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Novel Pharmacotherapies for Alcohol Dependence
relapse compared with placebo. In terms of time to relapse, the alcohol withdrawal symptoms in dependent patients.
57
In an uncontrolled
combination of naltrexone and acamprosate was significantly better than pilot study in 2004, Flannery and colleagues treated alcohol-dependent
acamprosate alone, but not better than naltrexone alone. subjects (n=13) over 12 weeks with baclofen 10mg three times daily and
four sessions of motivational interviewing, and found significant
More recently, in 2006 Feeney and colleagues tested acamprosate, naltrexone, reductions in drinks per drinking day and heavy drinking days.
58
A 30-day
and both in combination in a group of medication decliners over 12 weeks in double-blind RCT comparing baclofen 10mg three times daily with
an age-, gender-, and alcohol-severity-matched—but not randomized—cohort placebo in recently detoxified alcohol-dependent subjects (n=39)
of 236 recently alcohol-abstinent subjects who received eight CBT sessions for demonstrated significant increases in percentage total abstinence
alcohol dependence.
52
They found no significant between-group differences (70 versus 21%; p<0.005) and CAD (19.6 versus 6.3 days; p<0.005).
59
The
for the three medication groups in terms of total abstinence, CAD, or days to efficacy of baclofen in alcohol dependence is promising, but further
relapse, but the combined medication group showed significantly increased evidence is needed from controlled studies.
days to relapse compared with the acamprosate-alone group. Project
COMBINE—a multisite 16-week RCT that tested acamprosate 3g/day, Selective Serotonin Re-uptake Inhibitors
naltrexone 100mg/day, and both in combination, along with either low- or Although selective serotonin re-uptake inhibitors (SSRIs) decrease
high-intensity behavioral interventions—did not demonstrate significant added alcohol consumption in animal studies,
30
results of clinical studies for alcohol
benefit with the naltrexone/acamprosate combination.
29
All treatment groups dependence are more equivocal. SSRIs may have the most utlity in treating
showed substantial reductions in drinking. However, naltrexone significantly major depression in patients with comorbid alcohol dependence and major
reduced the rate of relapse to heavy drinking, as did the combined behavioral
intervention (CBI) with placebo, but adding the more intensive CBI did not
provide significant gains to a significant naltrexone effect on percentage of
abstinent days. Surprisingly, acamprosate did not demonstrate gains in
The efficacy of baclofen in alcohol
percentage of abstinent days or relapse to heavy drinking compared with
dependence is promising, but
placebo, which may have been due to the high placebo response rate and
methodological differences compared with the European studies in which the
further evidence is needed from
efficacy of acamprosate has been demonstrated.
53
controlled studies.
Investigational Medications for Alcohol Dependence
(Not Approved by the US Food and Drug Administration)
Many classes of drugs are under active study for the treatment of alcohol depression.
60
In non-depressed alcoholics (n=101), a double-blind RCT of
dependence. Here we will focus on a few promising medications that are fluoxetine (up to 60mg/day) demonstrated no significant reductions in
active on GABA-ergic and serotoninergic systems. drinking.
61
However, upon further analysis by type A/B alcoholism subtype,
the type B alcoholics—who had earlier onset, more severity of dependence,
Topiramate and greater psychopathology—demonstrated poorer drinking outcomes
In the CNS, topiramate is hypothesized to influence alcohol dependence by with fluoxetine than with placebo.
62
Analogous results were demonstrated
increasing GABA-ergic activity through binding GABA
A
receptors, as well as in alcohol-dependent patients (n=100) stratified by type A/B subtype in a
by inhibiting glutamatergic activity through binding alpha-amino-3-hydroxy- six-month follow-up of a 14-week RCT of sertraline 200mg/day.
63
The type
5-methyl-4-isoxazole propionic acid (AMPA)/kainate glutamate receptors, A alcoholics—who had later onset, less severity of dependence, and less
which are upregulated during chronic alcohol exposure. In 2003, Johnson psychopathology—had maintained improved drinking outcomes with
and colleagues compared topiramate (titrated to 300mg/day) with placebo sertraline six months after treatment, whereas sertraline-treated type B
in a 12-week double-blind RCT in subjects with alcohol dependence patients had increased heavy drinking.
(n=150) receiving outpatient psychosocial support.
54
The topiramate group
had 27.6% fewer heavy drinking days (p=0.0003) and 26.2% more Ondansetron
abstinent days (p=0.0003) compared with the placebo group. A replication The 5-hydroxytryptamine3 (5-HT3) receptor antagonist ondansetron was
study recently conducted by Johnson et al. in 2007 was a 14-week double- evaluated in an 11-week double-blind RCT of subjects (n=271) with
blind multisite RCT that compared topiramate (titrated to 300mg/day or early- or late-onset alcohol dependence, all of whom received weekly
maximum tolerated) with placebo in the treatment of alcohol-dependent CBT.
64
Only the subset of subjects with early-onset alcoholism who
subjects (n=364).
55
Again, the topiramate group had a significant reduction received 1, 4, or 16µg/kg ondansetron twice daily reported significant
in the percentage of heavy drinking days (p<0.001), an effect that increased reductions in drinking compared with placebo, findings that were
with time in the study. Adverse events that were significantly more frequent corroborated by significant reductions in plasma carbohydrate-deficient
(p<0.05) in the topiramate group were parasthesia (50.8%), altered taste transferrin. The most common adverse events for the ondansetron and
perception (23.8%), anorexia (19.7%), difficulty concentrating (14.8%), placebo groups, respectively, were headache (3.4 versus 4.2%),
dizziness (11.5%), and pruritis (10.4%). constipation (5.0 versus 1.4%), tachycardia (0.3 versus 0%), and
rash/pruritis (2.2 versus 2.8%). If these and the above findings are
Baclofen replicated, and subtyping methods are better refined, we may begin to
Baclofen is a GABA
B
agonist that has been shown to attenuate the self- generate differential therapeutics for serotonergic medications in the
administration of alcohol in animal models
56
and appears to decrease treatment of alcohol dependence. ■
US PSYCHIATRY 2007 27
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