Evidence-Based Guidelines for Pharmacotherapy in Alcohol Dependence Chandan Nayak, MD Addiction...
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Transcript of Evidence-Based Guidelines for Pharmacotherapy in Alcohol Dependence Chandan Nayak, MD Addiction...
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
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.