Medication Assisted Treatment for Polysubstance Users who have Opioid Use Disorder

1. Medication Assisted Treatment for Polysubstance Users who have Opioid Use Disorder University of Louisville CAPTASA 2019 Embassy Suites, Lexington, Kentucky January 25, 2019 Quintin T. Chipley, M.A., M.D., Ph.D.

2. DISCLOSURES Quinn T. Chipley, M.A., M.D., Ph.D. has disclosed no relevant, real or apparent personal or professional financial relationships with proprietary entities that produce health care goods and services.

3. Limitations of Use This presentation is intended for the use of the 2019 annual conference of the Clinical Application of the Principles of Treatment for Substance Abuse and Addiction. All other uses are restricted unless the presenter’s permission is given first in writing.

4. Learning Objectives • Participants will be able to distinguish among the three FDA approved MATs for patients with opioid use disorder. • Participants will be able to rank-order the diversion and abuse potential for each of the three MAT treatments. • Participants will be able to distinguish between 1) time-limited use of MAT with the goal of abstinence from all drugs of reward, 2) lifetime maintenance on MAT and 3) use of the MAT substances for harms reduction.

5. Sources The material for the history of buprenorphine is taken from an excellent, well-balanced, and carefully researched article: Nancy D. Campbell and Anne M. Lovell. 2012. “The History of the Development of Buprenorphine As an Addiction Therapeutic.” Annals of the New York Academy of Sciences. Issue: Addiction Reviews. 1248. It will be cited in the following slides as Campbell and Lovell, 2012. It is a crucial supplement to: Nancy D. Campbell. 2007. Discovering Addiction: The Science and Politics of Substance Abuse Research. Ann Arbor: University of Michigan Press. Common knowledge easily obtained by digital searches relates chemical compounds and pharmacology are not specifically cited. Other special references are given clearly and fully in slides.

6. A Brief Overview of the Relevant Pharmaceuticals Methadone: agonist – turns on the receptor Buprenorphine: agonist (some call it “partial” but this adjective lends confusion)- turns on the receptor Naltrexone: Antagonist – keeps the receptor from turning on

7. METHADONE METHADONE  EDDP  EMDP (ACTIVE AGONIST) (INACTIVE) (INACTIVE)

8. METHADONE – Cont. Trade Names are varied, but common are Dolophine and Methadose Taken Orally Only distributed through specified, licensed clinics. Some patients can qualify for take-home doses after well-established and determined to be a reasonable risk Metabolism varies extremely.

9. Methadone in-clinic dose Methadone take-home dosing

10. Buprenorphine Buprenorphine, a semisynthetic opioid derived from thebaine (a molecule in the poppy), is isolated in 1966 by the British company Reckitt and Coleman, now named Reckitt Benckiser. They had hoped to find an analgesic for acute pain that would be as effective as morphine, but non-addictive and eligible for over-the-counter sales. Since 2002, it is an Office- Based Treatment (OBOT) prescription MAT.

11. Metabolism of Buprenorphine   Liver metabolism of buprenorphine creates the active agonist metabolite, norbuprenorphine. This metabolite is also the precursor of buprenorphine in the manufacturing process.

12. Versions of sublingual buprenorphine/ naloxone tablets Orexo U.S., Inc. This product was allowed to compete with R-B around 2013-2014. The president of ASAM was Orexo’s medical director at the time. Reckitt-Benckiser, which spun off Indivior in 2014 to manage bupe products Buprenorphine has poor absorption when swallowed. Hence it is taken sublingually or trans-mucosal at the buccal surface. Naloxone is not absorbed s.l. or p.o.Nx is added to discourage parenteral, diverted use.

13. Sublingual tablet versions of buprenorphine monotherapy Generic version. Indicated in case of 1) naloxone allergy or 2) pregnancy. Reckitt-Benckiser voluntarily took this off the market Temgesic 0.2 mg, European market, and originally only indicated for pain (note the small dose).

14. Sublingual film version of Indivior’sSuboxone A quagmire of FDA approval of generic competitors in June, 2018, followed by court ordered blocks, then followed by a court decision that undercut Indvior’s patent claim on the delivery method is all in the works. Expect to see competition for the s.l. film market in the pharmacies and on the streets. Film versions have been prolific in the diversion market; especially for diversion into controlled facilities (locked wards, jails, prisons). The film is hidden in he adhesive band of envelopes, under postage stamps, and melted-then-smeared on letters or book pages.

15. Buccal film version of Bupe/Nx Biodelivery Sciences International (BDSI) , Inc. The transmuscosal absorption at the buccal surfaces is not as good as sublingual absorption, but better than p.o. This option was forced by the patent claim to the sublingual film. It will be threatened strongly in the market when sublingual generics of Bupe/NX arrive in force.

16. Implant buprenorhoone (Indivior) Probuphine Implant Illustrations

17. Sublocade: Buprenorphone extended release injection (Indivior)

18. Sublocade- Cont. INDICATIONS SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosalbuprenorphine–containing product, followed by dose adjustment for a minimum of 7 days. SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support. Sublocade requires periumbilcal, subcutaneous injection. The formulation is viscous in vial, syringe and needle, requiring a fairly large gauge. It requires refrigeration.

19. Brixadi by Braeburn (Trial name CAM2038) “Braeburn Announces Tentative FDA Approval of Brixadi (buprenorphine) Extended-Release Injection for the Treatment of Moderate to Severe Opioid Use Disorder.” https://www.drugs.com/nda/brixadi_181226.html Brixadi is administered subcutaneously. It is not viscous in vial, syringe and needle, and develops its gel consistency only after injection. This fact allows for he use of 23 gauge needle and multiple placemen options. It does not require refrigeration.

20. Naltrexone: metabolism Nalrexone 6-beta-nalrexol (Active antagonist) (Active antagonist)

21. Naltrexone versions Teva Pharmaceuticals (Wales, U.K. with a U.S. presence) Alkermes, Inc. Irish headquarters; global market, has U.S. presence. Administered gluteal I.M.

22. Relevant Research on Buprenorphine Robert Walker , MSW, LCSW, TK Logan , PhD, Quintin T. Chipley , MA, MD, PhD & Jaime Miller , BA. “Characteristics and experiences of buprenorphine-naloxone use among polysubstance users.” The American Journal of Drug and Alcohol Abuse. Received 08 May 2017, Accepted 03 Apr 2018, Published online: 25 Apr 2018 Download citation https://doi.org/10.1080/00952990.2018.1461876 Free access for two years from publication. Cited in: Edward V. Nunes (2018) “Buprenorphine in the real world: coming to terms with misuse and diversion.” The American Journal of Drug and Alcohol Abuse. DOI: 10.1080/00952990.2018.1504952 Download citation https://doi.org/10.1080/00952990.2018.1504952

23. Special study of buprenorphine-naloxone use • 1,674 Recovery Center clients responded to the bup-nx special study questions. • 896 (60.7%) reported opiate/opioid use. • The 896 opiate/opioid users were partitioned into 3 groups: • No Bup-nx Use (n=223) • Lifetime Bup-nx Use (n=241) • Recent Bup Use (n=432 • The data for this study were collected between September 1, 2015 and October 13, 2016 as part of an ongoing study of recovery center client outcomes in one state.

24. Substance use by Bup-nx groups *p<.05; **p<.01; ***p<.001 Subscripts that differ indicate significant differences at p<.05.

25. Bup-nx Among bup-nx users *p<.05; **p<.01

26. Among users withbup-nxprescriptions Lifetime Use Recent Use Tool other drugs/ alcohol with it To get high 70.1% 83.8% Sold, traded, or gave away the Prescribed Bupe-Nx 84.4% 80.3%

27. Conclusions from this population • Only about 25% of users (both lifetime and recent) said bup-nx helped them with their substance use. • 75% of bup-nx users reported that bup-nx either had no effect (average of about 37.5% of lifetime versus recent) or a negative effect (average of about 37.5% of lifetime and recent) on their drug problems. • Of the very few (4%-7%) obtaining bup-nxsolely through a prescription, over 90% reported relief from withdrawal. • However, over 80% of those who obtained bup-nx, whether only through illicit means or by both licit and illicit means, reported using bup-nxuntil their preferred drug could be obtained and also used it for its euphoriant effect. • Diversion of this scheduled opioid agonist medication was rampant

28. Diversion Continues to Increase

29. Different Warnings about Buprenorphine Products X = Black box warning in the prescribing information - = No boxed warning in the prescribing information

30. Lee et al. 2018 . “Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomized controlled trial. Lancet. 391: 10118. J309-318.. First published online November 14, 2017 http://dx.doi.org/10.1016/S0140-6736(17)32812-X . “Clinically, ease of induction is a well known limitation of naltrexone and an advantage of buprenorphine. Study sites varied in detoxification approaches and lengths of stay, but all had to wait, per protocol, for a negative-opioid urine sample before XR-NTX induction, which favoured both longer lengths of stay and non-agonist detoxification. Published strategiesto increase successful XR-NTX induction with single or minimal dosing of buprenorphine and oral naltrexone, and not dependent on a negative urine sample, might be more effective than some of the induction protocols used by our sites.” p. 316

31. Lee et al. 2018 . “Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomized controlled trial. Lancet. 391: 10118. J309-318.. First published online November 14, 2017 http://dx.doi.org/10.1016/S0140-6736(17)32812-X . “Once participants were successfully inducted to either XR-NTX or BUP-NX, they achieved similarly favourable and important clinical outcomes: relapse-free survival, overall relapse, retention in treatment, negative urine samples, days of opioid abstinence, and self-reported cravings. These findings align with results of noninferiority from the concurrent Norwegian study, which was also a randomised comparison of XR-NTX to BUP-NX treatment after a longer detoxification run-in,whichminimised induction failure. Few participants in the Norwegian trial were not able to induct onto either XR-NTX or BUP-NX treatment, and retention, opioid use, or adverse event outcomes did not differ between treatment groups, similar to what was observed in our per-protocol population.” p. 316

32. https://30qkon2g8eif8wrj03zeh041-wpengine.netdna-ssl.com/wp-content/uploads/2018/07/XBOT-Main-Results-7.31.18-1.pdfhttps://30qkon2g8eif8wrj03zeh041-wpengine.netdna-ssl.com/wp-content/uploads/2018/07/XBOT-Main-Results-7.31.18-1.pdf

33. “A Naturalistic Evaluation of Extended-Release Naltrexone in Clinical Practice in Missouri.” Crits-Christoph, Paul et al. Journal of Substance Abuse Treatment , Volume 70 , 50 – 57.ttps://www.journalofsubstanceabusetreatment.com/article/S0740-5472(16)30017-4/fulltext

34. http://www.mc.uky.edu/kiprc/reports/2016_DOFSS_Annual_Report.pdfhttp://www.mc.uky.edu/kiprc/reports/2016_DOFSS_Annual_Report.pdf

35. What Protection Against Overdose Do These Medications provide? The short answer: do not depend on any one of these medications to prevent a mortal overdose from use of opioid products purchased on he street. Even if the product is marketed as “heroin” there is no quality control. The fentanyl-family of drugs are proliferating. • Methadone activity will be increased by street opioids of all types. • Buprenorphine, naltrexone (and even the rescue Narcan (naloxone) will be in a “fist-fight” with plain fentanyl. • Buprenorphine, naltrexone and naloxone will usually take a beating from sufentanyl. Game is over if carfentanyl is in the mix.

36. Donna A. Volpe , Grainne A. McMahon Tobin , R. Daniel Mellon , Aspandiar G. Katki , Robert J. Parker , Thomas Colatsky, Timothy J. Kropp , S. Leigh Verbois . “Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs.” Regulatory Toxicology and Pharmacology . 59 (2011) 385–390.

37. Donna A. Volpe , Grainne A. McMahon Tobin , R. Daniel Mellon , Aspandiar G. Katki , Robert J. Parker , Thomas Colatsky, Timothy J. Kropp , S. Leigh Verbois . “Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs.” Regulatory Toxicology and Pharmacology . 59 (2011) 385–390.

38. Donna A. Volpe , Grainne A. McMahon Tobin , R. Daniel Mellon , Aspandiar G. Katki , Robert J. Parker , Thomas Colatsky, Timothy J. Kropp , S. Leigh Verbois . “Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs.” Regulatory Toxicology and Pharmacology . 59 (2011) 385–390.

39. http://thefederalist.com/2018/01/29/big-pharma-fox-anti-addiction-hen-house/http://thefederalist.com/2018/01/29/big-pharma-fox-anti-addiction-hen-house/

40. Conclusions • Buprenorphine products are now more frequently diverted to street markets, and more often show up in Kentucky overdose decedents’ toxicology analyses, than methadone. • When compared to buprenorphine, and when use is not confounded by other substances such as alcohol and benzodiazepines, methadone is more likely to cause respiratory depression. • Neither oral naltrexone nor extended release injectable naltrexone are found to be abused or diverted. • Only a small percentage of the population with opioid use disorder maintain long-term adherence to MAT with any of the three FDA approved molecules when tested for strict adherence to protocols (i.e. – no use of other substances). • Efficacy as prophylaxis against mortality in exposures to fentanyl-class molecules is not established by any studies. • Claims that it is intrinsically easier to induct patients onto bupe-nx than to extended release injectable naltrexone are suspect because the X:BOT study did no uniformly implement best-practices for naltrexone induction.

41. CONTACT INFORMATION Quintin Chipley can be contacted by email at q0chip01@louisville.edu