Evidence-Based Guidelines for Evidence-Based Guidelines for Pharmacotherapy in Alcohol Pharmacotherapy in Alcohol

DependenceDependence

Chandan Nayak, MDAddiction FellowUniversity of Michigan Department of Psychiatry

TopicsTopics

Alcohol & Society Neurobiology of Addiction Pharmacotherapy for Alcohol Dependence

– Disulfiram (DSF)– Naltrexone (NTX)– Acamprosate (ACP)

Summary

Alcohol & SocietyAlcohol & 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

Neurobiology of AddictionNeurobiology 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)

Neurobiology of AddictionNeurobiology of AddictionKalivas, Volkow. Am J Psychiatry 2005Kalivas, Volkow. Am J Psychiatry 2005

Neurobiology of AddictionNeurobiology of Addiction

Neurobiology of AddictionNeurobiology of Addiction

Pharmacotherapy for Alcohol Pharmacotherapy for Alcohol DependenceDependence

FDA-approved Medications Disulfiram (DSF)

– PO Antabuse (Odyssey)

Naltrexone (NTX)– PO ReVia (Barr)

– IM Vivitrol (Alkermes)

Acamprosate (ACP)– PO Campral (Forest)

Pharmacotherapy for Alcohol Pharmacotherapy for Alcohol DependenceDependence

DSFDSF NTXNTX ACPACP

Chemical Chemical MechanismMechanism

Enzyme Enzyme inhibitorinhibitor

Opioid Opioid antagonistantagonist

Glutamate Glutamate modulatormodulator

BehavioralBehavioralMechanismMechanism

Negative Re-Negative Re-InforcementInforcement

Blocks high Blocks high & craving& craving

↓↓ protracted protracted withdrawal Sxwithdrawal Sx

Abstinence Abstinence required?required?

YesYes NoNo YesYes

MetabolismMetabolism LiverLiver LiverLiver KidneyKidney

DosingDosing Once dailyOnce daily Once dailyOnce daily TIDTID

DisulfiramDisulfiram

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)

DisulfiramDisulfiram

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

DisulfiramDisulfiramFuller et al: JAMA 1986Fuller et al: JAMA 1986

49.0

75.4

86.5

0

10

20

30

40

50

60

70

80

90

Drinking Days in 1 yr

disulfiram 250 mg

disulfiram 1 mg

no disulfiram

RCT 605 alcoholic veterans

*

* p<.05

NaltrexoneNaltrexone

PO, FDA approval 1994 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

Practical Problems– Noncompliance, lack of prescribing

NaltrexoneNaltrexoneReview: Pettinati et al: JAMA 2006Review: 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

NaltrexoneNaltrexoneReview: Pettinati et al: JAMA 2006Review: 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

NaltrexoneNaltrexone

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

NaltrexoneNaltrexone

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

NaltrexoneNaltrexone

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)

AcamprosateAcamprosate

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

AcamprosateAcamprosate

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)???

SummarySummary

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)

AcknowledgementsAcknowledgements

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.