Evidence-Based Guidelines for Pharmacotherapy in Alcohol Dependence

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

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

3. Alcohol & Society • Americans love Alcohol • Legal, yet is the #1 Drug of Abuse, #2 Drug of Dependence • Yet, economic damage estimated at $184 billion annually (more so than Heart Disease) • 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 • “A Disease of the Will” – Benjamin Rush, MD • Our knowledge of the Neurobiology of Addiction is developing. Yes, there are structural changes, and yes, they are potentially reversible • Anatomy Involved in the “Brain Reward Center” • Prefrontal Cortex (PFC) • Nucleus Accumbens NA) • Ventral Tegmental Area (VTA) • Neural substrates implicated • Dopamine • Glutamate • GABA • Opioids • Serotonin • Etc ( the unknown)

5. Neurobiology of AddictionKalivas, Volkow. Am J Psychiatry 2005

6. Neurobiology of Addiction

7. Neurobiology of Addiction

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

9. Pharmacotherapy for Alcohol Dependence

10. Disulfiram • PO, FDA approval 1951 • 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 • Evidence • Mostly 250 mg (range 125-500 mg/d) • Works best with supervision* • Practical Problems • Up to 80% noncompliance • Not widely respected by medical community. 17M alcoholics, yet only 250K scripts/yr

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

13. Naltrexone • PO, FDA approval 1994 • Mechanism • Opioid Antagonist (high affinity for m) • 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 • Practical Problems • Noncompliance, lack of prescribing

14. NaltrexoneReview: Pettinati et al: JAMA 2006 • 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”) • 23 RCTs (79%) defined relapse as “heavy” drinking (>5 for M, >4 for F) • 16 RCTs (55%) defined it as “any” drinking

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

18. Naltrexone • 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 m-opioid receptor gene • enhanced opioid activity in response to EtOH ingestion (HPA axis-mediated)

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

20. Acamprosate • Evidence (cont) • NIAAA COMBINE study, prelim reports 05/2006 • 11-site, 16 wk, RCT • 1383 alcohol-dependent pts, randomized into 9 groups • (4 med groups X 2 psychotherapy groups) + psychotherapy alone • all pts had reduction in drinking(same outcome measures) • 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 • Alcoholism is an economically devastating disease. Much is unknown about its pathophysiology. Nevertheless, there is an urgency to treat it aggressively • 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 • Pharmacotherapy for alcoholism has strong evidence for use, but is highly underutilized by the medical community • Naltrexone, PO or IM, is “Recommended for all alcohol dependent patients who do not have a medical contraindication.” • The latest research, especially combinations of treatment (both psychotherapy and pharmacotherapy) are ever-evolving (e.g. Project COMBINE)

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