Translation: From opioid receptors To a new treatment for Alcoholism

1. Translation: From opioid receptors To a new treatment for Alcoholism Charles P. O’Brien, MD, PhD University of Pennsylvania

2. Disclosure • Consultant to • Embera (Research) • Alkermes (Depot Naltrexone, • no patent, no stock) • Gilead (drug development)

3. Endogenous Opioid System Opiate Receptors Simon 1973 Pert & Snyder 1973 Terenius 1973 Enkephalin 1975 ∂ B-Endorphin µ Dynorphin k Nociceptin OFQ/NOC 1990s

4. Early studies of morphine-alcohol connection • Low dose morphine stimulates alcohol drinking in rats • Naloxone reduces alcohol drinking • Claims that alcohol produced a condensation product – Salsolonol/ tetraisoquinolones 1979 Altshuler monkey study

5. Series of Lucky Coincidences • 1. Altshuler poster at 1979 CPDD

6. Naltrexone decreases Alcohol preference* % Change from Saline Pretreatment Response Levels (10 day mean) Days Naltrexone * Altshuler 1980

11. Post-Shock Drinking 25 20 15 Placebo Change in % Ethanol Consumption 10 Naltrexone 5 0 -5 1-2 3-4 5-6 Days Post-Shock

12. Saline .25 mg/kg Naltrexone Ethanol Responses Time (min) Time (min)

13. IND 1983-Begin open studies (1983-85)-50 mg dose based on experience with heroin-VA Medical Research Center Grant (alcohol & other drugs)-Alcohol program: day hospital, 12 step, counselors in recovery Propose an RCT of Heroin med in human alcoholics because of animal data ??

14. Protocol 1986 70 male alcoholics, DSM III Day hospital 27 hours per week x 12 AA groups Self report + breathalyzer 5x per week Endpoint = Relapse to heavy drinking “Slips” recorded, not as endpoint Craving recorded RECRUITMET OBSTRUCTIONS

15. Series of Lucky Coincidences • 1. Altshuler poster at CPDD • 2. Joe Volpicelli decides on Fellowship

16. Any Alcohol Drinking Percent of Subjects Naltrexone Placebo

17. Days Drinking Average Drinking Days per week Naltrexone Placebo

18. Subjective “high” in Naltrexone and Placebo Subjects 0.1 0 - 0.1 - 0.2 - 0.3 - 0.4 - 0.5 mean “high” rating * Naltrexone Placebo * p<.05

19. Pharmacological Treatments for Alcoholism Craving Scores by Week Mean (SEM) Craving Score (0-9) 0 1 2 3 4 5 6 7 8 9 10 11 12 Weeks on Medication

20. Alcohol Relapse coming to treatment appointment with a blood alcohol concentration > 100 mg% or B. self report of drinking five or more days within one week or C. self report of five or more drinks during one drinking occasion

21. Non-relapse “Survival” 1.0 0.9 0.8 0.7 Cummulative Proportion with No Relapse 0.6 0.5 0.4 0.3 Naltrexone HCL (N=35) Placebo (N=35) 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 No. of Weeks Receiving Medication Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880

22. Series of Lucky Coincidences • 1. Altshuler poster at CPDD • 2. Joe Volpicelli decides on Fellowship • 3. Roger Meyer joins Penn Advisory Bd • 4. Lilly rescinds permission to study Prozac in alcoholics

23. Rates of Never Relapsing According to Treatment Group (n=97) Naltrexone/coping skills Naltrexone/supportive therapy Placebo/coping skills Placebo/supportive therapy 100 80 60 40 n=97 20 0 0 20 40 60 80 Days O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992

24. Series of Coincidences • 1. Altshuler poster at CPDD • 2. Joe Volpicelli decides on Fellowship • 3. Roger Meyer joins Penn Advisory Bd • 4. Lilly rescinds permission to study Prozac in alcoholics • 5. Len Cook, PhD retires from Dup-Merck • 6. President wants good publicity • 7. Curtis Wright at FDA • 8. Obesity studies with 350 mg

27. Results: Heavy Drinking Days Baseline Placebo Vivitrol190 mg Vivitrol380 mg 75th Percentile 30 25th Percentile 25 21.5 19.3 19.3 20 15 Median Heavy Drinking Days per Month 10 7.0 5.9 5.6 5.4 4.9 4.4 4.0 5 3.1 2.1 0 Overall Male Female

28. Assumption: alcohol causes the release of endogenous opioids which are “required” for DA release in response to alcohol?

29. – Alcohol – Opioid Antagonism Dopamine Dopamine Nucleus Accumbens GABA -EndorphinNeuron Ventral Tegmental Area Arcuate Nucleus Gianoulakis. Alcohol-Seeking Behavior: The Roles of the Hypothalamic-Pituitary-Adrenal Axis and the Endogenous Opioid System. Alcohol Health and Research World. 1998;22(3).

30. Naltrexone Concurrently Antagonizes EtOH-Induced Accumbal DA Release and EtOH Self-Administration Gonzales & Weiss (2002) J Neurosci 18:10663-10671

31. Variable response to alcohol Alcohol seeking 10 of 22 Rhesus (Altshuler) 15% Vervets 10-15% H. sapiens Less variable in rodents µ receptor knock outs will not self administer alcohol

32. Opiate Receptors Post-Synaptic Neuron N NOC Kappa Mu Delta .. .. .. .. NX MOR MOR NX MOR NX MOR Affinity for Opiate Receptor KappaMuDelta Naltrexone 406 108 54 Morphine 1 1 1

33. Which opioid receptors? Stromberg, M.F., Casale, M., Volpicelli, L, Volpicelli, J.R. and O’Brien, C.P.: A comparison of the effects of the opioid antagonists naltrexone, naltrindole, and b- funaltrexamineon ethanol consumption in the rat. Alcohol, 15(4):281-289, 1998.

34. Individual Variation: two patients who both meet DSM-IV criteria for “alcohol dependence” but by a totally different neurophysiological mechanism.

35. Nalmephene: probably equal to naltrexone, comparisons not done Intermittent nalmephene: to be approved in Europe Blocking opioid receptors is key, but not certain which one:m, k, d

36. Alcohol effects become conditioned to environmental cuesNaltrexone blocks cue induced relapse better than stress induced(F. Weiss et al)

37. Pre-Alcohol“Craving”

39. ** ** * Bmax/Kd Cocaine Craving 2.5 2.0 1.5 1.0 0.50 0.0 -0.50 2.5 2.0 1.5 1.0 0.50 0.0 -0.50 Change in Craving (Post-Pre) Change in Craving (Post-Pre) 30 20 10 0 -10 -20 -30 -40 30 20 10 0 -10 -20 -30 -40 % Change Bmax/kd % Change Bmax/kd Caudate Putamen

40. Satisfy craving - agonists methadone, bup - Heroin methylphenidate - Cocaine, Meth - Cognitive craving decision Naltrexone alcoholism Naltrex Heroin Naltrex Boetiger

41. Pharmacological Treatments for Alcoholism Craving Scores by Week Mean (SEM) Craving Score (0-9) 0 1 2 3 4 5 6 7 8 9 10 11 12 Weeks on Medication

42. Opioid craving VAS scores: Change from baseline OCS Mean Change from Baseline P=0.0002 BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Visit Week

43. Addiction Therapy may be related to activation of Frontal Cortex (Boettiger, et.al. 2009) (Crews and Boettiger et.al. 2009)

44. Why do many alcoholics respond to naltrexone, but others show no response?

45. (PACS < 5) (PACS 6-15) (PACS > 15) Baseline Craving Scores 16 n = 57 14 12 % Days Heavy Drinking 10 NTX n = 44 8 PLA n = 72 6 4 2 0 Low Crave Mod Crave High Crave PACS = Penn Alcohol Craving Scale

46. Family History and Naltrexone Efficacy 16 n = 29 14 12 NXT 10 % Days Heavy Drinking n = 73 n = 77 PLA 8 6 4 2 0 < 25% Alc Problem 25%-50% Alc Problem > 50% Alc Problem Density of Familial Alcohol Problems

47. Change in b- Endorphin Levels after Alcohol Consumption % change in plasma b-endorphin levels Minutes after alcohol consumption

48. BAES Stimulation Scores Among FH+ and FH Subjects Placebo Naltrexone Base 2 30 min 60 min 120 min Base 2 30 min 60 min 120 min

49. Key effect: Sensitivity of Endogenous Opioid system to alcoholOne source of individual variability in response to ethyl alcohol

50. Conclusion: Opioid system modulates alcohol reward.This can be useful in rehabilitation program, but blocking opioid receptors is not a “cure”A genetic variant shows greater endorphin response