1. Evidence-Based Guidelines for Pharmacotherapy in Alcohol Dependence Chandan Nayak, MD Addiction Fellow University of Michigan Department of Psychiatry

2. Topics l Alcohol & Society l Neurobiology of Addiction l Pharmacotherapy for Alcohol Dependence –Disulfiram (DSF) –Naltrexone (NTX) –Acamprosate (ACP) l Summary

3. Alcohol & Society l Americans love Alcohol l Legal, yet is the #1 Drug of Abuse, #2 Drug of Dependence l Yet, economic damage estimated at $184 billion annually (more so than Heart Disease) l Prevalent Treatments… –12-step philosophy(Alcoholics Anonymous, Women for sobriety, Smart Recovery) –Psychosocial treatments(CBT + MET) …are often Ineffective. Relapse rates are HIGH

4. Neurobiology of Addiction l “A Disease of the Will” – Benjamin Rush, MD l Our knowledge of the Neurobiology of Addiction is developing. Yes, there are structural changes, and yes, they are potentially reversible l Anatomy Involved in the “Brain Reward Center” –Prefrontal Cortex (PFC) –Nucleus Accumbens NA) –Ventral Tegmental Area (VTA) l Neural substrates implicated –Dopamine –Glutamate –GABA –Opioids –Serotonin –Etc ( the unknown)

5. Neurobiology of Addiction Kalivas, Volkow. Am J Psychiatry 2005

6. Neurobiology of Addiction

8. Pharmacotherapy for Alcohol Dependence FDA-approved Medications l Disulfiram (DSF) –PO Antabuse (Odyssey) l Naltrexone (NTX) –PO ReVia (Barr) –IM Vivitrol (Alkermes) l Acamprosate (ACP) –PO Campral (Forest)

9. Pharmacotherapy for Alcohol Dependence DSFNTXACP Chemical Mechanism Enzyme inhibitor Opioid antagonist Glutamate modulator Behavioral Mechanism Negative Re- Inforcement Blocks high & craving ↓ protracted withdrawal Sx Abstinence required? YesNoYes MetabolismLiverLiverKidney Dosing Once daily TID

10. Disulfiram l PO, FDA approval 1951 l Mechanism –Blocks Acetylaldehyde Dehydrogenase, leading to increased levels of toxic acetaldehyde –Negative reinforcement (N&V, HA, flushing,  BP,  HR and other autonomic changes, etc)

11. Disulfiram l Evidence –Mostly 250 mg (range 125-500 mg/d) –Works best with supervision* l Practical Problems –Up to 80% noncompliance –Not widely respected by medical community. 17M alcoholics, yet only 250K scripts/yr

12. Disulfiram Fuller et al: JAMA 1986 RCT 605 alcoholic veterans * * p<.05

13. Naltrexone l PO, FDA approval 1994 l Mechanism –Opioid Antagonist (high affinity for  ) –Blocks ability of EtOH to increase Dopamine release in the Dopamine reward pathways leading from VTA to NA –Thus theorized to blocks the “high” associated with alcoholics’ alcohol intake l Practical Problems –Noncompliance, lack of prescribing

14. Naltrexone Review: Pettinati et al: JAMA 2006 l Cochrane search for NTX & nalmefene –NTX, Mostly 50mg/d –29 RCTs, double-blind. N>=20 –5997 pts with EtOH Dependence –Treatment Length 8-60 wks, median 12 wks –4(2) drinking outcomes (“relapses”) l 23 RCTs (79%) defined relapse as “heavy” drinking (>5 for M, >4 for F) l 16 RCTs (55%) defined it as “any” drinking

15. Naltrexone Review: Pettinati et al: JAMA 2006 l Conclusions –19 RCTs (70%), 3950 pts, showed dec “heavy” drinking. NTX > placebo –9 RCTs (36%), 2517 pts, showed dec “any” drinking. NTX > placebo –0 studies showed placebo > NTX

16. Naltrexone l NNT = Number Needed to Treat –How many patients must be treated with naltrexone to get one more good outcome (than if treated with placebo)? –NNT = 1 / (.425 -.277) = 6.8  7 –Need to treat 7 patients with naltrexone to get one less relapse

17. Naltrexone l IM, FDA approval 2006 l Mechanism –Maintains therapeutic [plasma NTX] for c. 1 month –addresses noncompliance concerns with PO NTX l Evidence –Large, 24-site study, 627 pts l Divided into 3 groups (380mg, 190mg, placebo) over 6mos. All received counseling l 380mg dose demonstrated greater reduction in heavy drinking than placebo

18. Naltrexone l Predictors of Good Response with NTX –“Intense” cravings (Jaffe et al, 1996; Monterosso et al, 2001) –FH of Alcoholism (Monterosso et al, 2001; Rubio et al., 2005) –specific genetic polymorphism in the  -opioid receptor gene –enhanced opioid activity in response to EtOH ingestion (HPA axis-mediated)

19. Acamprosate l PO, FDA approval 2004 l Mechanism –N-methyl-D-aspartate agonist (putative glutamate modulator) –Alleviates acute and subacute alcohol withdrawal –Affects neural pathways involved in brain reward system l Evidence –666mg TID –Several European RCTs show ACP> placebo, but only 2 recent American ones do

20. Acamprosate l Evidence (cont) –NIAAA COMBINE study, prelim reports 05/2006 l 11-site, 16 wk, RCT l 1383 alcohol-dependent pts, randomized into 9 groups –(4 med groups X 2 psychotherapy groups) + psychotherapy alone l all pts had reduction in drinking(same outcome measures) l However, ACP (-CBI, +CBI, +NTX), did not show clear benefit –Initial results: % abstinent days did not differ significantly b/w ACP & placebo –Posthoc analysis: significantly higher % abstinent days for ACP vs placebo. Effect more robust in those pts who has baseline goal of abstinence(vs moderation)???

21. Summary l Alcoholism is an economically devastating disease. Much is unknown about its pathophysiology. Nevertheless, there is an urgency to treat it aggressively l In addition to specialized psychotherapies, there are 3 FDA- approved meds for alcoholism. Each with a different mechanism of action. The latest meds are targeting the brain’s reward pathway l Pharmacotherapy for alcoholism has strong evidence for use, but is highly underutilized by the medical community l Naltrexone, PO or IM, is “Recommended for all alcohol dependent patients who do not have a medical contraindication.” l The latest research, especially combinations of treatment (both psychotherapy and pharmacotherapy) are ever-evolving (e.g. Project COMBINE)

22. Acknowledgements l Kirk Brower MD l Pettinati HM, Rabinowitz AR (2006) Choosing the Right Medication for the Treatment of Alcoholism. Current Psychiatry Reports 8: 383-388. l Pettinati HM et al (2006) The Status of Naltrexone in the Treatment of Alcohol Dependence. J Clin Psychopharmacol 26: 610-625. l Anton R et al (2006) Combined Pharmacotherapies and Behavioral Interentions for Alcohol Dependence. JAMA 295: 2003-2017. l Anton R (2001) Pharmacological Approaches to the Management of Alcoholism. J Clin Psychiatry 62: 11-17. l Kalivas PW, Volkow ND (2005) The Neural Basis of Addiction: A Pathology of Motivation and Choice. Am J Psychiatry 162, 1403-13. l Fuller RK et al (1986) Disulfiram treatment of alcoholism - A Veterans Administration cooperative study. JAMA 256: 1449-1455.