Pharmacotherapy Of Alcoholism

Currently, three drugs are approved in the U.S. for treatment of alcoholism: disulfiram (ANTABUSE), naltrexone (revia), and acamprosate. Disulfiram has a long history of use but has fallen into disfavor because of its side effects and problems with patient adherence to therapy. Naltrexone and acamprosate were introduced more recently. The goal of these medications is to assist the patient in maintaining abstinence.


Naltrexone is chemically related to the highly selective opioid-receptor antagonist naloxone (narcan) but has higher oral bioavailability and a longer duration of action. Neither drug has appreciable opioid-receptor agonist effects. These drugs were used initially in the treatment of opioid overdose and dependence because of their ability to antagonize all the actions of opioids (see Chapters 21 and 23). Animal research and clinical experience suggested that naltrexone might reduce alcohol consumption and craving; this was confirmed in clinical trials. There is evidence that naltrexone blocks activation by alcohol of dopaminergic pathways in the brain that are thought to be critical to reward.

Naltrexone helps to maintain abstinence by reducing the urge to drink and increasing control when a "slip" occurs. It is not a "cure" for alcoholism and does not prevent relapse in all patients. Naltrexone works best when used in conjunction with some form of psychosocial therapy, such as cognitive behavioral therapy. It typically is administered after detoxification and given at a dose of 50 mg/day for several months. Adherence to the regimen is important to ensure the therapeutic value of naltrexone and has proven to be a problem for some patients. The most common side effect of naltrexone is nausea, which is more common in women than in men and subsides if the patients abstain from alcohol. When given in excessive doses, naltrexone can cause liver damage. It is contraindicated in patients with liver failure or acute hepatitis and should be used only after careful consideration in patients with active liver disease.

Nalmefene (revex) is another opioid antagonist that appears promising in preliminary clinical tests. It has a number of advantages over naltrexone, including greater oral bioavailability, longer duration of action, and lack of dose-dependent liver toxicity.


Disulfiram (tetraethylthiuram disulfide; ANTABUSE) was taken in the course of an investigation of its potential anthelmintic efficacy by two Danish physicians, who became ill at a cocktail party and were quick to realize that the compound had altered their responses to alcohol. They initiated a series of pharmacological and clinical studies that provided the basis for the use of disulfiram as an adjunct in the treatment of chronic alcoholism. Similar responses to alcohol ingestion are produced by various congeners of disulfiram, namely, cyanamide, the fungus Coprinus atramentarius, the hypoglycemic sulfonylureas, metronidazole, certain cephalosporins, and animal charcoal.

Disulfiram, given alone, is a relatively nontoxic substance, but it inhibits ALDH activity and causes the blood acetaldehyde concentration to rise to 5—10 times above the level achieved when ethanol is given to an individual not pretreated with disulfiram. Acetaldehyde, produced as a result of the oxidation of ethanol by ADH, ordinarily does not accumulate in the body because it is further oxidized almost as soon as it is formed primarily by ALDH. Following the administration of disulfiram, both cytosolic and mitochondrial forms of ALDH are irreversibly inactivated to varying degrees, and the concentration of acetaldehyde rises. It is unlikely that disulfiram itself is responsible for the enzyme inactivation in vivo; several active metabolites of the drug, especially diethylthiomethylcarbamate, behave as suicide-substrate inhibitors of ALDH in vitro. These metabolites reach significant concentrations in plasma following the administration of disulfiram.

The ingestion of alcohol by individuals previously treated with disulfiram gives rise to marked signs and symptoms of acetaldehyde poisoning. Within 5—10 minutes, the face feels hot and soon afterward becomes flushed and scarlet in appearance. As the vasodilation spreads over the whole body, intense throbbing is felt in the head and neck, and a pulsating headache may develop. Respiratory difficulties, nausea, copious vomiting, sweating, thirst, chest pain, considerable hypotension, orthostatic syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion are observed. The facial flush is replaced by pallor, and the blood pressure may fall to shock levels.

Alarming reactions may result from the ingestion of even small amounts of alcohol in persons being treated with disulfiram. The use of disulfiram as a therapeutic agent thus is not without danger, and it should be attempted only under careful medical and nursing supervision. Patients must be warned that as long as they are taking disulfiram, the ingestion of alcohol in any form will make them sick and may endanger their lives. Patients must learn to avoid disguised forms of alcohol, as in sauces, fermented vinegar, cough syrups, and even aftershave lotions and back rubs.

The drug never should be administered until the patient has abstained from alcohol for at least 12 hours. In the initial phase of treatment, a maximal daily dose of500 mg is given for 1—2 weeks. Maintenance dosage then ranges from 125—500 mg daily depending on tolerance to side effects. Unless sedation is prominent, the daily dose should be taken in the morning, the time when the resolve not to drink may be strongest. Sensitization to alcohol may last as long as 14 days after the last ingestion of disulfiram because of the slow rate of restoration of ALDH.

Disulfiram and/or its metabolites can inhibit many enzymes with crucial sulfhydryl groups; thus, disulfiram has a wide spectrum of biological effects. It inhibits hepatic CYPs and thereby interferes with the metabolism of phenytoin, chlordiazepoxide, barbiturates, warfarin, and other drugs.

Disulfiram by itself usually is innocuous, but it may cause acneform eruptions, urticaria, lassitude, tremor, restlessness, headache, dizziness, a garlic-like or metallic taste, and mild GI disturbances. Peripheral neuropathies, psychosis, and ketosis also have been reported.

384 SECTION III Drugs Acting on the Central Nervous System Acamprosate

Acamprosate (N-acetylhomotaurine, calcium salt), an analog of GABA, is used widely in Europe for the treatment of alcoholism and was approved recently for use in the U.S. A number of doubleblind, placebo-controlled studies have demonstrated that acamprosate decreases drinking frequency and reduces relapse drinking in abstinent alcoholics. It acts in a dose-dependent manner (1.3-2 g/day) and appears to have efficacy similar to that of naltrexone. Acamprosate generally is well tolerated, with diarrhea being the main side effect. No abuse liability has been noted. The drug undergoes minimal metabolism in the liver, is excreted primarily by the kidneys, and has an elimination t122 of 18 hours after oral administration. Concomitant use of disulfiram appears to increase the effectiveness of acamprosate, without any adverse drug interactions being noted. The mechanism of action of acamprosate is obscure, although there is some evidence that it modulates the function of NMDA receptors in brain.

Other Agents

Ondansetron, a 5-HT3-receptor antagonist and antiemetic drug (see Chapters 11 and 37), reduces alcohol consumption in laboratory animals and currently is being tested in humans. Preliminary findings suggest that ondansetron is effective in the treatment of early-onset alcoholics, who respond poorly to psychosocial treatment alone, although the drug does not appear to work well in other types of alcoholics. Ondansetron administration lowers the amount of alcohol consumed, particularly by drinkers who consume <10 drinks per day. It also decreases the subjective effects of ethanol on 6 of 10 scales measured, including the desire to drink, while at the same time not having any effect on the pharmacokinetics of ethanol.

Topiramate, a drug used for treating seizure disorders (see Chapter 19), appears useful for treating alcohol dependence. Compared with the placebo group, patients taking topiramate achieved more abstinent days and a lower craving for alcohol. The mechanism of action of topi-ramate is not well understood but is distinct from that of other drugs used for the treatment of dependence (e.g., opioid antagonists), suggesting that it may provide a new and unique approach to pharmacotherapy of alcoholism.

For a complete Bibliographical listing see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., or Goodman & Gilman Online at

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