1. Evidence Based Medicine Pharmacological Treatment of Alcohol Dependence

2. Case Presentation 49yo m with HTN, HLP, DM2 presents to clinic for possible medical treatment for his 20 year h/o chronic alcohol use. He drinks about 6- 12pack/day. Denies any legal problems. Retired. Wife recently divorced him secondary to issues that could be related to his alcohol use. He has been sober for a week now “cold turkey.” He has some urges/cravings and His friend from the VFW got medicine that helped him with that. He was wondering if I could prescribe him something similar.

3. Question? Can a pharmacotherapy approach (I.e “medical management”) be used to treat alcohol dependence? (I.e. can I try to treat him myself?) Should I refer AND medicate, or just refer?

4. Alcohol Background 100,000 deaths annually in US 30% of all traffic fatalities Affect 10% of Americans at some point in their lives 2002 survey of 43,000 adults – prevalence about 12.5%(1) 2006 Survey of 2,397 EM residents (2) – 3.3% daily drinkers – 12.6% increased consumption during residency

5. Definition Alcohol Dependence per DSMIV : 3+ – Tolerance – Withdrawal (E) – Substance taken in larger quantities than intended – Persistent desire to cut down or control use (C ) – Time is spent obtaining, using or recovering (G) – Social, occupational or recreational tasks are sacrificed (AG?) – Use continues despite physical and psychological problems (G?)

6. Alcohol GABA (stim, sedate, intoxicate) GLUTAMATE (stim, sedate, intoxicate) DOPAMINE (reinforce, reward, craving) OPIATE (reinforce, reward, craving)

7. How it works?

8. What about medicines? US FDA approval – Disulfiram (antabuse) – Naltrexone (Vivitrol 380mg IM q4week or ReVia 50mg po qday) – Acamprosate(Campral) 666mg to 1g po tid

9. Disulfiram (antabuse)

10. Disulfiram Data Double blind trial – “core journals” 1 trial 1986 JAMA – VA CoOp study – 605 patients randomized + CBT 250mg disulfiram 1mg disulfiram Nothing

11. Disulfiram Data 80% noncompliant – 10% abstinent rate 20% Compliant – 50% abstinent NO difference in time to first drink, abstinent days, patients in the 250mg Disulfiram group did drink less. No difference at 1 year follow up.

12. Disulfiram Other studies Author, YrFollow-upDisulfiramAbstinence Gerrein, 197385%, 39% Monitored Unmonitored 40% 7% Azrin, 197690%Monitored90-98% Azrin, 1982100%Monitored73%* Liebson, 197878%Monitored98%

13. Disulfiram Summary Works well when patients are compliant. – (i.e not very good for outpt use) Use if goal is zero alcohol use. Warn patients when using other products that may contain alcohol (mouthwash, etc,.)

14. Naltrexone Opioid receptor antagonist, can blunt the pleasurable effects and reduce cravings Can’t use in patients taking chronic opiates Hepatotoxicity

15. ~homotaurine ~GABA (gamma aminobutyric acid) Decrease excitatory glutamergic neurotransmission during alcohol withdrawal, and reduce cravings Usual dose is 666mg po tid Renally cleared so c/i in renal disease. FDA approved in 2004 Acamprosate

16. Search Pubmed search – 1996-present RCT, CT ‘naltrexone + alcoholism’ – 1996-present RCT, CT ‘camprosate + alcoholism’ Results: Acamprosate – 1996 Lancet VA study Naltrexone 2001 COMBINE study 2006

17. Acamprosate (Whitworth et al, Lancet 1996) Multicenter, DBPCT 448 Adult patients Randomized to – 1998 mg (666mg tid) – Placebo F/u 0, 30, 90, 180, 270 and 360 days Primary Outcome – Time to treatment Failure (relapse or non attendance)

18. Acamprosate Results 448 patients – 224 acamprosate arm 94 completed 52 withdrawn, 33 lost to f/u, 31 refused, 15 ill, 2died 6 side effects – 224 placebo arm 85 completed 52 withdrawn, 36 lost to f/u, 32 refused, 11 ill, 1died 4 side effects

19. Acamprosate Results At end of study – Day 360 – Abstinent 41/224 (18.3%) abstinent 16/224 (7.1%) abstinent, (p=0.007) – Mean abstinent duration 138.8 days vs 103 days (p=0.012) not significant 11% (1 in 9 NNT) to get abstinent

20. 2001. Multicenter – RCT 627 Veterans with alcohol dependence – 12months naltrexone 50mg a day – 3monts of naltrexone then placebo 9months – 12months placebo – +Counseling Primary Outcome – Time to relapse (I.e 1 st day of heavy drinking) – Number of drinks/day

21. VA - Demographics

22. Compliance

23. Outcome

24. VA Summary Pt population of mainly men (97%), avg 13drinks/day, started drinking regular at 23. Naltrexone 50mg a day + therapy – Not different than placebo in Time to relapse Calendar days drinking

25. Naltrexone (Cochrane 2005) 27 RCT 12 weeks of Naltrexone – Decreases relapse 36% – Reduce the chance of returning to drink 13% Faults – short duration, small sizes.

26. 11sites, 1383 patients, alcohol dependence Excluded patients with other drug use (x/c cannabis) Avg age 44, avg 12drinks/day, 67%men, 40%married 4 days abstinence then -> Randomized (naltrexone 100mg/day, acamprosoate 666mg tid) MM – 9 sessions/16weeks, and at 26,52,68 weeks (0,1,2,4,6,8,10,12,16 week) CBT – alcohol specialist Alcohol use was self reported and verified by level of %CDT (abnormal serum transferrin protein) End Point - % days abstinent, time to >1 heavy drinking days (>5 men >4women)

27. COMBINE – arms

32. “Good clinical outcome” – – no more than 2days of heavy drinking per week, – (14drinks per week/men 11drink/women) – and without alcohol related problems

33. COMBINE SUMMARY Combined therapy - no additive benefit. Acamprosate not statistically beneficial. Naltrexone – %days abstinent 80.6% vs 75.1% = p=.009 – Heavy drinking day (66.2% vs 73.1%) p=0.15 – “Good clinical outcome” – 73.7% vs 58.2%

34. Costs Disulfiram – 250mg po qday/month $112.00 ($77.70 CHCS) Naltrexone – 50mg po qday/month $205.00, $18.00 generic (CHCS) – 380mg IM q month. $504.40 (CHCS) Acamprosate – 333mg po tid/month - $150.00 ($30.00 CHCS)

35. NMCSD Formulary? We carry all meds but restricted to SARP / Psychiatry

36. Summary Disulfiram helpful in a monitored setting Naltrexone data conflicting – Reviews show helpful short term. – VA DBCT – not helpful at 50mg for one year – COMBINE study – benefit at 100mg Camprosate – Benefit with CBI at one year – COMBINE study – showed no benefit

37. Follow up Checked labs (LFT, CBC, B12, Folate, TSH) were normal Recommended AA treatment – www.aa.org www.aa.org

38. Questions?