Medication Summary
Treatment of alcohol withdrawal is best accomplished with benzodiazepines. Avoid fixed-dose therapy, and treat patients for symptoms. This results in use of lower doses of benzodiazepines, less patient sedation, and earlier patient discharge. Lorazepam and oxazepam are preferred for patients with significant liver disease because the half-lives of other benzodiazepines can be significantly prolonged. These shorter-acting benzodiazepines require more frequent patient monitoring. Use longer-acting drugs (eg, chlordiazepoxide) when monitoring is not reliable.
Other agents that have been used with some success in the treatment of withdrawal include beta-blockers, clonidine, phenothiazines, and anticonvulsants. All can be used with benzodiazepines, but none has been proven to be adequate as monotherapy. A number of medications have been tried in the treatment of alcoholism. Disulfiram (Antabuse) has been used as an adjunct to counseling and AA with motivated patients to reduce the risk of relapse. Patients are reminded of the risks of adverse effects when tempted to drink. Disulfiram causes nausea, vomiting, and dysphoria with coincident alcohol use. In a large trial, disulfiram did not increase abstinence. If a patient asks for disulfiram and thinks it will help, it might be worth considering.
Naltrexone blocks opiate receptors and works by decreasing the craving for alcohol, resulting in fewer relapses. A recent positron emission tomography study demonstrated that persons with alcoholism have increased opiate receptors in the nucleus accumbens of the brain and that the number of receptors correlates with craving.
Most, but not all, studies found that naltrexone decreases relapses but the effect is modest (12–20%). Combining naltrexone therapy with cognitive behavioral therapy enhanced benefit. One study showed benefit with an intensive primary care intervention. Studies suggest that virtually all placebo patients who sampled alcohol relapsed, while only half the naltrexone patients who sampled alcohol relapsed.
Most studies are of short duration, and more long-term trials are needed. In short-term studies when naltrexone was stopped, patients relapsed. Naltrexone has a greater effect on reducing relapse to heavy drinking than it does on maintaining abstinence. Extended-release intramuscular naltrexone resulted in reduced relapse to heavy drinking in a large, randomized trial. Its effects on complete abstinence were more modest. The main adverse effects are nausea and/or vomiting, abdominal pain, sleepiness, and nasal congestion.
In 2001, Sinclair reviewed 8 studies and suggested that naltrexone is safe to administer in patients who are still drinking and that it will gradually result in the patient consuming less alcohol (this is the case in laboratory animals). [51] Patients should take the naltrexone daily initially and then only when they have a strong urge to drink. Patients should carry naltrexone with them indefinitely. Patients should agree to always take the naltrexone prior to drinking alcohol. Daily naltrexone may be counterproductive in patients who remain abstinent. It is most helpful in those who sample alcohol after stopping (lower chance of a relapse). More data are needed before this approach can be adapted because it challenges the conventional wisdom that complete abstinence is always the goal of treatment.
Nalmefene is another opioid antagonist, and it blocks delta, kappa, and mu receptors; naltrexone acts primarily on mu receptors. One randomized trial with 100 patients using 10 mg PO bid has been completed, and nalmefene appears to have efficacy similar to naltrexone (reduces relapse to heavy drinking in patients who sample alcohol). At present, the drug is approved only for intravenous use for opiate addiction.
The 2010 Cochrane review on opioid antagonists for alcohol dependence included 50 studies with 7793 participants. [52] In most studies, treatment was provided over 3 months. The review showed that more patients who took naltrexone were able to reduce the amount and frequency of drinking compared with patients who took placebo. On average, 1 in 9 patients were helped by naltrexone. For injectable formulations of naltrexone, which can be advantageous for patients who have problems with taking their medication on schedule, and for the second opioid antagonist (nalmefene), the evidence was too limited to allow final conclusions. Nevertheless, available studies indicated that these drugs might have effects on drinking comparable to oral naltrexone.
A number of studies have focused on antidepressants. Early studies with the selective serotonin reuptake inhibitors (SSRIs) have been disappointing. Two fairly good studies used tricyclic antidepressants (ie, desipramine, imipramine), which showed some short-term benefit. More data are needed. SSRIs probably do not benefit patients who are not depressed but might benefit those who are depressed. Topiramate facilitates GABA function and antagonizes glutamate, which should decrease mesocorticolimbic dopamine after alcohol and reduce cravings. One double-blinded trial with 150 subjects for 12 weeks suggests this is the case (decreased drinking, decreased craving, and greater abstinence). Topiramate is not approved for this use by the US Food and Drug Administration.
The largest and longest studies on the treatment of alcohol abuse have been performed in Europe with acamprosate (Campral). At 1 year, the continuous abstinence rates were 18% in the acamprosate group and 7% in the placebo group. At 2 years, the continuous abstinence rates were 12% in the acamprosate group and 5% in the placebo group. Most patients returned to drinking while still using the drug. The drug is approved in the United States. It stimulates GABA transmission, inhibits glutamate, and decreases alcohol consumption in alcohol-dependent rats. The main adverse effect is diarrhea.
Two short-term trials have compared acamprosate and naltrexone. Both found naltrexone to be superior. One of these studies compared the combination with either drug alone and with placebo. The combination was statistically superior to placebo and acamprosate alone and superior (but not statistically) to naltrexone alone. Larger and longer trials of the combination therapy are needed.
Results from a 12-week, randomized, placebo-controlled trial of 150 adults with current alcohol dependence showed that patients treated with the anticonvulsant gabapentin were more likely to stop drinking or at least abstain from heavy drinking than those taking a placebo. In addition, gabapentin significantly reduced cravings, sleeplessness, and depression. [53, 54, 55]
A 2015 study funded by the National Institutes of Health (NIH) found that an antibiotic typically used to treat tuberculosis reduces alcohol cravings and may enhance cue-related extinction therapies in individuals with alcohol use disorders. Results showed that low doses of D-cycloserine (50 mg) significantly reduced alcohol cravings for up to 3 weeks, leading to significant reductions in alcohol consumption. [56, 57]
Glutamate receptor blockers
Class Summary
Mechanism of action is unknown, but it enhances GABA transmission and inhibits glutamate transmission. Compared with placebo, reduces drinking frequency and effectively increases abstinence in patients with alcoholism.
Acamprosate (Campral)
Synthetic compound with a chemical structure similar to that of the endogenous amino acid homotaurine (structural analogue of GABA). Mechanism of action to maintain alcohol abstinence not completely understood. Hypothesized to interact with glutamate and GABA neurotransmitters centrally to restore neuronal excitation and inhibition balance. Not associated with tolerance or dependence development. Use does not eliminate or diminish alcohol withdrawal symptoms. Indicated to maintain alcohol abstinence as part of a comprehensive management program that includes psychosocial support. Available as a 333-mg tab.
Aldehyde dehydrogenase inhibitors
Class Summary
Disulfiram inhibits aldehyde dehydrogenase, and, as a result, acetaldehyde accumulates. This leads to nausea, hypotension, and flushing if a person drinks alcohol while taking disulfiram.
Disulfiram (Antabuse)
Decreases number of drinking days but does not increase abstinence. Directly observed therapy might be more beneficial but has not been studied in a good randomized trial.
Opiate antagonists
Class Summary
Alcohol has been shown to bind to opiate receptors in the brain. Studies show that blocking opiate receptors decreases cravings for alcohol.
Naltrexone (ReVia, Vivitrol)
Patients must be abstinent for 5-7 d before beginning therapy. Monitor liver function during treatment. Expensive, approximately $4.50/pill. Pure antagonist and is not addicting.
IM administration of Vivitrol reduces first-pass hepatic metabolism as compared with oral naltrexone. No significant increase from baseline in mean AST or ALT levels.
Vivitrol does not appear to be a hepatotoxin at recommended doses but patients should be warned of risk of hepatic injury. Preparation is considered nonaddicting.
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Deaths while intoxicated. Data from the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
Tables
Questions |
0 Points |
1 Point |
2 Points |
3 Points |
4 Points |
1. How often do you have a drink containing alcohol? |
Never |
Monthly or less |
2-4 times a month |
2-3 times a week |
4 or more times a week |
2. How many drinks containing alcohol do you have on a typical day when you are drinking? |
1 or 2 |
3 or 4 |
5 or 6 |
7-9 |
10 or more |
3. How often do you have 6 or more drinks on 1 occasion? |
Never |
Less than monthly |
Monthly |
Weekly |
Daily or almost daily |
4. How often during the past year have you found that you were not able to stop drinking once you had started? |
Never |
Less than monthly |
Monthly |
Weekly |
Daily or almost daily |
5. How often during the past year have you failed to do what was normally expected of you because of drinking? |
Never |
Less than monthly |
Monthly |
Weekly |
Daily or almost daily |
6. How often during the past year have you needed a first drink in the morning to get yourself going after a heavy drinking session? |
Never |
Less than monthly |
Monthly |
Weekly |
Daily or almost daily |
7. How often during the past year have you had a feeling of guilt or remorse after drinking? |
Never |
Less than monthly |
Monthly |
Weekly |
Daily or almost daily |
8. How often during the past year have you been unable to remember what happened the night before because you had been drinking? |
Never |
Less than monthly |
Monthly |
Weekly |
Daily or almost daily |
9. Have you or has someone else been injured as a result of your drinking? |
No |
|
Yes, but not in the past year |
|
Yes, during the past year |
10. Has a relative, friend, or a doctor or other health care worker been concerned about your drinking or suggested you cut down? |
No |
|
Yes, but not in the past year |
|
Yes, during the past year |
Biomarker |
Sensitivity (%) |
Specificity (%) |
AST |
15-69 |
47-68 |
ALT |
18-58 |
50-57 |
GGT |
34-85 |
11-95 |
MCV |
34-89 |
26-95 |
CDT |
39-94 |
82-100 |
CDT + GGT |
90 † |
98 |
Alcohol |
0-100 |
0-100 |
EtG |
76-91 |
77-92 |
*Values vary considerably according to gender, age, drinking pattern, prevalence of alcohol abuse/dependence, and prevalence of comorbidity, among other factors. [40, 6, 41, 43, 44] † The sensitivity comes from one study in Finland, which uses a special formula. This study needs to be replicated. [45] |
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