal changes

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Medication Assisted Treatment of Opioid Use Disorder

• Opioid agonist treatment Methadone

Buprenorphine

• Pharmacologic withdrawal - “detoxification” Medication-free treatments

• Opioid antagonist treatment Naltrexone

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Opioid Agonist Treatment

• Rationale Cross-tolerance

− prevent withdrawal

− relieve craving for opioids

Narcotic blockade

− block or attenuate euphoric effect of exogenous opioids

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Taper vs. Maintenance

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Taper vs. Maintenance

• Bottom line from this literature: All outcomes are best while patients are receiving

medication − Retention in treatment − Illicit drug use

Ball and Ross, 1991 Sees, JAMA, 2000 Kakko, Lancet, 2003 Woody, JAMA, 2008 Weiss, Archives of Psych, 2011 Sigmon, JAMA Psych, 2013 Fiellin, JAMA IM, 2014

Detoxification vs. Maintenance Kakko, Lancet 2003

No. Assessed for Eligibility: 84

No. Randomized: 40

No. Excluded: 44

Not Meeting Inclusion Criteria: 41

Refused to Participate: 2

Other Reasons: 1

Allocated to Buprenorphine: 20

Received Buprenorphine: 20

Allocated to Detox: 20

Received Detox: 20

Included in analysis: 20

Excluded from analysis: 0

Included in Analysis*: 20

Excluded from Analysis: 0

All Patients:

Group CBT Relapse Prevention

Weekly Individual Counseling

Three times Weekly Urine Screens

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Retention in Treatment Kakko, Lancet 2003

Treatment duration (days)

Rem

aini

ng in

trea

tmen

t (n

r)

0

5

10

15

20

0 50 100 150 200 250 300 350

Detoxification Maintenance

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Mortality Kakko, Lancet 2003

Detoxification Maintenance Cox regression

Dead 4/20 (20%) 0/20 (0%) χ2=5.9; p=0.015

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POATS Design

Phase 1: Brief treatment (2 weeks with taper) Bup/nx - adjusted dose per individual needs ≤32 mg Medication management (MM) or MM + Drug

Counseling

If unsuccessful… Phase 2: Extended treatment (12 weeks)

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Phase 1 Successful Outcome (N=653)

MM+ Drug

Counseling MM p

6% 7% 0.45

Phase 1 Successful Outcome Criteria • ≤ 4 days opioid use per month • No positive urines for opioids on 2 consecutive weeks • No other formal substance abuse treatment • No injection of opioids

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Phase 2 Successful Outcome (n=360)

Phase 2 Successful outcome criteria • Abstinent for > 3 of final 4 weeks (including final week) of bup/nx stabilization (urine-confirmed self-

report)

MM+ Drug

Counseling MM p

Week 12 (end of stabilization)

52% 47% 0.3

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Prescription opioid dependence outcomes in primary care-based buprenorphine

Fiellin D et al. JAMA Internal Medicine 2014 Dec;174(12):1947-54.

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Taper Duration

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Duration of Buprenorphine Taper Systematic Review

• Bottom line from literature (28 studies): Taper duration, not maintenance duration, is

associated with abstinence during taper Maintenance duration is associated with opioid

negative urine on last day of treatment High rate of relapse (70%) No association between taper duration and

retention in treatment or peak withdrawal severity

Dunn et al. DAD 2011;119:1-9

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Prescription opioid dependence outcomes in research clinic-based buprenorphine

Sigmon S et al. JAMA Psychiatry 2013 Dec;70(12):1347-54

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Buprenorphine Taper Outcomes

Bentzley et al. JSAT 2015

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Buprenorphine Taper Unknowns

• Bottom line from literature: Few studies provide sustained follow up

− Many only provide early outcomes - completion of taper, opioid negative on final day…

− Only 34% of studies reported urinalysis-testing outcomes from later follow-up assessments, and the median opioid abstinence rate was 23%.

Not known:

− If patient characteristics predict success − Role of ancillary services − Fixed or flexible dosing schedule

Dunn et al. DAD 2011;119:1-9

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Buprenorphine Taper Unknowns

• Only anecdotal reports (no large RCTs or observational studies) regarding: Tramadol Very low dose oral naltrexone Naltrexone “facilitation” Slow taper vs. “Detox” Daily to every other day dosing of buprenorphine Inpatient vs. outpatient Fractions of buprenorphine strips or tablets Patient characteristics (pain, type of opioid)

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Taper Considerations- Patient Selection

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Considerations for Taper from Buprenorphine Treatment

• Elimination of illicit opioid use; duration? • Interference from alcohol, stimulant,

benzodiazepine or other substance use • Recovery support system • Major unresolved psychiatric or medical

conditions • Aftercare treatment plan

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Likely Less Ideal Candidates

• History of multiple relapses with taper • Failure to attain prolonged abstinence • Untreated comorbid substance use disorders • Social instability • Pregnant • “Forced” tapers

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Taper Considerations- Patient Education

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Patient Education

• Role of buprenorphine maintenance Positive framing (time, relationships, leisure, work,

medical and psychiatric) • Potential for return to maintenance • Role of counseling services • Role of relapse prevention • Overdose education • Anticipatory guidance regarding withdrawal

symptoms

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Taper Considerations- Overdose Education

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Opioid Overdose

• Increasing cause of morbidity and mortality in the US

• Tapered patients are at increased risk due to decreased tolerance Risk should be part of conversation (informed

consent) about taper

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Opioid Overdose Education

• Resources http://store.samhsa.gov/shin/content//SMA14-

4742/Overdose_Toolkit.pdf http://pcssmat.org/new-pcss-mat-online-

module-preventing-opioid-overdose-with-education-and-naloxone-rescue-kits-online-module-with-case-vignette/

• Naloxone http://pcss-o.org/event/putting-naloxone-into-

action/

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Taper Considerations- Withdrawal Management

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Opioid Withdrawal

• Symptoms: craving, anxiety, irritability, restlessness, nervousness, insomnia, rhinorrhea, lacrimation, nausea, abdominal cramps, myalgias, arthralgias

• Signs: tachycardia, hypertension,

mydriasis, piloerection, diaphoresis, tremor • Depending on opioid abused, starts within

4-6 hours, full intensity at 24 to 72 hours, can last for 7-14 days

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Clonidine for Opioid Withdrawal

Principle: Alpha-2 adrenergic agonist, suppresses activity in locus ceruleus, decreases most withdrawal symptoms

Advantages: relief of certain symptoms Disadvantages: requires dose titration,

hypotension, dry mouth, does not treat insomnia, myalgias or craving

One protocol: 0.1-0.2 mg. q 4 hours, up to 1.2

mg/24 hours for 10 to 14 days

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Adjuvant Therapy for Opioid Withdrawal

• Non-steroidals for cramping, arthralgias/myalgias • Medications, e.g. benzodiazepines (cautiously) for

insomnia • Anti-emetics for nausea

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Taper Considerations- Relapse Prevention

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Relapse

• Anticipated recurrence of underlying condition

• Explained by neurobiology of opioid use disorder

• Places patient at risk for adverse consequences of opioid use disorder Medical, social, legal, etc.

• Requires treatment to prevent and/or manage Visits, counseling, urine monitoring, etc.

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Rationale for Naltrexone Block Pleasurable Drug Effects

• Extinction paradigm—patients will cease use if drug pleasurable effects blocked

• Craving decreases when opioid agonist “not available”

• Decreases cue-induced craving and priming-induced craving

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Oral Naltrexone vs. Placebo Retention and Abstinence

Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database of Systematic Reviews 2011

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Oral Naltrexone vs. Buprenorphine Retention and Abstinence

Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A. Oral naltrexone maintenance treatment for opioid dependence. Cochrane Database of Systematic Reviews 2011

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Sustained Release Naltrexone Time to Drop Out

Lobmaier P, Kornor H, Kunoe N, Bjørndal A. Sustained-Release Naltrexone For Opioid Dependence. Cochrane Database of Systematic Reviews 2008

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Sustained Release Naltrexone vs. Placebo Opioid Abstinence

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 randomised trial. Lancet. 2011 Apr 30;377(9776):1506-13.

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Taper Considerations- Psychiatric disorders

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Managing Co-Occurring Psychiatric Disorders

• Patients with Opiate Use Disorder have a high incidence of co-occurring psychiatric disorders

• Depression and anxiety disorders are very common

• Buprenorphine (and other opiates) may have significant

psychoactive properties • It may be difficult to distinguish the dysphoria and anxiety

associated with buprenorphine taper/opiate withdrawal from underlying psychiatric symptoms that are uncovered during withdrawal from MAT

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NESARC: Odds Ratios for Drug Use Disorders & other Psychiatric Disorders. W. Compton 2007

DSM-IV DISORDER 12 MONTH O.R. LIFETIME O.R. Alcohol Use Disorder 9.0 10.4 Alcohol Abuse 2.7 1.9 Alcohol Dependence 9.7 7.6 Nicotine Dependence 5.8 5.5 Any Mood Disorder 3.5 3.2 Bipolar I 5.1 4.8 Bipolar II 2.4 2.4 Any Anxiety Disorder 2.7 2.6 Panic with Agoraphobia 5.8 4.5 Panic without Agoraphobia 3.1 2.9

GAD 4.5 2.8 Antisocial Personality Disorder 6.4 7.8

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Managing Co-Occurring Psychiatric Disorders

• Patients undergoing a taper from MAT should be warned to expect transient dysphoria and anxiety during the final stages of withdrawal. • If symptoms persist for more than two weeks after the final taper, the patient should be evaluated for an independent psychiatric disorder.

• The following guidelines are recommended for managing co-occurring psychiatric disorders.

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Managing Co-Occurring Depressive Disorders

First confirm the diagnosis: • Wait 2 to 3 weeks for withdrawal symptoms to

clear

• Positive family history

• +/- Symptoms antedate drug or alcohol use

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• Most standard pharmacotherapies for depression are effective in patients with substance use disorders

• SSRI’s are the first line medications

Managing Co-Occurring Depressive Disorders

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PHARMACOTHERAPY OF DEPRESSIVE DISORDER & OPIOID USE DISORDERS

TRY ANOTHER SSRI

TCA VENLAFAXINE MIRTAZAPINE

TRY ANOTHER SSRI / NEFAZODONETHEN CONSIDER

TRY SSRIPLUS PSYCHOTHERAPY

DEPRESSIVE DISORDER

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Managing Co-Occurring Anxiety Disorders

First confirm the diagnosis: • Wait 4 to 6 weeks for withdrawal symptoms to clear

(or for the patient to stabilize on BUP/NX)

• Positive family history

• +/- Symptoms antedate alcohol/drug use

Begin treatment with behavioral therapies If no response after 2-3 weeks, add pharmacotherapy

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Managing Co-Occurring Anxiety Disorders

Pharmacotherapy recommendations: • Generalized anxiety disorder: BUSPIRONE

• Panic disorder: ANTIDEPRESSANTS

BEHAVIORAL THERAPY

• Agoraphobia: ANTIDEPRESSANTS BEHAVIORAL THERAPY

• Social phobia: PROPRANOLOL or CLONIDINE

Benzodiazepines are only recommended if the patient has failed to respond to less abuseable medications

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Anxiety Disorders in Patients with Addiction

The Role of Benzodiazepines: • Comprehensive literature review • Efficacy demonstrated for: GAD, panic disorder and agoraphobia • Probable efficacy for:

Social phobia, alcohol induced anxiety disorders • Little evidence of added risk for medication abuse or

increased relapse Posternak & Mueller. Am J Addict. 2001;10:48-68.

However, deaths have been reported with the combination of buprenorphine and benzodiazepines; caution should be used when prescribing

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References

• Ball JC, Ross A. The Effectiveness of Methadone Maintenance Treatment. New York, NY: Springer-Verlag Inc; 1991.

• Bentzley BS, Barth KS, Back SE, Book SW. Discontinuation of buprenorphine maintenance therapy: perspectives and outcomes. J Subst Abuse Treat. 2015;52:48-57. Epub 2015/01/21. doi: 10.1016/j.jsat.2014.12.011. PubMed PMID: 25601365; PubMed Central PMCID: PMCPmc4382404.

• Dunn KE, Sigmon SC, Strain EC, Heil SH, Higgins ST. The association between outpatient buprenorphine detoxification duration and clinical treatment outcomes: a review. Drug Alcohol Depend. 2011;119(1-2):1-9. Epub 2011/07/12. doi: 10.1016/j.drugalcdep.2011.05.033. PubMed PMID: 21741781; PubMed Central PMCID: PMCPmc3205338.

• 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 internal medicine. 2014;174(12):1947-54. Epub 2014/10/21. doi: 10.1001/jamainternmed.2014.5302. PubMed PMID: 25330017.

• Hser Y, Hoffman V, Grella C, Anglin M. A 33-year follow-up of narcotic addicts. Archives of General Psychiatry. 2001;58:503-8.

• Kakko J, Svanborg KD, Kreek MJ, Heilig M. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. The Lancet. 2003;361:662-8.

• Kosten TR, O'Connor PG. Current concepts - management of drug withdrawal. New England Journal of Medicine. 2003;348:1786-95.

• 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 randomised trial. Lancet. 2011;377(9776):1506-13. Epub 2011/05/03. doi: 10.1016/s0140-6736(11)60358-9. PubMed PMID: 21529928.

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References

• Lobmaier P, Kornor H, Kunoe N, Bjorndal A. Sustained-release naltrexone for opioid dependence. The Cochrane database of systematic reviews. 2008(2):Cd006140. Epub 2008/04/22. doi: 10.1002/14651858.CD006140.pub2. PubMed PMID: 18425938.

• Minozzi S, Amato L, Vecchi S, Davoli M, Kirchmayer U, Verster A. Oral naltrexone maintenance treatment for opioid dependence. The Cochrane database of systematic reviews. 2011(4):Cd001333. Epub 2011/04/15. doi: 10.1002/14651858.CD001333.pub4. PubMed PMID: 21491383.

• Nestler EJ, Aghajanian GK. Molecular and Cellular Basis of Addiction. Science. 1997;278(5335):58-63. • Sees KL, Delucchi KL, Masson C, Rosen A, Clark HW, Robillard H, Banys P, Hall SM. Methadone maintenance vs

180-day psychosocially enriched detoxification for treatment of opioid dependence. A randomized controlled trial. JAMA. 2000;283(10):1303-10.

• Sigmon SC, Dunn KE, Saulsgiver K, Patrick ME, Badger GJ, Heil SH, Brooklyn JR, Higgins ST. A randomized, double-blind evaluation of buprenorphine taper duration in primary prescription opioid abusers. JAMA psychiatry. 2013;70(12):1347-54. Epub 2013/10/25. doi: 10.1001/jamapsychiatry.2013.2216. PubMed PMID: 24153411.

• Weiss RD, Potter JS, Fiellin DA, Byrne M, Connery HS, Dickinson W, Gardin J, Griffin ML, Gourevitch MN, Haller DL, Hasson AL, Huang Z, Jacobs P, Kosinski AS, Lindblad R, McCance-Katz EF, Provost SE, Selzer J, Somoza EC, Sonne SC, Ling W. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Archives of General Psychiatry. 2011;68(12):1238-46. PubMed PMID: 22065255.

• Woody GE, Poole SA, Subramaniam G, Dugosh K, Bogenschutz M, Abbott P, Patkar A, Publicker M, McCain K, Potter JS, Forman R, Vetter V, McNicholas L, Blaine J, Lynch KG, Fudala P. Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth: a randomized trial.[Erratum appears in JAMA. 2009 Feb 25;301(8):830], [Erratum appears in JAMA. 2013 Apr 10;309(14):1461]. JAMA. 2009;300(17):2003-11. PubMed PMID: 18984887.

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PCSS-O Colleague Support Program and Listserv

• PCSS-O Colleague Support Program is designed to offer general information to health professionals seeking guidance in their clinical practice in prescribing opioid medications.

• PCSS-O Mentors comprise a national network of trained providers with expertise in addiction medicine/psychiatry and pain management.

• Our mentoring approach allows every mentor/mentee relationship to be unique and catered to the specific needs of both parties.

• The mentoring program is available at no cost to providers.

• Listserv: A resource that provides an “Expert of the Month” who will answer questions about educational content that has been presented through PCSS-O project. To join email: pcss-o@aaap.org.

For more information on requesting or becoming a mentor visit: www.pcss-o.org/colleague-support

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PCSS-O is a collaborative effort led by American Academy of Addiction Psychiatry (AAAP) in partnership with: Addiction Technology Transfer Center (ATTC), American Academy of Neurology (AAN), American

Academy of Pain Medicine (AAPM), American Academy of Pediatrics (AAP), American College of Physicians (ACP), American Dental Association (ADA), American Medical Association (AMA), American

Osteopathic Academy of Addiction Medicine (AOAAM), American Psychiatric Association (APA), American Society for Pain Management Nursing (ASPMN), International Nurses Society on Addictions (IntNSA), and

Southeast Consortium for Substance Abuse Training (SECSAT).

For more information visit: www.pcss-o.org For questions email: pcss-o@aaap.org

Twitter: @PCSSProjects

Funding for this initiative was made possible (in part) by Providers’ Clinical Support System for Opioid Therapies (grant no. 1H79TI025595) from SAMHSA. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department

of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government.