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* Days Naltrexone Days Naltrexone * Altshuler 1980 % Change from Saline Pretreatment Response Levels (10 day mean)

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

12. Saline.25 mg/kg Naltrexone Ethanol Responses 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 Naltrexone Placebo Percent of Subjects

17. Days Drinking Naltrexone Placebo Average Drinking Days per week

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

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

20. A.coming to treatment appointment with a blood alcohol concentration > 100 mg% > 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 Alcohol Relapse

21. Non-relapse “Survival” Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880 No. of Weeks Receiving Medication 1023 4 56789101112 0.0 0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.3 Naltrexone HCL (N=35) Placebo (N=35) Cummulative Proportion with No Relapse

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) O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992 Naltrexone/coping skills Naltrexone/supportive therapy Placebo/coping skills Placebo/supportive therapy Days 0 20 40 60 80 100 n=97 020408060

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

25. Studies supporting efficacy Studies not supporting efficacy Study# SsNotes Study# SsNotes Volpicelli, et al 199270NoneKranzler, et al 1999 183 None O’Malley, et al 199297NoneKrystal, et al 2002627 None Mason, et al 1994 [Nalmefene] 21None Oslin, et al 199744Elderly Volpicelli, et al 199797None Mason, et al 1999 [Nalmefene] 105None Kranzler, et al 199820Depot Anton, et al 2000131None Chick, et al 2000 (UK)169Adherence Monterosso, et al 2001183None Morris, et al 2001 (Australia) 111None Heinala, et al 2001 (Finland) 121Nonabstine nt Lee, et al 2001 (Singapore) Kiefer et al 2003 (Germany) 53 160 None

26. Studies supporting efficacyStudies not supporting efficacy Study# SsNotesStudy# SsNotes Latt et al 2002107Family Prac Balldin et al 2003118None Feeney et al 200150Hist. cont Rubio et al 2001157v. Acamp. Rubio et al 200230Cont. Drink. Gastpar et al 2002105Neg. in self report Pos. GGT Gastpar et al 2002105Neg. in self report Pos. GGT Guardia et al 2002202Relapse Kranzler et al 2003153Heavy drinkers O’Malley et al 200218Human lab Anton et al 20061383RCT, depot

27. Results: Heavy Drinking Days Baseline Placebo Vivitrol 190 mg Vivitrol 380 mg 75 th Percentile 25 th Percentile Median Heavy Drinking Days per Month 0 5 10 15 20 25 30 OverallMaleFemale 19.3 7.0 5.6 4.9 4.0 2.1 5.4 19.3 3.1 5.9 4.4 21.5

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

29. Dopamine Opioid Antagonism – GABA Ventral Tegmental Area Arcuate Nucleus  -Endorphin Neuron Nucleus Accumbens – Alcohol Dopamine 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. Post-Synaptic Neuron Kappa Mu Delta Affinity for Opiate Receptor NX NX NX NX Opiate Receptors Kappa Mu Delta Naltrexone 406 108 54 Naltrexone 406 108 54 Morphine 1 1 1 Morphine 1 1 1 MOR MOR MOR MOR.. NOC N

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- funaltrexamine on 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:  

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

37. Pre-Alcohol “Craving”

39. Bmax/Kd Cocaine Craving 30 20 10 0 -10 -20 -30 -40 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 Bmax/kd Caudate % Change Bmax/kd 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 Mean (SEM) Craving Score (0-9) 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 Weeks on Medication Craving Scores by Week

42. 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 P=0.0002 OCS Mean Change from Baseline Opioid craving VAS scores: Change from baseline

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. % Days Heavy Drinking (PACS 15) 0 2 4 6 8 10 12 14 16 Low CraveMod CraveHigh Crave NTX PLA n = 44 n = 72 n = 57 PACS = Penn Alcohol Craving Scale Baseline Craving Scores

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

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

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

49. Key effect: Sensitivity of Endogenous Opioid system to alcohol One 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

51. A Double-Blind, Placebo-Controlled Trial Combining Sertraline and Naltrexone for Treating Co-Occurring Depression and Alcohol Dependence Helen M. Pettinati, Ph.D. David W. Oslin, M.D. Kyle M. Kampman, M.D. William D. Dundon, Ph.D. Hu Xie, M.S. Thea L. Gallis, B.A. Charles A. Dackis, M.D. Charles P. O’Brien, M.D., Ph.D.

52. How Prevalent are Co-Occurring Depression and Alcohol Dependence, and What is the Prognosis? Prevalence of major depression in alcoholism –10 - 20% of clinical patients with an alcohol disorder have a current depressive disorder dx; 50% have a lifetime depressive disorder dx. Prognosis of alcohol dependent patients with co-occurring psychiatric dxs –Psychiatric diagnosis (e.g. major depression) by history or structured interview is usually associated with poor drinking outcomes.

53. Status over the Last Decade of Using Antidepressants to Treat Comorbid Depression and Alcohol Dependence (1993-2006) DOUBLE-BLIND STUDIES MEDICATIONSRESULTS DEPRESS SXS DRINKING (med v plac) (med v plac) (med v plac) (med v plac) Mason et al, 1996 Desipramine M<P M<P M<P M<P McGrath et al, 1996 Imipramine M<P M=P M<P M=P Cornelius et al, 1997 Fluoxetine M<P M<P M<P M<P Roy-Byrne et al, 2000 Pettinati et al, 2001 Moak et al, 2003 Hernandez-Avila, 2004 Pfizer multi-site, 2006 NefazodoneSertralineSertralineNefazodoneSertraline M<P M=P M<P M=P M=P M=P M=P M=P M<P + M=P M<P + M=P M=P M<P M=P M=P + True only under certain circumstances

54. Time to First Heavy Drinking Day and Time to First Drinking Day in Depressed Alcohol-Dependent Patients Randomly Assigned to Medication Treatment or Placebo

55. Hamilton Score Change From Baseline

56. CNN Special Addiction: Life on the edge 5 patients followed for one year Different parts of country Admissions Admissions Graduations Graduations Relapses Relapses Interviews with counselors at famous programs Interviews with counselors at famous programs

57. Sanjay Gupta, MD Interviews, patients, families, reasons for relapses Last show: Tall patient from Brown University Tall patient from Brown University Not one of the 5 index patients Not one of the 5 index patients Interviewed near end of series Interviewed near end of series Apparently only patient treated with medication Apparently only patient treated with medication

58. This time he got counseling once a week and a daily pill, a medicine called naltrexone. About two months into it, Walter Kent suddenly noticed the world around him looked and felt different. GUPTA: And so he tried again. He checked himself into an experimental program run by Brown University. This time he got counseling once a week and a daily pill, a medicine called naltrexone. About two months into it, Walter Kent suddenly noticed the world around him looked and felt different. for the first time in my life that I never had this sensation where I didn’t want a drink KENT: And I had just turned around and I said, this is really something for the first time in my life that I never had this sensation where I didn’t want a drink. And this, to me, was like a godsend because of the fact that for someone who had to have a drink, now all of a sudden I don't need that -- I don't have that feeling anymore. He hasn’t had a drink in more than eight years. He’s healthy, back at work, fixing up carburetors. GUPTA: He hasn’t had a drink in more than eight years. Even after his doctor stopped the medication. He’s healthy, back at work, fixing up carburetors.. And now he's part of a running debate. Is addiction an illness you can treat with a pill or a character flaw to be tackled with therapy and self-help? Addiction: Life on the Edge – CNN Correspondent Dr. Sanjay Gupta aired April 19, 2009

59. Despite the evidence, most fancy rehab centers use medication only rarely, if at all. The focus is much more on therapy. GUPTA: Despite the evidence, most fancy rehab centers use medication only rarely, if at all. The focus is much more on therapy. With the health care professional staff here at Hazelden, our experience tells us having that network of support in recovery is what really makes the difference. Head Counselor Minnesota: With the health care professional staff here at Hazelden, our experience tells us having that network of support in recovery is what really makes the difference. GUPTA: More so than medication? CLARK: More so than just medication, exactly. GUPTA: And that's the conventional wisdom. Addiction: Life on the Edge – CNN Correspondent Dr. Sanjay Gupta aired April 19, 2009

60. California Program What about medications? GUPTA: What about medications? We do not use them at the Betty Ford Center. Head Counselor California Program: We do not use them at the Betty Ford Center. No comment from the interviewer, no follow up questions. Addiction: Life on the Edge – CNN Correspondent Dr. Sanjay Gupta aired April 19, 2009

61. FOR MORE INFORMATION http://www.med.upenn.edu/csa/o r obrien@mail.trc.upenn.edu

62. Psychopharmacology: the Fourth Generation of Progress, edited by Floyd E. Bloom and David J. Kupfer. Raven Press, Ltd., New York 1995. Chapter 149 Pharmacotherapy of Alcoholism Charles P. O’Brien, Michael J. Eckardt, and V. Markku I. Linnoila