Medication-Assisted Treatment: What’s in the Cupboard and Why

1. Medication-Assisted Treatment: What’s in the Cupboard and Why Walter Ling, M.D Director Integrated Substance Abuse Programs UCLA LA County Drug Court Conference May 16, 2013 Los Angeles, California lwalter@ucla.edu www.uclaisap.org

2. Scope of the Talk • From methadone to naltrexone and buprenorphine • The role of medication in overcoming the brain disease addiction • So addiction is a brain disease: Now what?

3. Opioid Addiction Treatment • Reduced heroin use • Improved general health • Increased gainful employment • Reduced criminal activities • Dole VP & Nyswander ME (1965) A Medical Treatment for Diacetylmorphine(Heroin) Addiction JAMA 193: 646-650

4. Methadone: Clinical Properties Morphine-like synthetic analgesic and CNS depressant Orally active, quick absorption, slow elimination, long half-life up to 24 hours; once daily dosing Prevents withdrawal, reduces craving and use Long term use normalizes physiological functions Facilitates rehabilitation

5. Methadone Treatment vs Untreated Heroin Addicts: Mortality Rate After 8 years 85% of addicts in treatment are alive; more than half of those untreated are dead Untreated addicts mortality rate is 9 times that of methadone patients

6. Not in Tx 50% 47% 40% Currently in Tx 30% No needle use since admission to Tx In Tx 5 years 23% 20% 17% 12.5% 10% 6% 0% A B C D C&D Methadone Maintenance: HIV Rate and Costs HIV Rates

7. What Really Matters in Methadone Treatment

8. Detoxification: Opioids • The most common outcome of detoxification, by whatever means and for however long, is relapse. “Detoxification may be good for a lot of things; staying off drugs is not one of them”

9. Methadone: An Appraisal • Pioneering role as first effective medication • Most widely used—gold standard • Moderate clinical success • Significant draw backs • Marginal commercial enterprise • Public health failure

10. Opioid Pharmacotherapy Development • Preoccupation with detoxification • Societal-political ambivalence about methadone • Enthusiasm about non-dependence producing medications: antagonists (naltrexone) Addicts are sick, they need help; But they also sin, don’t help them too much

11. Opioid Antagonist: Background • Based on Extinction in animal behavioral studies. • By blocking the positive reinforcing effects of agonists, an antagonist leads to extinction of drug seeking behavior. • Prevents—re-addiction • Antagonists are not abused and may prevent overdose when agonist is used.

12. Naltrexone: The “Perfect” DrugTen Reasons to Take 1. Orally Effective 2. Rapid onset of action 3. Long duration of action 4. Safe 5. Few side effects 6. Completely blocks effects of heroin 7. Non-addicting 8. No tolerance 9. No dependence 10. No withdrawal EN 1639-A

13. Naltrexone Successes: Motivations • Prisoners on work release program • Physicians, pharmacists, nurses and other medical professionals with ready access to narcotics under threat of license loss • Other professionals under similar threats • People with no other, more palatable options: prison, exile, lions den • “Dollar a-day” contingency

14. FDA Approval • 1984: FDA approves Naltrexone as a treatment for heroin addiction  • DuPont brand-names the drug Trexan • Marketing issues become problematic • Difficult to convince patients to use medication • Resistance on part of methadone clinics - cost • Trexan fails to impact treatment community in a significant way

15. Only Reason Not to Take Naltrexone: Can’t get high! • A near “perfect medication” proved to be a “Victimless cure”. Why? • There were a few successes in people who actually took the medication. • We need a better naltrexone: one that once taken patients cannot get away from. • Answer: sustained-release naltrexone

16. d d d Drug Plasma Levels 6-beta naltrexol conc (Initial Release) (Sustained Release) 0 7 3 30 Days Following Injection Alkermes Medisorb®Microspheres Porous polymer matrix Naltrexone drug particles Initial Release (diffusion) Sustained Release (polymer erosion) Alkermes, Inc. Cambridge, Massachusetts

17. Vivitrol: The Russian study Key Efficacy Outcomes 3A. % Opioid-Free Urines by Week 3B. Mean Change From Baseline in Craving 3C. Time-to-Discontinuation (Kaplan-Meier)

18. Vivitrol for Opioid Addiction • Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomized trial • Evgeny Krupitsky, Edward V Nunes, Walter Ling, Ari Illeperuma, David R Gastfriend, Bernard L Silverman • Lancet 2011; 377: 1506-13

19. Vivitrol • October 13, 2010 Alkermes received FDA approval for Vivitrol as treatment for opioid addiction • Criticisms: directed at FDA • Single study in Russia • Not “made in USA” but “made AS in USA”? • Ethical considerations • No “ post treatment” safety data • Compared to other treatment—buprenorphine

20. Reflection: Will Power vs Wouldn’t Power • People don’t behave like animals • Not extinction but cognition • What drives the compulsive gambler to act? • “Coercive treatment” does work • Dr. Jaffe’s reflections • Who decides what’s good? Personal nature of addiction

21. No Crystal Ball But Time and Chance “I returned, and saw under the sun, that the race is not to the swift, nor the battle to the strong, neither yet bread to the wise, nor yet riches to men of understanding, nor yet favor to men of skill; but time and chance happeneth to them all”. Ecclesiastes 9: 11 Those who live by the crystal ball end up eating glass

22. Full agonist - Superagonist - fentanyl morphine/heroin hydromorphone Positive effect Potentiallylethal dose Agonist+partial agonist Partialagonist = - buprenorphine addictive potential Antagonist - naltrexone dose Negative Antagonist + agonist/partial agonist effect Buprenorphine and the Opioid Receptor Family

23. Buprenorphine: Pharmacological Characteristics Partial Agonist (ceiling effect) • high safety profile • low dependence Tight Receptor Binding • long duration of action • slow onset of mild abstinence on cessation

24. Drug Addiction Treatment Act of 2000(Enacted September 27, 2000signed into law by President Clinton October 17, 2000) Allows practitioner to prescribe narcotics in schedule III IV V approved for treatment of opioid dependence to treat opioid addicted patients. Practitioner must meet certain requirements • Provide or refer for counseling • Limit # of patients “The Great Social Experiment”

25. Will Buprenorphine Succeed? • As a medication? Yes. (Safety and efficacy) • As a treatment strategy? Yes. (Ease of delivery and high patient acceptance) • As a new treatment philosophy? It depends • “The great social experiment”: return of opioid addiction treatment to the physician • Change your chemistry, change your brain; change your brain, change your lives • The role of the clinicians; we must change before our patients’ lives can change.

26. Addiction: How The Brain Got its Disease • Drugs release dopamine which makes you feel good and want to repeat the experience and you remember. • Conditioned learning incorporates meaning and value to the drug memory giving it higher and higher power to drive to repeat the drug experience. • Repeated seeking of drug use experience becomes your way of life. “First the man takes a drink, then the drink takes a drink, then the drinks takes the man”. Japanese proverb

27. Becoming Addicted and Staying Addicted: Getting Off and Staying Off Drugs • Becoming addicted depends drug effects • Staying addicted depends on drug memory • The problem of addiction is not getting off drugs; it’s staying off. • Detoxification helps getting off drugs, not staying off . • Relapse is a matter of memory: no memory, no relapse • All Substitution pharmacotherapies are for relapse prevention; it is not substituting one drug for another, but one memory for another

28. Relapse: A Three Character Play • Drug memories: …everything, seems to bring memories of you…(Eubie Blake) • Cues and triggers: external and internal; craving and desire for love lost—regression & comfort • Emotional buildup: justification for use—the internal dialogue making use ok and natural • Relapse does not happen by accident.

29. Medications to Prevent Relapse • Medications to help staying off illicit opioids • Methadone • buprenorphine • Naltrexone • Depo-naltrexone • No approved medications to help staying off stimulants “Sorry, no water. We’re just a support group”

30. Creating Non-Drug Memories: The Old Fashion Way • Experience –activities—leads to protein synthesis • Protein synthesis activates new gene expressions • Gene expressions create new brain connections • New brain connections produce new memories • New non-drug memories create non-drug belief systems which determine behaviors that determine how life turns out. • The only way to change your life is to do things differently so they will turn out differently.

31. Eight Steps to Relapse Prevention and to a Drug Free Balanced Life • Sound physical health • Sound mental health • Stay off drugs and stay busy • Take care of business: out of jail and on the job • Taking personal responsibilities • Live in harmony with family and friends • Be a good member of the community • Search for a meaning in life.

32. Summing Up • Methadone introduced the modern era of addiction pharmacotherapy and we now have medications ranging from agonists to antagonists • Addiction medicine has unfortunately been largely outside main stream medical practices. • Socio-political forces influence our development and application of medications; they reflect our value and our view of addiction and addicts • Our understanding of addiction as a brain disease should change us, not just inform us.

33. Thank you, thank you, and thank you… “ Yes, you can change a person’s life by altering his genes, but you can also do that by paying off his credit card”. James Watson