JOHN B. STANDRIDGE, MD, Associate Professor, Department of Family Medicine, University of Tennessee Health Science Center College of Medicine, Chattanooga
Unit, Chattanooga.
GINA M. DeFRANCO, DO, Instructor, Department of Family Medicine, University of Tennessee Health Science Center College of Medicine, Chattanooga
Unit, Chattanooga.
Despite the widely recognized and significant health consequences of alcohol dependence, few medical treatments have been
available to physicians to help patients combat this devastating problem. During the past decade, however, new developments
in our understanding of the dopamine, opiate, serotonin, gamma-aminobutyric acid (GABA), and glutamate neurotransmitter systems
in the pathophysiology of alcohol dependence and withdrawal and in subtypes of alcoholism has led to the use of novel drug
treatments for alcoholism. This article reviews the medications used to treat alcohol dependence and how these drugs, including
naltrexone (ReVia), acamprosate (Campral), topiramate (Topamax),* and other anticonvulsants, fit into treatment plans for
alcohol withdrawal and protracted abstinence syndromes.
*Unlabeled use.
Defining problem drinking
The disease of addiction is a compulsive destructive behavior that is remarkable for continued use of a substance despite
its adverse consequences. Alcohol abuse is a pattern of excessive drinking for at least 12 months that is associated with
biological, psychological, and/or social problems. Alcohol dependence is a pattern of alcohol abuse and a preoccupation with
drinking, loss of control of drinking, drinking despite knowledge of its adverse effects, and previous unsuccessful attempts
to quit drinking.
Alcohol is the most frequently abused drug in the United States, and those 18 to 25 years old have the highest rates of binge
(41.6%) and heavy (15.6%) drinking. Alcoholism is more than twice as prevalent in men as in women, with a lifetime prevalence
of 20% in men and 8% in women.1
Neurobiology of addiction
Our understanding of the neurobiology of addiction has increased dramatically in recent decades, and we now know that drugs
of abuse have some common cellular and anatomic pathways. Neurons, such as corticomesolimbic dopaminergic neurons, interact
with other neurotransmitters that adjust the effects of dopamine in the nucleus accumbens and other structures of the brain
and nervous system. These medial forebrain bundle reward pathways constitute a powerful and primitive reinforcement mechanism
directed at behaviors that are not subject to control by the neocortex.2 It is this neurocircuitry that is "highjacked" and corrupted by the disease of addiction.
Extended or repeated drug use changes the brain, especially the reward circuitry, in fundamental and lasting ways. Among these
neuroadaptive changes are the amount of neurotransmitter released, the number of receptors activated, the number of transporters
that deactivate the neurotransmitter, a change in the intracellular transduction machinery, changes in structural proteins
that affect the morphology of brain cells, and changes in transcription factors regulating gene expression.2,3
Pharmacotherapy in detoxification
Detoxification does not treat the alcohol dependence but is often necessary before a patient can enter an alcohol rehabilitation
program or a program such as Alcoholics Anonymous. The twin goals of pharmacotherapy in detoxification are to control the
symptoms of alcohol withdrawal (tremor, nausea, sweating, agitation, pruritus, and hallucinations) and to prevent the associated
seizures and delirium. Pharmacotherapies described here can be used in both outpatient and inpatient settings. (Note that
thiamine supplementation is warranted to prevent Wernicke's encephalopathy in alcoholic patients who are malnourished.)
Table 1 Suggested alcohol detoxification regimen using CIWA-Ar scores
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Long-acting benzodiazepines, such as chlordiazepoxide (Librium) and diazepam (Diazepam Intensol, Valium), are the preferred
agents during detoxification, owing to their efficacy at preventing the seizures and delirium associated with alcohol withdrawal,
but they must be given in sufficient doses (see Table 1 for a sample regimen). The Clinical Institute Withdrawal Assessment
of Alcohol Scale, Revised (CIWA-Ar) is a useful tool in determining the patient's status and dosing schedule with a long-acting
benzodiazepine. Short-acting benzodiazepines without active metabolites, such as oxazepam (Serax) or lorazepam (Ativan), are
acceptable alternatives in the elderly or in patients with advanced liver disease.*,4 Nonbenzodiazepine anticonvulsants such as carbamazepine, valproic acid (Depacon, Depakene, Depakote), gabapentin (Gabarone,
Neurontin), and topiramate have also been used in detoxification.*,5,6*Unlabeled use.
Mood-altering drugs or other controlled substances—particularly benzodiazepines—should not be prescribed to recovering alcoholics
once abstinence is achieved. Patients who require an opiate for acute pain should be closely monitored until the drug is successfully
discontinued.
Pharmacotherapy to maintain abstinence
Table 2 Pharmacotherapy for alcoholism
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The 3 drugs approved by the FDA for use in maintaining abstinence from alcohol are naltrexone, acamprosate, and disulfiram
(Antabuse), although the latter is rarely used today (see Table 2).7-9 The drugs act differently in the brain, and their clinical profiles are different—acamprosate appears to be particularly
useful in achieving abstinence, and naltrexone seems more useful when used in patients who are participating in programs designed
to limit consumption. Both naltrexone and acamprosate are safe and usually well tolerated, but patient adherence is a factor
in their usefulness in clinical practice.10 Naltrexone
is a relatively selective competitive antagonist at opioid receptors, and this receptor blocker activity may explain
its antirelapse action. Naltrexone is thought to inhibit the reinforcing effects of alcohol because endogenous opioids are
involved in the positive reinforcing effects of alcohol.7 The drug is further believed to inhibit the craving for alcohol because these same transmitters are involved in the conditioned
anticipation of these effects.9
When combined with substance abuse counseling, naltrexone significantly decreases heavy drinking by patients who adhere to
the regimen.9 Although naltrexone contributes little toward abstinence, the intensity and frequency of any drinking that does occur is
diminished. Patients who are more likely to benefit from naltrexone are those with a strong alcohol craving, with a family
history of alcoholism, or with limited cognitive function. The difficulty with naltrexone is that many alcohol-dependent patients
resist its use, and many who do start the drug discontinue it because of the perception that the mechanism of opioid receptor
blockade also diminishes endorphin-mediated pleasure. Physicians can increase the likelihood of adherence by helping patients
to manage adverse effects and by bolstering patients' beliefs in the benefits of naltrexone. Initiate oral naltrexone therapy
with a 25-mg test dose and, if no withdrawal from opiates occurs, repeat the dose in 1 hour. The FDA-approved dosage is 50
mg/d or 100 mg/q2d, although some patients—especially those with lower blood concentrations of the drug—may benefit from a
higher dosage.11 Higher dosages are more likely to cause liver toxicity, and the potential for hepatotoxicity warrants liver function monitoring.
Naltrexone should not be used in patients with peripheral neuropathy, epilepsy, or cirrhosis.
Because adherence to a daily oral regimen of naltrexone is often poor, a long-acting IM formulation of naltrexone is undergoing
late-stage review by the FDA and is expected to be available for use in 2006. Results of a 6-month, randomized, double-blind,
placebo-controlled trial of monthly injections of 380 mg of long-acting naltrexone appeared to reduce the event rate of heavy
drinking days by 25%, and monthly injections of naltrexone, 190 mg, resulted in a 17% decrease. Discontinuation due to adverse
events occurred in 14.1% in the 380-mg group, 6.7% in the 190-mg group, and 6.7% in the placebo group.12
Acamprosate
is associated with both a significant improvement in abstinence rate and days of cumulative abstinence and is better
tolerated than naltrexone.10,13 Abstinence rates of patients taking acamprosate are 18% to 61%, compared with 4% to 45% with placebo.14 Acamprosate is similar to naltrexone as monotherapy, although some evidence indicates that the combination of acamprosate
with naltrexone or disulfiram leads to better outcomes.15
The drug seems to inhibit the glutamatergic transmitter system involved in both the negative reinforcing effects of alcohol
and the conditioned so-called pseudowithdrawal that appears to be important in cue-induced relapse.8,9 Acamprosate is thought to affect GABA and glutaminergic receptors in the nucleus accumbens, a brain region responsible for
the reinforcing effects of alcohol. Acamprosate may also suppress neuropathologic mechanisms that result from chronic alcohol
exposure.15 The drug is not substantially metabolized by the liver and can be used in patients with liver disease. Diarrhea is the
most commonly reported adverse effect and is generally dose related and transient.
Acamprosate may help prevent relapse by reducing both cravings and the pleasurable effects of alcohol ingestion. Because relapses
while taking acamprosate appear to be shorter and less severe, a patient should be advised to continue the medication even
during a relapse. Acamprosate may also be an option for recovering alcoholics for whom naltrexone is ineffective in decreasing
relapse or for those who can not tolerate naltrexone's side effects.
Disulfiram
is an aversive agent that inhibits the metabolism of acetaldehyde, the primary metabolite of ethanol. High levels of
acetaldehyde can cause nausea, vomiting, diarrhea, facial flushing, tachycardia, and, rarely, death. Disulfiram is no longer
commonly used or recommended by addiction medicine specialists due to its punitive effects, potential for harm, and lack of
demonstrated efficacy in preventing relapse.
Topiramate
is not FDA approved in alcohol treatment, but dosages up to 300 mg/d have been shown superior to placebo at improving abstinence
rates and decreasing alcohol seeking.16 Topiramate principally potentiates inhibitory GABA(A) receptor-mediated input and antagonizes excitatory glutamatergic afferents
to the corticomesolimbic dopaminergic system. The drug appears to improve quality of life and reduce the severity of dependence.16
Combination therapy
may offer an advantage for some patients, and the safety of acamprosate and naltrexone in combination has been supported
by 2 independent double-blind studies.13 An increase in acamprosate plasma levels with no clinically significant elevation in adverse events may be seen when the
2 drugs are used in combination, and dose-response studies for acamprosate alone suggest that adding naltrexone may have clinical
benefits.17 In 3 strains of alcohol-preferring rats, low doses of either naltrexone, fluoxetine (a thyrotropin-releasing hormone analog),
a mixture of all 3 drugs, or placebo were administered. The combination of the 3 drugs significantly reduced alcohol intake
in all 3 strains but had no effect on food intake. These findings show that a combination treatment designed to target simultaneously
serotonergic, dopaminergic, and opioidergic systems can reduce alcohol intake, even though the relatively low doses of the
individual drugs are ineffective when given as monotherapy.18 Combination therapies are useful in many complex chronic illnesses, and perhaps clinicians will one day have effective
combination therapy that targets the dysfunctional neurocircuitry associated with alcohol dependence.
Anticonvulsants
may prevent alcohol relapse. Even though there is growing evidence in the literature that supports the effectiveness of anticonvulsants
such as carbamazepine, valproic acid, gabapentin, and topiramate in preventing alcohol relapse, none of these drugs has been
granted FDA approval for this use.5 Both ondansetron (Zofran) and sertraline (Zoloft) appear to have some efficacy in treating subgroups of alcoholic patients.*
Ondansetron is an effective treatment for patients with early-onset alcoholism (so-called type B), while sertraline is an
effective treatment for patients with less severe alcohol dependence and co-occurring early-onset posttraumatic stress disorder.
*Unlabeled use.
Under study and on the horizon
The relative lack of success of the available pharmacotherapies for alcohol dependence has spurred research into other areas
of addiction. Some of this research has found that ethanol increases the release of the endogenous cannabinoid ligands, potentially
downregulating the cannabinoid CB1 receptor.19,20
Evidence suggests that the activation of cannabinoid receptors stimulates the release of opioid peptides, presumably altering
opioid peptide release and reducing ethanol consumption. There are several mechanisms by which the cannabinoid receptor antagonists
are thought to work. One mechanism involves the blockade of CB1 receptors, thus modulating the opioid release triggered by
alcohol intake. Another has the cannabinoid receptor antagonists reducing the ethanol-induced increase in mesencephalic dopamine
neurons—or blocking the disinhibition of GABAergic neurons—that results in the activation of dopamine neurons.
Results of trials using animal models conflict; one study in rats describes increased alcohol consumptive behavior with a
high dose of the CB1-receptor antagonist and equivocal response with a low dose, while other studies report a decrease in
the propensity for rats to freely consume alcohol while taking the CB1-receptor antagonist.21,22 Other researchers found selectively reduced beer craving in rats using a combination of the cannabinoid receptor antagonist
SR141716A and the opioid receptor antagonist naltrexone.23 Research continues into the plausibility of using cannabinoid receptor antagonists alone and in concert with other treatments
for alcohol dependence and for determining which populations would benefit from this therapy.
In addition to sertraline and ondansetron, topiramate is under investigation for use in the treatment of alcoholism. This
anticonvulsant has been shown more effective than placebo at reducing alcohol consumption and promoting abstinence in alcohol-dependent
patients.24,25 Other drugs such as tiapride (Tiapridex) and calcium carbimide (Temposil), which are not available in the United States,
have shown some promise as adjuvant treatment.25
This article was contributed by Drs Standridge and DeFranco and edited by Julia M. Russell.
Dr Standridge discloses that he is a member of the speakers program for Forest Laboratories.
Dr DeFranco discloses that she has no financial relationship with any manufacturer in this area of medicine.
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A snapshot of complementary treatments
Several herbal therapies have been suggested for the treatment of alcohol dependence, including the isoflavone derivatives
of kudzu root, St John's wort (Hypericum perforatum), and ibogaine, a root-derived alkaloid. Among the few formal randomized trials in human subjects, some results are more
promising than others. Currently, the most published data is available on the derivatives of kudzu root and St John's wort.
Chinese medical texts dating to AD 600 describe the use of kudzu, a vine used to control soil erosion. Kudzu contains isoflavones
that have been shown in animal studies to decrease the total consumption of alcohol, although results in human subjects are
lacking. An initial study of kudzu root in a population of military veterans showed no significant difference in alcohol craving
reduction or sobriety promotion when compared with placebo.1 A recent placebo-controlled trial of kudzu root showed significant decrease in number of beers consumed, a parallel increase
in number of sips taken, and an increase in time to consume each beer. There was no change in the desire to drink alcohol
in the kudzu group. Thus, it may be possible that kudzu root derivatives do not decrease the desire to drink alcohol but slow
down the consumption process.2
Studies in alcohol-preferring rats have suggested that St John's wort is effective in decreasing alcohol consumption both
acutely and chronically. Ibogaine, an alkaloid compound purified from the root bark of the African shrub Tabernanthe iboga, has been studied for its effects as an N-methyl-D-aspartate (NMDA) antagonist in opioid and methamphetamine addiction. A study of the acute effects of H perforatum derivatives and the kudzu root derivatives and ibogaine in alcohol-preferring rats showed a dose-dependent reduction in alcohol
intake, with no effect on food or water intake. Although anecdotal reports and recent studies suggest that ibogaine reverses
behaviors associated with addiction by alleviating withdrawal and reducing cravings, the neurotoxic side effects of ibogaine—cerebellar
degeneration and tremors—prohibit its clinical use. Researchers using intracerebral administration of ibogaine in rat subjects
report upregulation of the expression of glial-derived neurotrophic factor (GDNF) in the ventral tegmental area. This increase
in GDNF is believed to mediate the decrease in alcohol self-administration, a mechanism that suggests a new direction for
the pharmacologic treatment of alcohol addiction.3
1. Shebek J, Rindone JP. A pilot study exploring the effect of kudzu root on the drinking habits of patients with chronic
alcoholism. J Altern Complement Med. 2000;6:45-48.
2. Lukas SE, Penetar D, Berko J, et al. An extract of the Chinese herbal root kudzu reduces alcohol drinking by heavy drinkers
in a naturalistic setting. Alcohol Clin Exp Res. 2005;29:756-762.
3. He DY, McGough NN, Ravindranathan A, et al. Glial cell line-derived neurotrophic factor mediates the desirable actions
of the anti-addiction drug ibogaine against alcohol consumption. J Neurosci. 2005;25:619-628.
Drugs mentioned in this article
Acamprosate (Campral)
Calcium carbimide (Temposil)*
Carbamazepine
Chlordiazepoxide (Librium)
Diazepam (Diazepam Intensol, Valium)
Disulfiram (Antabuse)
Fluoxetine (Prozac, Sarafem Pulvules)
Folic acid (Folvite)
Gabapentin (Gabarone, Neurontin)
Lorazepam (Ativan)
Naltrexone (ReVia)
Ondansetron (Zofran)
Oxazepam (Serax)
Sertraline (Zoloft)
Thiamine
Tiapride (Tiapridex)*
Topiramate (Topamax)
Valproic acid (Depacon, Depakene, Depakote)
*Unavailable in the United States.
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