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REVIEW
Pharmacological Treatment
of Alcohol Dependence
A Review of the Evidence
James C. Garbutt, MD
Suzanne L. West, PhD, MPH
Timothy S. Carey, MD, MPH
Kathleen N. Lohr, PhD
Fulton T. Crews, PhD
A
LCOHOL DEPENDENCE, OR AL-
coholism, is often a progres-
sive chronic disorder that both
the American Medical Asso-
ciation and the American Psychiatric As-
sociation recognize as a disease.
1
It is a
common disorder posing a heavy bur-
den on patients, their families, and so-
ciety. Epidemiological studies indicate
that alcoholism will affect approxi-
mately 10% of Americans at some time
in their lives, with men affected more
than women.
2-5
This is a high preva-
lence rate compared with many other
diseases and highlights the public health
significance of alcohol dependence. In
addition to the estimated 100 000 US
citizens who die each year because of al-
cohol-related causes, including traffic
collisions and cirrhosis of the liver,
6
al-
coholism costs the nation an estimated
$166 billion annually in direct and in-
direct health and social costs.
7
Treating alcoholism involves sev-
eral stages. The initial stage deals with
acute withdrawal and detoxification.
8
Later stages attempt to maintain pa-
tients in remission and develop a life-
style compatible with long-term absti-
nence (ie, avoidance of any alcohol
consumption). This latter aspect of pa-
tient management has traditionally in-
volved psychosocial interventions (in-
cluding Alcoholics Anonymous and
various counseling approaches), phar-
PhD, MPH, Research Triangle Institute, 3040 Corn-
wallis Rd, PO Box 12194, Research Triangle Park, NC
27709-2194 (e-mail: swest@rti.org).
Context Alcoholism affects approximately 10% of Americans at some time in their
lives. Treatment consists of psychosocial interventions, pharmacological interven-
tions, or both, but which drugs are most effective at enhancing abstinence and pre-
venting relapse has not been systematically reviewed.
Objective To evaluate the efficacy of 5 categories of drugs used to treat alcohol
dependence—disulfiram, the opioid antagonists naltrexone and nalmefene, acamprosate,
various serotonergic agents (including selective serotonergic reuptake inhibitors), and lithium.
Data Sources Reports of randomized controlled trials, nonrandomized trials, and other
study designs in English, French, and German identified from multiple searches of MEDLINE,
EMBASE, and specialized databases; hand searching bibliographies of review articles;
searches for unpublished literature; and discussions with investigators in the field.
Study Selection We included all studies on alcohol-dependent human subjects aged
18 years or older from all inpatient and outpatient settings between 1966 and De-
cember 1997 that met our inclusion criteria.
Data Extraction We abstracted the following information: study design and blind-
ing, diagnostic instrument and severity assessment, drug interventions and cointer-
ventions, demographic and comorbidity details about patients, compliance, and nu-
merous outcome measures (eg, relapse, return to drinking, drinking or nondrinking
days, time to first drink, alcohol consumed per unit of time, craving). We graded qual-
ity of the individual articles (scale, 0-100) independently from the strength of evi-
dence for each drug class (A, strong and consistent evidence of efficacy in studies of
large size and/or high quality; B, mixed evidence of efficacy; C, evidence of lack of
efficacy; and I, insufficient evidence).
Data Synthesis Of 375 articles evaluated, we abstracted and analyzed data from 41
studies and 11 follow-up or subgroup studies. Naltrexone (grade A) reduces the risk of
relapse to heavy drinking and the frequency of drinking compared with placebo but does
not substantially enhance abstinence, ie, avoidance of any alcohol consumption. Acam-
prosate (grade A, from large-scale studies in Europe) reduces drinking frequency, although
its effects on enhancing abstinence or reducing time to first drink are less clear. Controlled
studies of disulfiram (grade B) reveal a mixed outcome pattern—some evidence that drink-
ing frequency is reduced but minimal evidence to support improved continuous abstinence
rates. The limited data on serotonergic agents were not very promising (grade I), although
most studies were confounded by high rates of comorbid mood disorders. Lithium lacks
efficacy (grade C) in the treatment of primary alcohol dependence.
Conclusions Recent reports documenting that naltrexone and acamprosate are more
effective than placebo in the treatment of alcoholism justify clinical interest in use of
these medications for alcohol-dependent patients. Use of disulfiram is widespread but
less clearly supported by the clinical trial evidence; however, targeted studies on su-
pervised administration of disulfiram may be warranted. Use of existing serotonergic
agents or lithium for patients with primary alcohol dependence does not appear to be
supported by the efficacy data available at this time; these medications may still have
a positive effect in patients with coexisting psychiatric disorders.
JAMA. 1999;281:1318-1325 www.jama.com
Author Affiliations are listed at the end of this
article.
Corresponding Author and Reprints: Suzanne L. West,
See also Patient Page.
1318 JAMA, April 14, 1999—Vol 281, No. 14 ©1999 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ on 02/25/2013
macological modalities (primarily di-
sulfiram), and combinations of both. Al-
though many individuals do achieve
long-term sobriety with treatment, oth-
ers continue to relapse and deteriorate
despite multiple courses of treatment.
Pharmacological treatment is emerg-
ing as another means to enhance absti-
nence and prevent relapse, complement-
ing psychosocial interventions that have
been in use for many years. The find-
ings we report here are part of a rigor-
ous systematic review of the relevant
scientific literature on the pharmacolo-
gical treatment of alcoholism conduc-
ted by the Research Triangle Institute–
University of North Carolina at Chapel
Hill Evidence-based Practice Center and
sponsored by the Agency for Health Care
Policy and Research (AHCPR).
9
METHODS
Drugs and Outcomes Reviewed
We conducted a detailed search of the
scientific literature on 5 classes of
drugs.
9
We focused on early drugs used
for alcoholism (disulfiram and lithium)
and pharmacotherapies that have been
used more recently (the opiate antago-
nists naltrexone and nalmefene, acam-
prosate, and various serotonergic
agents) (T
ABLE 1). These classes of
medications represent the major agents
used or recently tested for the treat-
ment of alcohol dependence after al-
cohol withdrawal.
With the advice of a technical expert
advisory group (see “Acknowledg-
ment” section), we developed study ques-
tions and methods. We reviewed the effi-
cacy of these agents for reduction in the
number of standard drinks of alcohol,
reduction in the number of drinking days
(or increase in the number of nondrink-
ing days), overall resumption of drink-
ing, number of episodes of heavy drink-
ing, time to first drink, reduction in the
rate of relapse determined by a priori cri-
teria, and craving. Our results are drawn
largely from intention-to-treat analyses;
the full evidence report
9
provides infor-
mation on subgroup and follow-up analy-
ses, occurrence rates of adverse effects,
and patient compliance.
Literature Searched
TABLE 2 shows the inclusion and exclu-
sion criteria for articles selected for re-
view. We used the following databases:
MEDLINE, HealthSTAR, the American
Society of Health-System Pharmacists In-
ternational Pharmaceutical Abstracts da-
tabase, EMBASE, Alcohol and Alcohol
Problems Database, and PsycINFO.
Search strategies included all medica-
tions of interest and related classes of
medications, alcoholism, alcohol drink-
ing, and study and design characteris-
tics. We also reviewed materials avail-
able from the Cochrane Collaboration,
published abstracts, and US Food and
Drug Administration documents.
To obtain data for our evidence
tables, we developed a data extraction
form, a follow-up results form, a co-
morbid study results form, an adverse-
effect profile, and an extraction guide.
We used dual abstraction procedures
(1 content reviewer and 1 methods re-
viewer); the principal investigators
(S.L.W. and J.C.G.) completed a third
conflict-resolution review.
To assess the quality of individual ar-
ticles, reviewers completed a quality rat-
ing form covering study design, diag-
nostic and outcome measures, statistical
analyses, and discussion. The form used
standard methodological items, such as
loss to follow-up, blinding, and compa-
rability between treatment groups. It also
included items specific to alcohol de-
pendence, such as authors’ alcoholism
criteria and method of assessment. The
Table 1. Pharmacotherapies Used for Maintaining Abstinence in Alcohol-Dependent Patients
Pharmacotherapies Known or Potential Mechanisms of Action
Disulfiram Inhibits aldehyde dehydrogenase, leading to elevations in
acetaldehyde levels after alcohol is consumed;
increases in acetaldehyde levels produce a variety
of physiological effects, including nausea,
hypotension, and flushing; disulfiram produces an
adverse experience when alcohol is consumed and,
more importantly, functions as a psychological
deterrent to prevent alcohol consumption
Naltrexone/nalmefene Antagonists of endogenous opioids, such as
b-endorphin and enkephalins
Acamprosate Mechanism of action unknown; appears to interact with
glutamate receptors and calcium channels
Serotonergic agents
Citalopram, fluoxetine, fluvoxamine Selective serotonin reuptake inhibitors
Buspirone hydrochloride Serotonin agonist (5-HT
1a
)
Ondansetron hydrochloride Serotonin antagonist (5-HT
3
)
Lithium Exact mechanism of action unknown; affects
phosphoinositide signaling and enhances
serotonin actions in the brain
Table 2. Pharmacotherapy for Alcohol Dependence: Inclusion/Exclusion Criteria
Categories Criteria
Study population Male/female adults (aged $18 y) who were alcohol dependent
Excluded children and infants; pregnant women
Location of study United States, Canada, Europe, Latin America, Asia, Australia/New Zealand
Excluded locations based on language of publication
Publication language English, French, or German
Admissible evidence Study design: double- or single-blind randomized controlled trial
Prospective and retrospective cohort studies, case-control studies
(nonrandomized controlled trial)
Other designs (meta-analysis, meta-regression, cross-design synthesis,
review article for reference list searches, cost-effectiveness, quality of life)
Sample size: $10 subjects
Study setting Inpatient and outpatient settings (all study settings reflected current practice)
Time period 1966 to December 1997 (depended on date of approval for pharmaceutical
products)
PHARMACOLOGICAL TREATMENT OF ALCOHOL DEPENDENCE
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quality score was independent of the ar-
ticle’s findings on efficacy of the phar-
macological intervention. Individual
scores summed to 40 points and were
rescaled to 100 points (scale available
from the authors on request). We judged
the overall strength of the evidence on
efficacy based on the consistency across
studies, quality of studies, sample size,
and magnitude of effects (T
ABLE 3).
After applying our inclusion and ex-
clusion criteria and reviewing the titles
and/or abstracts of 375 articles, we fully
abstracted and analyzed data for 41 stud-
ies and 11 follow-up or subgroup evalu-
ations, including 11 disulfiram studies,
with 1 subgroup publication; 1
nalmefene article; 3 naltrexone stud-
ies, with 5 subgroup publications; 9
acamprosate articles; 9 serotonergic
agent studies not restricted to comor-
bid populations, with 1 subgroup study;
3 serotonergic agent studies restricted
to persons with coexisting depression or
anxiety, with 1 subgroup analysis; and
6 lithium articles, with 3 subgroup analy-
ses. One article addressed both fluox-
etine and acamprosate. We did not ex-
clude any articles from analysis on the
basis of poor quality ratings; this judg-
ment is reflected in the discussions and
rating of the strength of evidence.
RESULTS
Primary Outcomes
for Individual Medications
TABLE 4 shows the primary findings with
evidence graded on the A-B-C-I scale de-
fined in Table 3. When multiple citations
refer to the same trial, only the original
is included in Table 4. We included in
Table 4 only those studies that provided
information on standard alcohol out-
comes, including drinking days, return
to drinking, time to first drink, alcohol
consumed per unit of time, episodes of
heavy drinking, craving, or relapse.
Disulfiram. Although the literature is
substantial on use of this drug to treat
alcoholism (135 studies), the number of
controlled clinical trials is limited; of the
11 trials we reviewed, 5 concerned oral
disulfiram
10-15
and the remainder stud-
ied disulfiram implants.
16-21
Oral Disulfiram (Maintenance Dos-
age, 200-250 mg/d). The 5 oral disul-
firam studies involved 1207 subjects; 3
were placebo controlled and used
double-blind random assignment.
10,11,13
Outcome measures and results varied;
they provide modest evidence that disul-
firam reduces drinking frequencies with-
out significantly enhancing abstinence
rates (Table 4). The only group that stud-
ied supervised administration of the drug
found that subjects taking disulfiram had
significantly improved outcomes in
drinking frequency and amount con-
sumed
14
; however, the trial did not main-
tain double-blind standards (subjects
were told after randomization if they
were receiving disulfiram).
Disulfiram Implants (1-Time Dose,
800-1000 mg). Although implants of di-
sulfiram appear to be an attractive
method to ensure compliance, the bio-
availability of disulfiram following im-
plantation has not been demonstrated
in the therapeutic trials. Six studies (com-
bined enrollment, n = 282) used disul-
firam implants; 5 used a placebo, most
commonly a saline injection.
17-21
The out-
come measures reflect diverse results
(Table 4).
We judged the efficacy evidence for
disulfiram (modalities combined) as
warranting a grade of B—inconsistent
but positive evidence that disulfiram re-
duces the number of drinking days, and
inconsistent but more often negative evi-
dence about other outcome measures.
Opiate Antagonists. Of the 77 re-
search articles identified, 3 controlled
studies evaluated the efficacy of naltrex-
one in alcohol-dependent patients
22-24
and 1 pilot study evaluated nalmefene.
25
We also reviewed substudies of these
trials.
26-30
Naltrexone (50 mg/d). Although the
overall sample size for the 3 naltrexone
studies is modest (n = 271 randomized
patients), the trials are recent and of good
quality, with consistent results on relapse
rates and drinking frequencies (Table 4).
One study investigated the effect of both
naltrexone vs placebo and supportive
therapy vs coping skills therapy, thus
providing the only work to address the
interaction between pharmacological
and psychosocial interventions.
22
Nal-
trexone had a positive effect (on ab-
stinence) only when combined with
supportive psychotherapy; patients
receiving naltrexone and coping skills
therapy showed no such effect. Other
outcomes show a more consistent pat-
tern (Table 4). Among all patients in the
first 2 trials,
22,23
relapse rates at the end
of the trials were higher for the placebo
groups (54%
23
and approximately 80%
22
)
than for the naltrexone groups (23%
23
and approximately 40%
22
). In a third
trial,
24
end-of-study relapse rates for all
subjects were 53% and 35% for placebo
and naltrexone patients, respectively;
however, for compliant patients, the fig-
ures were 52% and 14%. Of 2 studies
that measured a biological marker for
alcohol consumption (g-glutamyl trans-
peptidase [GGTP]), one found that nal-
trexone recipients had significantly lower
GGTP levels at the end of the trial
24
and
the other earlier trial had a nonsignifi-
cant trend in that direction.
23
O’Malley
et al
28
studied patients for an additional
6 months after trial completion and
found that compared with subjects
Table 3. Grade of Strength of Evidence on the Efficacy of Pharmacotherapies
for Alcohol Dependence
Grades Definitions
A (good) Sufficient data for evaluating efficacy; sample size is adequate; data are
consistent and indicate that the key drug is clearly superior to placebo for
treatment of alcohol dependence
B (fair) Sufficient data for evaluating efficacy; sample size is adequate; data indicate
inconsistencies in findings for alcohol outcomes between the drug and
placebo such that the efficacy of the key drug for treatment of alcohol
dependence is not clearly established
C (poor) Sufficient and consistent evidence that the key drug is no more efficacious for
treating alcohol dependence than placebo; sample size is adequate
I (insufficient) Inadequate data for assessing efficacy (based on limited sample size or poor
method)
PHARMACOLOGICAL TREATMENT OF ALCOHOL DEPENDENCE
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Table 4. Randomized Controlled Trials to Evaluate the Efficacy of Pharmacotherapies Used for Maintaining Abstinence
in Alcohol-Dependent Patients
*
Source, y
Initial/
Final
Sample Size
Trial
Length,
wk
Efficacy
Quality
Rating
Drinking/
Nondrinking
Days
Return to
Drinking
Time to
First Drink
Alcohol
Consumed Per
Unit of Time Craving Relapse
Disulfiram (Grade, B)
Oral Disulfiram
Fuller and Roth,
10
1979 128/NA 52 − − NM/R NM/R NM/R NM/R 62
Fuller et al,
13
1986 605/577 52 + − − NM/R NM/R NM/R 88
Schuckit,
12
1985† 348/348 52 − NM/R NM/R − NM/R NM/R 69
Chick et al,
14
1992 126/69 24 + NM/R NM/R + NM/R NM/R 72
Disulfiram Implants
Whyte and O’Brien,
16
1974† 45/NA NA NM/R NM/R + NM/R NM/R NM/R 34
Wilson et al,
17
1976 20/NA NA NM/R − − NM/R NM/R NM/R 26
Wilson et al,
19
1980 100/78 48 + − NM/R NM/R NM/R NM/R 41
Johnsen et al,
20
1987 21/21 20 − NM/R − − NM/R NM/R 60
Johnsen and Morland,
21
1991 76/63 40 − − − − NM/R NM/R 71
Naltrexone (Grade, A)
O’Malley et al,
22
1992 104/68 12 + + NM/R −/+‡ −/+‡ + 88
Volpicelli et al,
23
1992 70/44 12 + − NM/R NM/R + + 90
Volpicelli et al,
24
1997 97/71 12 −/+§ −/+§ NM/R NM/R − −/+§ 95
Acamprosate (Grade, A)
Gerra et al,
31
1992\ 28/NA 4 NM/R NM/R NM/R −/+¶ NM/R NM/R 72
Ladewig et al,
32
1993 61/NA 24 + − NM/R NM/R NM/R NM/R 75
Paille et al,
33
1995 538/NA 52 + − + NM/R − NM/R 63
Roussaux et al,
34
1996 127/90 12 NM/R − NM/R NM/R − NM/R 65
Sass et al,
35
1996 272/134 48 + + + NM/R − NM/R 91
Whitworth et al,
36
1996 448/180 52 + + NM/R NM/R NM/R NM/R 52
Geerlings et al,
37
1997 262/94 24 + − − NM/R NM/R NM/R 60
Pelc et al,
38
1997 188/119 12 + + + NM/R + NM/R 66
Poldrugo,
39
1997 246/112 26 + + + NM/R − NM/R 83
Serotonergic Agents (Grade, I)
Patients With Varying Comorbidity
Gerra et al,
31
1992 (fluoxetine)\ 28/NA 4 NM/R NM/R NM/R −/+# NM/R NM/R 72
Gorelick and Paredes,
40
1992
(fluoxetine)
20/17 4 NM/R NM/R NM/R − − NM/R 72
Kranzler et al,
41
1995 (fluoxetine) 101/95 12 − NM/R NM/R − NM/R NM/R 73
Janiri et al,
42
1996 (fluoxetine) 50/33 8 NM/R + NM/R NM/R − + 69
Kabel and Petty,
43
1996 (fluoxetine) 28/19 12 NM/R NM/R NM/R NM/R + − 87
Malec et al,
47
1996 (buspirone
hydrochloride)
57/36 12 − − NM/R − − NM/R 68
Sellers et al,
45
1994 (ondansetron
hydrochloride)
71/56 6 NM/R NM/R NM/R −/+
**
NM/R NM/R 82
Tiihonen et al,
46
1996 (citalopram) 62/34 12 NM/R NM/R NM/R NM/R NM/R NM/R 66
Patients With Anxiety or Mood Disorders
Malcolm et al,
48
1992 (buspirone
hydrochloride)
67/20 26 NM/R − − − − NM/R 90
Kranzler et al,
49
1994 (buspirone
hydrochloride)
61/42 12 − NM/R + − NM/R NM/R 95
Cornelius et al,
50
1997 (fluoxetine) 51/46 12 + − − + NM/R NM/R 93
Lithium (Grade, C)
Merry et al,
52
1976 71/38 52 +†† NM/R NM/R NM/R NM/R NM/R 59
de la Fuente et al,
56
1989 53/27 26 − + NM/R NM/R NM/R NM/R 71
Clark and Fawcett,
57
1989 122/NA 72 NM/R +‡‡ NM/R NM/R NM/R NM/R 77
Dorus et al,
58
1989 457/280 52 − − NM/R NM/R NM/R NM/R 94
*
NA indicates information not available; NM/R, outcome was not measured or data not reported; plus sign, intervention showed efficacy compared with placebo (P,.05); and
minus sign, intervention did not show efficacy compared with placebo. Grades are explained in Table 3. Quality rating is based on a scale of 1 to 100.
†Nonrandomized study.
‡Interaction between medication and psychotherapy was significant (P,.05 for amount consumed per unit of time and P,.01 for craving).
§Compliant subjects showed positive drug effect.
\Fluoxetine and acamprosate (crossover study design).
¶In nonfamilial alcohol-dependent subjects only.
#In familial alcohol-dependent subjects only.
**
Low dosages in light drinkers only.
††Patients with depression only.
‡‡High-blood-level lithium subjects only.
PHARMACOLOGICAL TREATMENT OF ALCOHOL DEPENDENCE
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receiving placebo, those receiving nal-
trexone had lower rates of heavy drink-
ing. Reports on subsets of patients who
sampled alcohol found that naltrexone
diminished the subjective “high” after
alcohol consumption.
24,26,29
Nalmefene (10-40 mg/d). The
nalmefene trial randomized 21 sub-
jects to placebo and 2 nalmefene dos-
age groups; 8 subjects completed the
study.
25
The significant finding was a
lower relapse rate in the high-dosage
nalmefene group (data not shown).
The high quality of these trials coupled
with the consistent finding for an effect
of naltrexone in reducing relapse rates and
drinking frequencies warranted a grade
of A; we gave nalmefene a grade of I.
Acamprosate (1300-2000 mg/d). Of
the 37 acamprosate studies identified in
our literature search, we abstracted data
for 9.
31-39
A total of 2170 patients were en-
rolled; all trials used a double-blind
method and 1 used a crossover design.
31
The most consistent finding in the
acamprosate trials has been its effect on
drinking frequency (Table 4); nondrink-
ing days were typically increased by 30%
to 50% (eg, from 162 to 225 nondrink-
ing days
35
). Several studies also found
that acamprosate approximately doubled
abstinence rates, although a majority of
patients returned to drinking while tak-
ing acamprosate. The acamprosate tri-
als did not assess relapse rates. Of 4 tri-
als assessing GGTP, 2 reported improve-
ments among acamprosate recipients,
33,39
1 indicated a trend toward improve-
ment,
34
and 1 reported no effect.
35
Among subjects followed up for 48
weeks after trial completion, patients tak-
ing acamprosate showed a greater num-
ber of cumulative nondrinking days than
did those receiving placebo since entry
into the trial (387 vs 250 days) and a
higher abstinence rate (40% vs 17%).
35
Among subjects followed up for 12
months after trial completion, acampro-
sate continued to exert a positive effect
on abstinence rates but not number of
nondrinking days.
36
Acamprosate recipi-
ents had higher rates of abstinence at 6
months after treatment than controls
(43% vs 30%).
39
Ladewig et al
32
did not
find a carryover effect for acamprosate
up to 6 months after active treatment had
ended, but this group also failed to find
any effect for acamprosate during the lat-
ter part of their active trial.
Based on the large number of sub-
jects and the consistent finding in the
trials that acamprosate reduces drink-
ing frequency, we gave acamprosate an
efficacy rating of A.
Serotonergic Agents (Dosages Var-
ied by Drug). We reviewed 3 classes of
serotonergic agents: selective seroto-
nin reuptake inhibitors (SSRIs, princi-
pally fluoxetine), buspirone hydrochlo-
ride, and ondansetron hydrochloride
(Table 1). The US Food and Drug Ad-
ministration approved SSRIs for use in
depression and anxiety disorders, buspi-
rone for anxiety, and ondansetron for
nausea. In recent years, these drugs have
been evaluated off label in alcohol de-
pendence, especially when patients ex-
hibit comorbid mood or anxiety disor-
ders. Thus, an adequate examination of
their effects on alcohol dependence must
take into account whether an affective
or anxiety disorder is present. We di-
vided trials (Table 4) into those that
studied alcohol-dependent individuals
with varying rates of psychiatric comor-
bidity (including none)
31,40-47
and those
that prospectively selected alcohol-
dependent subjects with a known de-
pressive or anxiety disorder.
48-50
Trials in Subjects With Varying
Rates of Comorbid Depression or
Anxiety. The SSRI fluoxetine has been
studied in 5 double-blind placebo-
controlled trials (n = 227 subjects); 1
used a crossover design,
31
2 used ran-
domization,
41,42
and 2 did not use ran-
domization.
40,43
Outcomes are mixed re-
garding the efficacy of fluoxetine for
alcohol-dependent patients. Citalo-
pram had no effect on GGTP or epi-
sodes of heavy drinking.
46
The 1 trial
of buspirone (n = 57 subjects, using a
double-blind placebo-controlled de-
sign) showed no therapeutic effect on
several measures, including GGTP lev-
els.
47
One trial of ondansetron (n = 71
subjects, using a double-blind placebo-
controlled design, with random assign-
ment to high dosage [4 mg/d] and low
dosage [0.5 mg/d]) found that low-
dosage ondansetron reduced drinking
only among light drinkers.
45
Trials of Alcohol-Dependent Sub-
jects With Depression or Anxiety. Tri-
als among patients who also had depres-
sion or anxiety totaled 179 subjects
(n = 51 for a fluoxetine trial
50
;n=128
for 2 buspirone trials
48,49
). Depressed al-
cohol-dependent patients taking fluox-
etine showed improved amount and fre-
quency of drinking compared with those
receiving placebo; the buspirone stud-
ies showed only 1 positive change in
drinking outcomes (time to first drink).
Generally, the studies of fluoxetine in-
volved a modest number of patients and
results are at best mixed, as is true of the
buspirone and ondansetron studies. We
judged that the limited nature of these
data warranted efficacy ratings of I.
Lithium (Dosages and Blood Lev-
els Varied). Six trials and 3 related sub-
studies (n = 823 subjects) have ap-
peared on the effects of lithium in
alcohol-dependent subjects with and
without depression or bipolar
disorder
51-59
; about 55% of all subjects
were studied in the large cooperative trial
sponsored by the Department of Veter-
ans Affairs.
58
All trials (Table 4) re-
ported comorbid depression in sub-
jects; only 2 controlled for depression in
their data analyses.
52,58
The strongest and
largest trial found no positive effect for
lithium in either depressed or nonde-
pressed alcoholic-dependent sub-
jects.
58
One study (not controlling for co-
morbidity) found improved drinking
outcomes in subjects with high lithium
levels (compliant by definition).
57
Based on the negative findings of the
large well-conducted study and the fact
that all positive findings with lithium
were limited to studies that did not con-
trol for comorbidity, we gave lithium
an efficacy rating of C.
Secondary Measures
Compliance. In a clinical trial, the ex-
tent to which patients are compliant may
affect whether a drug effect will be found.
In the reviewed studies, investigators
monitored compliance in diverse ways,
including self-report, proxy report, pill
counts at return visits, urine markers,
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and blood levels of active medication.
The effect of compliance on outcome
measures was rarely analyzed. In 2 cases
in which compliance was studied, Fuller
et al
13
found that compliant subjects had
improved outcomes regardless of as-
signed drug and Volpicelli et al
24
found
a positive outcome for naltrexone only
in compliant subjects.
Adverse Events. In assessing the use-
fulness of a medication, clinicians must
balance efficacy against risks (adverse ef-
fects, morbidity, and mortality). We
noted risks (when described in the tri-
als) and gathered information from 1
large safety and tolerability study of
naltrexone.
60
Given the incomplete pic-
ture of risk provided by clinical trials,
the risk-benefit ratio for any of the re-
viewed medications cannot be fully
specified. Disulfiram, lithium, SSRIs, and
buspirone, although generally well tol-
erated, are associated with adverse ef-
fects and occasional morbidity. These tri-
als reported no deaths attributed to any
of these agents; dropout rates due to ad-
verse effects, when reported, were low.
In the naltrexone trials, no mortality was
reported and the most common ad-
verse effects were nausea and dizzi-
ness. The naltrexone safety and toler-
ability study
60
reported higher rates for
2 adverse effects, new-onset nausea
(9.8% for naltrexone vs 0% for non-
medication group) and headache (6.6%
for naltrexone vs 1.7% for nonmedica-
tion group) and a 15% discontinuance
rate for naltrexone subjects because of
adverse effects. In the acamprosate tri-
als, no mortality attributed to medica-
tion was reported. The most common
adverse effect was diarrhea; dizziness,
itching, and increased sexual desire were
also significantly greater in the active vs
placebo groups. Dropout rates were less
than 1% for any 1 adverse effect.
COMMENT
The pharmacotherapy of alcohol depen-
dence has significantly changed during
the past few years. The discovery of new
medications may positively affect core
components of the alcohol dependence
syndrome, such as loss of control of drink-
ing, preoccupation with alcohol use, or
protracted abstinence symptoms. The de-
velopment of new classes of medicines
specifically effective for the primary symp-
toms of alcohol dependence represents an
advance of historic importance.
Results from our evidence report
9
that
are reviewed here are noteworthy in 2
broad areas: (1) understanding the clini-
cal implications of the efficacy of the re-
viewed medications and (2) addressing
the remaining gaps in the knowledge
base. No study examined the efficacy of
these agents compared with each other;
variations in study design, duration of fol-
low-up, and outcome measures pre-
vented comparison of these medica-
tions for relative efficacy.
Although we attempted to identify
the nature and extent of psychosocial
interventions based on information pro-
vided by the authors, typically these in-
terventions were poorly described.
Thus, the literature did not allow us to
evaluate the important question of ef-
ficacy of pharmacotherapy when used
in conjunction with varying types and
intensities of psychosocial therapies.
Efficacy of Medications
Naltrexone and Acamprosate. The in-
terest generated by recent reports docu-
menting that naltrexone and acampro-
sate are more effective than placebo in the
treatment of alcoholism appears war-
ranted by the strength of the evidence
(evidence grade, A), showing their effi-
cacy among alcohol-dependent patients.
The naltrexone trials involved a modest
number of subjects (n = 271), but the
quality of the trials was high and the find-
ings consistently showed that naltrex-
one reduced drinking frequency and re-
lapse rates, controlling for compliance.
Although requiring confirmation, nal-
trexone’s primary effect appears to be its
ability to reduce the patient’s emotional
response to alcohol consumption; this
may deter patients who sample alcohol
from progressing to heavy drinking (re-
lapse) and decrease alcohol intake over
time. Other actions of naltrexone are
likely operative, given the evidence that
abstinence was enhanced in 2 of the 3 tri-
als. The clinical impact of naltrexone is
not yet clear—for some patients it may be
profound, for others it may bring no ben-
efit. Current work will expand this knowl-
edge base considerably; 18 National In-
stitute on Alcohol Abuse and Alcoholism
(NIAAA)–sponsored trials targeting ap-
proximately 3000 subjects and 1 mul-
tisite Department of Veterans Affairs study
involving 600 subjects are under way or
just completed.
The acamprosate trials involved a
large number of subjects (n = 2170),
were of moderate to good quality, and
consistently showed positive effects on
reducing drinking frequency, with some
evidence of enhancing abstinence. The
acamprosate trials have been limited to
European populations, although re-
sults from a just-completed US-based,
placebo-controlled, double-blind, mul-
tisite trial sponsored by Lipha Pharma-
ceuticals Inc, New York, NY (n = <450
subjects), should be published within the
next year. To date, acamprosate has not
been used clinically in the United States;
its impact on US practice is not yet clear.
Disulfiram. The disulfiram trials (evi-
dence grade, B) were less consistent in
both quality and results; they provided
moderate evidence of reduced drink-
ing frequency but no evidence of
enhanced abstinence. Supervised disul-
firam administration has been posited
as a particularly effective treatment
method,
61
but the only placebo-
controlled trial with this approach did
not maintain double-blind condi-
tions.
14
The bioavailability of implanted
disulfiram was not shown; alcohol chal-
lenges after implantation did not pro-
duce a disulfiram-ethanol reaction.
Disulfiram presents an interesting
clinical dilemma. It has been used for
close to 50 years and many practition-
ers believe it has great value. Neverthe-
less, the controlled clinical trials yield am-
biguous conclusions about its efficacy.
Is this divergence between clinical prac-
tice and clinical trials a real phenom-
enon? On one hand, given the appro-
priate subjects and research design (eg,
supervised administration), disulfiram
might demonstrate greater efficacy than
in the data we reviewed. On the other
hand, a large portion of the disulfiram
effect is related to fear of a disulfiram-
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ethanol reaction; hence, in a placebo-
controlled trial, an active drug effect
would be more difficult to ascertain.
Serotonergic Agents and Lithium.
The controlled studies of serotonergic
agents were limited and yielded mixed re-
sults (evidence grade, I). Coexisting mood
and anxiety disorders greatly compli-
cate interpretation of the findings, but the
limited evidence available does not sup-
port the use of serotonergic agents for
treating primary alcohol-dependent pa-
tients. The 2 studies that evaluated buspi-
rone in alcohol-dependent subjects with
anxiety had primarily negative effects, al-
though 1 was suggestive for some posi-
tive effects.
49
The 1 fluoxetine trial in al-
cohol-dependent subjects with depression
was positive.
50
This minimal database on
these medications will be greatly ex-
panded by a Pfizer Inc (New York, NY)
multisite trial of the SSRI sertraline hy-
drochloride for clinically depressed al-
cohol-dependent subjects and by 7
NIAAA trials (n = <1100 subjects).
The controlled trials of lithium did not
demonstrate efficacy in either nonde-
pressed or depressed alcohol-depen-
dent subjects (evidence grade, C). We
concluded that the literature does not
support use of lithium for treatment of
primary alcohol dependence.
Improving the Knowledge Base
Our evidence tables document signifi-
cant variability in trial design.
9
First, the
alcohol outcomes measured in each study
vary substantially. Of the work reviewed,
24 measured number of drinking/non-
drinking days; 22, abstinence; 14, drinks
per unit of time; 13, time to first drink;
12, at least 1 biological measure (eg,
GGTP); and 6, a criteria-based defini-
tion of relapse. Second, the meaning and
use of the term relapse vary consider-
ably. In the naltrexone trials, a relapse is
a bout of heavy use with an a priori defi-
nition, such as consuming at least 5 drinks
per occasion (for men), whereas in the
European acamprosate trials, relapse re-
fers to return to any drinking. Third, the
concept of craving is not often addressed;
of 41 studies reviewed, 17 measured crav-
ing using many different assessment tech-
niques. Fourth, compliance with medi-
cation was irregularly addressed. Fifth, the
type and intensity of psychosocial treat-
ment, as well as compliance with that
treatment, were typically not described.
Moreover, the presence of psychiatric dis-
orders was sometimes not mentioned or,
when acknowledged, was not controlled
for in the analysis. Sixth, external valid-
ity and generalizability are problems be-
cause subjects were commonly recruited
from specialized substance abuse set-
tings; the requirements of many proto-
cols would inevitably produce subject se-
lection bias. In addition, dropout rates
were, with some exceptions, in the 20%
to 50% range and sometimes higher.
The lack of consistency in research
design across these trials is a major is-
sue that prohibits cross-study compari-
sons, and it deterred us from conduct-
ing meta-analyses of the pooled efficacy
data in these studies. These method-
ological problems appear to be improv-
ing, but additional standardization (eg,
uniform definitions, recommended core
outcome measures for clinical trials)
would clearly be an important ad-
vance, to which funding and profes-
sional organizations such as the NIAAA,
the Research Society on Alcoholism,
and the American Society of Addic-
tion Medicine could contribute greatly.
Efficacy and Effectiveness
of These Medications
Efficacy trials examine whether a health
intervention works in an ideal treat-
ment setting; effectiveness studies fo-
cus on the impact of an intervention in
everyday settings. Now that efficacy has
been established for at least some of the
medications reviewed here, effective-
ness issues in primary care settings
should be examined, including:
• Which psychosocial interven-
tions are effective when combined with
medication therapy?
• Do combinations of pharmacologi-
cal treatments have additive benefit with
acceptable adverse effects?
• What is the optimum duration of
medication use (most studies to date have
examined therapy for only 3-6 months)?
The work we reviewed invariably com-
bined medications with some type of
psychosocial intervention. Thus, these
medications have been tested only in
conjunction with psychosocial interven-
tions; their effectiveness used in isola-
tion is unknown. Although 2 medica-
tions, naltrexone and acamprosate, did
bring clinically and statistically signifi-
cant improvement compared with pla-
cebo in drinking outcomes, most sub-
jects did resume drinking during
treatment. Clinicians and researchers re-
main challenged by the problem of al-
cohol dependence; these pharmaceuti-
cal agents are only the beginning of
improved treatment strategies.
CONCLUSION
The pharmacotherapy of alcohol de-
pendence is experiencing a major shift
in direction. Traditional medications
(such as disulfiram) that show limited
efficacy may be used less frequently, al-
though they may still have value. New
medications, including naltrexone and
acamprosate, are likely to be used at in-
creasing rates, although additional clini-
cal experience is needed to ascertain
their range of effectiveness. We herald
the advances in the pharmacotherapy
of alcohol dependence as valuable de-
velopments, but we note that treat-
ment of patients with alcoholism should
continue to incorporate a biopsycho-
social perspective in an effort to change
a life from a pattern of addiction to a
pattern of sobriety and improved physi-
cal, mental, and social health.
Author Affiliations: Departments of Psychiatry (Drs
Garbutt and Crews), Medicine (Dr Carey), and Phar-
macology (Dr Crews) and Bowles Center for Alcohol
Studies (Drs Garbutt and Crews), School of Medi-
cine, and the School of Public Health (Drs West and
Lohr), University of North Carolina at Chapel Hill; and
Research Triangle Institute, Research Triangle Park, NC
(Drs West and Lohr).
Funding/Support: This study was supported by con-
tract 290-97-0011 from the AHCPR.
Alternate Source: An executive summary of this re-
port was posted on the Agency for Health Care Policy
and Research Web site (http://www.ahcpr.gov/clinic/
alcosumm.htm) in January 1999.
Acknowledgment: We acknowledge the assistance of
Jacqueline Besteman, JD, MA, the AHCPR task order
officer for the Evidence-based Practice Program; and
Ernestine Murray, RN, MAS, the AHCPR task order
officer for this project. We appreciate the consider-
able help of the members of the technical expert ad-
visory group: Raymond F. Anton, MD, Center for Drug
and Alcohol Programs, Medical College of South Caro-
lina, Charleston; Raye Z. Litten III, PhD, the Treat-
ment Research Branch of the NIAAA, Rockville, Md;
PHARMACOLOGICAL TREATMENT OF ALCOHOL DEPENDENCE
1324 JAMA, April 14, 1999—Vol 281, No. 14 ©1999 American Medical Association. All rights reserved.
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Michael Mayo-Smith, MD, MPH, Manchester Veter-
ans Affairs Medical Center, Manchester, NH; Charles
P. O’Brien, MD, PhD, the Treatment Research Cen-
ter of the University of Pennsylvania, Philadelphia; Ste-
phanie S. O’Malley, PhD, Division of Substance Abuse
Research, Yale University School of Medicine, New Ha-
ven, Conn; Linda L. Powell, MSW, CCSW, Employee
Assistance Program, Merit Behavioral Care Corp, Ra-
leigh, NC; William F. Renn, CCSW, CSAC, the Behav-
ioral Medicine Center of Cumberland Hospital, Fay-
etteville, NC (now with the Department of Psychiatry,
University of North Carolina at Chapel Hill); and Con-
stance M. Weisner, DrPH, Alcohol Research Group and
the Kaiser Permanente Medical Care Program, Berke-
ley, Calif. We thank the following staff from the Uni-
versity of North Carolina at Chapel Hill: Gordon De-
Friese, PhD, codirector of the Research Triangle
Institute–University of North Carolina at Chapel Hill
Evidence-based Practice Center; Anne Jackman, MA,
project administrator; David Overstreet, PhD; Alexei
Kampov, PhD; Sue Tolleson-Rinehart, PhD; and Lynn
Whitener, DrPH. We also thank the following Re-
search Triangle Institute staff: Linda Lux, MPA, project
administrator; Nancy Berkman, PhD; and Alicia Wil-
son, MS, RPh; as well as Linda Fonville for excellent
secretarial work and Nicole Walker for skilled con-
tract administration assistance.
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