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Follow-up Q and A Webinar: 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 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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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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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

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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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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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Clonidine for Opioid Withdrawal

Principle: Alpha-2 adrenergic agonist, suppresses activity in locus coeruleus, 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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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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Managing Co-Occurring Psychiatric Disorders

• 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.

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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• Begin with the combination of pharmacotherapy and behavioral psychotherapy

• 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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Managing Co-Occurring Anxiety Disorders

Begin treatment with behavioral therapies If no response after 2-3 weeks, add pharmacotherapy 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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Question 1

• What evidence exists that opioid antagonists reverse some of the neuroadaptations brought on by chronic agonist misuse? For example, the upregulation of receptors that had been downregulated by agonists.

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Question 2

• Can you discuss tapering patients in an inpatient detox center regarding type of opiate? Example: Heroin vs buprenorphine/naloxone tapering, length of time and amount of use.

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Question 3

• How often are you tapering patients from buprenorphine? Most patients do not want to do that.

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Question 4

• Isn't the average duration on buprenorphine, according to the largest studies (from insurers and the City of Baltimore), 3-4 months?

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Question 5

• If the length of taper duration supports improved abstinence, then over time fewer NEW patients can be treated with the current limit of 100 patients. Maybe there could be another tier of treatment that would allow 100 patients to be kept on stabilization/maintenance and another 100 to be on taper.

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Question 6

• The data you present seems to suggest that one could urge a general stance of supporting chronic buprenorphine therapy with limited support for some patients to end therapy if they are doing extremely well with buprenorphine. I encounter more than a few providers who either personally believe that buprenorphine should always be time-limited or who believe they are required to time-limit by local institutional rules. Is that common?

• Dr. Renner to discuss

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Question 7

• What is the optimum length of time to be on buprenorphine?

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Question 8

• I have had the most difficulty getting people to taper off the last 1/4 of a 2mg buprenorphine. Any suggestions?

• Do you have any suggestions for dealing with the frequently very difficult terminal withdrawal symptoms encountered with removing the last couple of mgs of buprenorphine?

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Question 9

• How do you approach a patient who is coming with opiate and benzo dependence and wants to stop both? Do you medically treat both at the same time or in a particular order?

• Dr. Renner to discuss

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Question 10

• How would you tease out the reemergence of psych disorders (e.g. anxiety, depression) from opioid withdrawal sxs during an opioid taper?

• Dr. Renner to discuss

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Question 11

• What about the stories we hear from patients reporting that buprenorphine taper is way worse than methadone and heroin withdrawal?

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Question 12

• Everyone says monitor closely--What is monitor closely when the patient is not in the office?

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Question 13

• Did anyone think about making a combination medication taper for discontinuation from buprenorphine to naltrexone? It might consist of decreasing levels of buprenorphine from 1 mg - 0 mg with increasing levels of naltrexone from 0 - 50mg.

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Question 14

• What would you suggest if patient complains of intolerable anxiety during taper? Would you hold the taper? It's hard to taper a patient completely off opioids (to the point of 4-6 weeks after cessation to diagnosis a mental health disorder) if they're complaining of intolerable MH sxs that they presume is due to withdrawal.

• Dr. Renner to discuss

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Question 15

• Have you had success initiating the injectable extended-release naltrexone following taper off of buprenorphine?

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Question 16

• Please discuss different medication and doses to help patients with withdrawal symptoms associated with tapering.

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Question 17

• How many weeks/months should a patient be tapered off buprenorphine/naloxone?

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Question 18

• Is there any data on abstinence rates past 6 months following a detox?

• What are the rates of sustained remission (i.e. at least 12 months after discontinuation) after 12 or more months of MAT?

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Question 19

• Is there any role for psychostimulants to manage lethargy experienced amidst taper?

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Question 20

• Please discuss taper for patients who have been on buprenorphine for a long time, are doing very well in recovery, how to minimize SE of taper.

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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. 5H79TI025595) 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.