Is there a role for medications in the treatment of Alcohol Dependence?
Vania Modesto, M.D., M.P.H.
A. The major goal of this lecture is to review the literature on the
development of medications as adjunctive agents for the treatment of
B. An optional exercise is to ask:
1. How many of you have treated detoxifying alcoholics?
- How many of you have prescribed a pharmacological agent to help the patient stay sober (after detoxification)?
Point out that question number one is well established, at least for cases of moderate to severe withdrawal.
For the second question, however, pharmacologic Calvinism appears to
prevail—that is, the notion that the only good drug is a dead drug.
C. There are at least three situations in which medications can be used in the treatment of alcohol dependence.1
- The most widely accepted circumstance is in the treatment of alcohol withdrawal.
- The treatment of independent psychiatric conditions that may
co-occur with alcohol dependence (major depression, anxiety disorders,
- The last and perhaps most controversial clinical situation is for
the continued rehabilitation of alcohol dependence. This will be the
topic of this lecture.
II. Medications in Alcohol Dependence Rehabilitation: An Introduction
A. While detoxification is seen as a legitimate period of treatment
in which medication (benzodiazepines) has an established role, there
are few studies relevant to the rehabilitation phase of treatment. In
fact, traditional treatment approaches have been primarily psychosocial
and consist of group counseling and 12-step programs.
- Alcohol is a chronic disorder with high relapse rates.2
- Prevention of relapse to heavy drinking is a major challenge to treatment.
- As a result, there has been increasing interest in the use of
pharmacological agents to improve the efficacy of existing treatments.
B. Several medications are currently being used in alcohol rehabilitation.3
- Renewed interest led to the FDA approval of naltrexone (Trexan or Revia) in 1994 for the treatment of alcohol dependence.
- Disulfiram (Antabuse) sensitizing or deterrent agent, was approved for the treatment of alcoholism nearly 50 years earlier.
- Acamprosate (Campral) has been available by prescription since 1985
in France and more recently in European as well as Latin American
Countries. A multi-center trial evaluating the safety and efficiency of
acamprosate in alcohol dependent outpatients was recently completed in
the United States.
- Nalmefene (Revex), like naltrexone, is an opiate antagonist
currently approved for acute opioid intoxication. It has greater
affinity for kappa and delta receptors than naltrexone, and appears to
be less hepatotoxic than naltrexone.
C. Neurobiology and the development of medications
- In order to understand the mechanism of actions that
reduce alcohol consumption, it is important to understand the actions
of alcohol on specific neurotransmitters and the neurotransmitter
changes that mediate continued alcohol use and the development of
dependence.5 This is explained in more detail in the lecture by Dr. Ramchandani.
- An example occurs with dopamine.6
- At low alcohol doses intoxication is characterized by
pleasurable, stimulating effects. Most individuals also report
reductions in anxiety and tension and a sense of well-being. These
behavioral effects promote drinking and are believed to be mediated in
part through brain dopaminergic systems. (Ventral tegmentun area ® nucleus accumbens)
- With repeated alcohol use, this system may become increasingly
sensitized so that behavioral stimuli associated with alcohol use may
also release dopamine and act as a primer for alcohol consumption.
- The dopamine system is tied to the opioid system.7
- Given the importance of the reinforcing effects of
alcohol to initiate and maintain drinking, a medication that reduces
these effects may decrease alcohol consumption.
- These same systems might be affected by medications that change other neurochemical systems such as serotonin and GABA.
- An alternative approach involves using medications that increase
the aversive effects of alcohol (sedation, nausea, vomiting). This
should also decrease consumption by discouraging alcohol-drinking
III. The Possible Use of Disulfiram
A. Disulfiram is an alcohol-sensitizing agent approved in 1950.
Using alcohol after taking this drug causes unpleasant effects such as
nausea, diarrhea, and changes in blood pressure.
B. How does it work?2
- Disulfiram inhibits aldehyde dehydrogenase (ALDH), the
enzyme that catalyzes the oxidation of acetaldehyde to acetic acid. If
alcohol is ingested after ALDH is inhibited, blood acetaldehyde levels
rise, which produce the DER (Disulfiram-ethanol-reaction).
- The DER is an aversive reaction that varies in intensity both with
the dose of disulfiram and the volume of alcohol consumed – it is the
prospect of such a reaction that is thought to deter drinking.
C. What is Disulfiram’s efficacy?
Although some small-scale studies have shown it to be superior to
placebo, in the largest controlled trial, a multi-center VA study8,
more than 600 alcoholics were randomly assigned to disulfiram (either 1
mg or 25 mg) or a control group. In this study, disulfiram failed to
- The Possible Use of Opioid Antagonists
A. Opioid neurotransmission has been implicated in alcohol consumption. Three lines of evidence support this association.9
- The administration of a mu-opioid agonist increases
alcohol consumption in animals. Also, humans on methadone maintenance
may increase their alcohol consumption.
- While opioid agonists appear to increase ethanol consumption in
animals, opioid antagonists have the opposite effect in several animal
species including alcohol- preferring and non-alcohol-preferring
rodents. So, opiate receptor antagonists generally decrease alcohol
- A third line of evidence is that alcohol dependent people may have low baseline serum b-endorphin levels.
B. The observation that naltrexone decreases drinking in animals led
to studies assessing the effects of naltrexone on human alcohol
1. Naltrexone was approved in the U.S. for the treatment of alcohol
dependence based on the results of 2 controlled trials showing the
medication to be superior to placebo in the prevention of alcoholic
2. A study of 70 alcohol dependent subjects10 in a
veteran population determined that 50 mg per day of naltrexone was an
effective augmentation to an intensive day treatment program in
preventing relapse to heavy drinking. This study revealed that
naltrexone-treated patients had a significant delay in the time
interval between detoxification and first drink consumption when
compared with placebo-treated patients. Naltrexone also slowed the
progression from the first drink to heavy drinking when compared with
3. Although the study by O’Malley et al.11 showed similar
results, they also evaluated the combined effects of naltrexone with
either relapse prevention training or supportive therapy. Thus, this
study was clearly unique in examining not only the pharmacologic, but
also the psychotherapeutic aspects of treatment as well. This study
showed that naltrexone was more efficacious in preventing the
initiation of drinking when paired with supportive therapy. However,
once the subject sampled alcohol, naltrexone plus cognitive behavioral
therapy was better at preventing full-blown relapse.
C. Naltrexone’s most commonly reported side effects are nausea, headache, anxiety, and sedation.10,11
- Individuals taking naltrexone can also be insensitive to
opioid analgesia for up to 72 hours of administration. This effect can
be countered with higher doses of opioids.12
- High doses of naltrexone (300 mg/day) have been associated with
hepatotoxicity, but this is rarely observed with doses of 50 mg per day.13 Nevertheless, naltrexone should be used with extreme caution in persons with hepatitis or severe liver dysfunction.
- Liver function should be monitored prior to naltrexone treatment and periodically during treatment in these patients.
b. This agent should not be administered to patients currently using
opioids or to those who have received opioids within 2 weeks prior, as
it may precipitate opioid withdrawal.
D. How might naltrexone work in alcoholics?
- We have discussed that the stimulant, pleasurable reinforcing
effects of alcohol are mediated through the dopaminergic systems of the
brain. Opiate antagonists appear to block alcohol-induced dopamine
release in the nucleus accumbens, presumably resulting in decreased
pleasure and a decrease in alcohol intake. Indeed, a reduction in the
pleasurable effects of alcohol by opiate antagonists has been observed
in several studies14 including some studies of social drinkers in naturalistic bar settings.15
- Naltrexone may decrease drinking by alleviating
cravings, as has been reported by subjects receiving naltrexone during
placebo-controlled trials.10,11 In fact, in one of those
trials, naltrexone reduced drinking more effectively in patients
reporting the highest levels of craving at study entry.11
- Naltrexone might work by increasing some of the aversive effects of alcohol, such as nausea and vomiting.
- Finally, naltrexone may decrease alcohol consumption by altering neuroendocrine responses to alcohol.6
Ethanol consumption is associated with activation of
hypothalamic-pituitary-adrenal axis and release of ACTH,
beta-endorphins and glucocorticoids. Some of the positive effects of
alcohol are hypothesized to be mediated by this neuroendocrine
E. Some additional issues regarding naltrexone
- Subsequent clinical studies with naltrexone have been mixed, sometimes supporting its effectiveness,16 sometimes not.17
- In another study,18 Volpicelli found that
compliance with naltrexone is variable. Only among highly-compliant
patients was naltrexone significantly better than placebo on a variety
of drinking measures. In the United States, naltrexone has not been
studied in patients who did not receive psychotherapy. So, as of now,
there is no evidence that it is effective as a sole treatment.
- Hence, naltrexone is to be used in the context of a comprehensive
psychosocial program. It is recommended for use in the first 50 days of
- The usual dose is 50mg/day although doses of 25 mg/day to 100 mg/day have been reported to be useful.6
In sum, while some studies of naltrexone are encouraging,
a number of questions remain regarding optimal dosing, treatment
duration, psychosocial therapy interactions and types of patients more
likely to benefit.
- A few studies have examined another opioid antagonist, nalmefene.19,20
- The largest was a 12-week double-blind placebo-controlled trial20
comparing 20 mg and 80 mg/day of nalmefene in 105 alcohol dependent
patients. All groups received CBT. There were no significant
differences on drinking outcomes among the subjects on 20 mg and 80 mg
of nalmefene. There was, however, a significant advantage of nalmefene
over placebo. Significantly fewer patients treated with nalmefene
relapsed to heavy drinking compared to those treated with placebo.
- Nalmefene was relatively well tolerated. Headaches, insomnia and nausea were the most common side effects.
- Perhaps the main advantage of nalmefene over naltrexone is that unlike naltrexone, nalmefene is not hepatotoxic at higher doses.
- The Possible Importance of Serotonin Boosting Drugs
A. The serotonin (5-HT) system also appears to be involved in
the consumption of alcohol. Preclinical studies have considered the
association between drinking behaviors and 5-HT systems in several
- Acute administration of alcohol has been shown to cause
the release of 5-HT in the nucleus accumbens of rodents. Conversely,
chronic administration of alcohol results in decrease release of 5-HT
in the nucleus accubens in rodents.
- Various neuropathologic studies examined the density of 5-HT
receptors and the concentration of 5-HT and its metabolite
5-hydroxyindoleacetic acid (5-HIAA) in various brain regions of
rodents. 5HT and 5HIAA were found to be less concentrated in the
nucleus accumbens in "high level" alcohol-drinking rats compared with
"low-level" alcohol-drinking rats.
- In sum, the majority of basic science research demonstrates an
apparent relationship between abnormal 5-HT neurotransmission and
excessive alcohol consumption.
B. Some human studies also support a relationship between alcohol consumption and a reduction in 5-HT transmission.21
- Reduced levels of 5-HIAA were found in the cerebral spinal fluid of heavy drinkers.
- Reduced levels of 5-HIAA were found in individuals with lack of
impulse control, aggressiveness, and with vulnerability to mood and
anxiety disorders. Perhaps the overlap between these behaviors and
alcohol dependence is mediated by 5-HT dysfunction.
3. The effects of 5-HT pharmacotherapy were assessed in a variety of
drinkers (heavy, alcohol dependent, and comorbidly depressed) in
clinical trials. The Selective Serotonin Reuptake Inhibitors (SSRIs)
[e.g., citalopram (Celexa), fluoxetine (Prozac) and others] were shown
to produce modest reductions in alcohol consumption among heavy social
drinkers. These reductions were observed at higher daily dosages than
antidepressant dosages.22 These promising findings led to the study of SSRIs in alcoholics.
C. There were some positive studies:
- The results of a study23 involving pretreatment of
alcoholics on an inpatient unit who then consumed alcohol showed a
reduction in alcohol consumption. However, the effect was observed for
only a one-week period.
- Another study24 compared the effects of fluoxetine,
acamprosate and placebo in alcoholics with "positive" and "negative"
family histories. Both treatment groups were more effective than
placebo in reducing the number of drinks consumed. The effect of
fluoxetine, however, was significant only in "positive" family history
patients. In contrast, the effect of acamprosate was significant only
in "negative" family history patients.
D. Other studies showed negative results:
- The results of a study by Kranzler et al.25 showed 75%
reductions in drinking in both fluoxetine and control groups receiving
cognitive behavioral therapy (CBT). In this study of 101 alcohol
dependent patients randomized to either 60 mg/day of fluoxetine or
placebo, no advantage of fluoxetine over placebo was observed.
- The study by Kabel and Petty26 also showed no effect of
fluoxetine compared with placebo among severe alcoholics recruited from
an alcohol treatment program at a VA. These negative results have cast
a dimmer light on the idea of treating alcohol dependence with SSRIs.
E. In addition to the SSRIs, other medications
affecting the serotonergic system were also studied. Results were
either negative or mixed.
F. Thus, the effects of serotonergic medications on human drinking
behavior are more limited and the results less consistent than in
- There is no clear answer to the question of whether there is a role
for a serotonergic medication in the treatment of alcohol dependence.
2. Some investigators21 have argued that
results of 5-HT pharmacotherapy have been inconsistent because trials
were conducted in heterogeneous alcoholic populations. Perhaps not all
alcohol dependent individuals have 5-HT abnormalities. Male antisocial
alcoholics (e.g., type 2 or type B) may represent a useful subtype.
- Medications that target the 5-HT system may have the
greatest impact in alcohol-dependent individuals With impairment in
mood and anxiety disorders.
- The Possible Importance of Acamprosate
A. Acamprosate (calcium acetylhomotaurinate) is a synthetic compound
that has a chemical structure similar to that of naturally occurring
amino acid mediators, homotaurine and GABA.27
B. It has been available in France since 1989 and most recently in
most European and Latin American Countries. More than 1.4 million
patients have been treated with acamprosate since it became
C. Fourteen out of 16 controlled clinical trials (4,500 subjects)
conducted across 11 European countries have demonstrated evidence for
acamprosate’s efficacy. These studies have shown that
acamprosate-treated patients had a significantly greater rate of
treatment completion, time to first drink, and abstinence rates than
patients treated with placebo.27
D. Although the precise mechanism of action or cellular target of
acamprosate is unknown, it appears to act primarily by restoring NMDA
receptor tone in the glutamate system, which is deranged during chronic
alcohol consumption. Acamprosate also affects GABA neurotransmission.
It may work by decreasing cravings. 28
- Unlike other medications used in the prevention of relapse to heavy
drinking, acamprosate is primarily excreted by the kidneys and is not
metabolized in the liver to any meaningful extent.28 Since
many alcohol-dependent patients have liver dysfunction, this medication
can be an important addition to the treatment of alcohol dependence.
- No serious adverse effects were reported in double-blind trials.
Main adverse effects were diarrhea (10%), rash, and fluctuations in
libido. These side effects were mild and transient and the percentage
of patients withdrawing from European trials did not differ between
placebo and acamprosate.28
- Unlike naltrexone, acamprosate will not precipitate an acute opioid withdrawal syndrome in patients on opioid agonists.
H. Further studies are needed to identify subgroups of
alcoholics who may be most responsive to acamprosate. This is
underscored by the findings of Gerra et al.24 who found that
acamprosate significantly reduced the number of drinks consumed only in
patients without a family history of alcoholism. Although there is
consistent evidence that acamprosate is efficacious in decreasing the
number of days drinking, its effects are modest.
VII. Some Conclusions
A. Is there a role for the use of medications in the rehabilitation of alcohol dependence?
- Overall, medications have not shown large effects in the prevention of heavy drinking:
- Disulfiram, an alcohol-sensitizing agent, has shown limited efficacy. It may be of value for more motivated patients.
- Naltrexone, an opioid antagonist, has shown mixed results; three
well-conducted trials have supported its efficacy. In contrast, two
others have shown either lack of efficacy or efficacy limited to highly
compliant patients. Initial studies on nalmefene, another opiate
antagonist, appear promising. There is a current US multicenter trial
- There is no clear answer to the question of whether there is a role
for serotonergic medications in the treatment of alcohol dependence.
- Although the results of a US acamprosate multicenter trial are
pending, this medication has the best documented efficacy in the
European literature. Its effects, although consistent, are modest.
- Other unresolved issues:
- There is a need to determine what medications are most effective in various types of alcohol-dependent individuals.
- The optimal dosing, treatment duration, and interactions with
existing psychosocial treatments need to be defined for each medication.
- Pharmacological (e.g., depot formulations) and psychosocial (e.g.,
motivation enhancement) strategies to promote compliance need to be
- As data become available, it is important to educate physicians,
the community, and AA groups to improve the acceptability of
medications to treat alcohol dependence and counteract the historical
sense of pharmacologic Calvinism in this field.
- In sum, although medications to reduce alcohol consumption have not
shown large effects, the FDA approval of naltrexone, along with studies
on acamprosate and nalmefene, suggest growing interest in this field.
This interest is fueled by increasing understanding of neurobiological
mechanisms that maintain alcohol dependence and awareness that
medications can be combined with psychosocial treatments to improve the
treatment outcomes of patients with alcohol dependence.
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- Garbutt JC, West SL, Carey TS, Lohr KN, Crews FT: Pharmacological
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- Le AD, Tomkins DM, Sellers EM: Use of serotonin (5-HT) and
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- Fuller RK, Branchey L, Brightwell DR, et al: Disulfiram treatment
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- Ulm RR, Volpicelli JR, Volpicelli LA: Opiates and alcohol
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- Mason BJ, Ritvo EC, Morgan RO, Salvato FR, et al: A double-blind,
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- Mason BJ, Salvato FR, Williams LD, Ritvo EC, et al: A double-blind,
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- Naranjo CA, Sellers EM: Serononin uptake inhibitors attenuate
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