Evidence Based Medicine Pharmacological Treatment of Alcohol Dependence

Evidence Based MedicineEvidence Based Medicine

Pharmacological Treatment of Pharmacological Treatment of Alcohol DependenceAlcohol Dependence

Case PresentationCase 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.

Question?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?

Alcohol BackgroundAlcohol 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

DefinitionDefinition

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?)

AlcoholAlcohol

GABA (stim, sedate, intoxicate)GLUTAMATE (stim, sedate, intoxicate)

DOPAMINE (reinforce, reward, craving)OPIATE (reinforce, reward, craving)

How it works?How it works?

What about medicines?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

Disulfiram (antabuse)Disulfiram (antabuse)

Disulfiram DataDisulfiram Data

Double blind trial – “core journals” 1 trial1986 JAMA – VA CoOp study

– 605 patients randomized + CBT 250mg disulfiram 1mg disulfiram Nothing

DisulfiramDisulfiram Data 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.

Disulfiram Other studiesDisulfiram Other studies

Author, Yr Follow-up Disulfiram Abstinence

Gerrein, 1973 85%, 39%

MonitoredUnmonitored

40%

7%

Azrin, 1976 90% Monitored 90-98%

Azrin, 1982 100% Monitored 73%*

Liebson, 1978 78% Monitored 98%

Disulfiram SummaryDisulfiram 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,.)

NaltrexoneNaltrexone

Opioid receptor antagonist, can blunt the pleasurable effects and reduce cravings

Can’t use in patients taking chronic opiatesHepatotoxicity

~homotaurine ~GABA (gamma aminobutyric acid)

Decrease excitatory glutamergic neurotransmission during alcohol withdrawal, and reduce cravings

Usual dose is 666mg po tidRenally cleared so c/i in renal disease.FDA approved in 2004

AcamprosateAcamprosate

SearchSearch

Pubmed search– 1996-present RCT, CT ‘naltrexone +

alcoholism’– 1996-present RCT, CT ‘camprosate +

alcoholism’Results:

Acamprosate – 1996 LancetVA study Naltrexone 2001

COMBINE study 2006

AcamprosateAcamprosate(Whitworth et al, Lancet 1996)(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)

Acamprosate ResultsAcamprosate 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

Acamprosate ResultsAcamprosate 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

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 1st day of heavy drinking)– Number of drinks/day

VA - DemographicsVA - Demographics

ComplianceCompliance

OutcomeOutcome

VA SummaryVA 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

Naltrexone (Cochrane 2005)Naltrexone (Cochrane 2005)

27 RCT12 weeks of Naltrexone

– Decreases relapse 36%– Reduce the chance of returning to drink 13%

Faults – short duration, small sizes.

11sites, 1383 patients, alcohol dependenceExcluded patients with other drug use (x/c cannabis)Avg age 44, avg 12drinks/day, 67%men, 40%married4 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 specialistAlcohol 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)

COMBINE COMBINE –– arms arms

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

COMBINE SUMMARYCOMBINE 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%

CostsCosts

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)

NMCSD Formulary?NMCSD Formulary?

We carry all meds but restricted to SARP / Psychiatry

SummarySummary

Disulfiram helpful in a monitored settingNaltrexone 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

Follow upFollow up

Checked labs (LFT, CBC, B12, Folate, TSH) were normal

Recommended AA treatment– www.aa.org

Questions?Questions?