Alcohol dependence is one of the leading causes of morbidity and mortality in the United States. Approximately 10% of Americans will develop alcoholism at some point in their lives,1 and an estimated 100,000 individuals die each year due to alcohol-related medical complications, automobile accidents, and homicides.2 Alcohol dependence also costs the U.S. billions of dollars annually in health care costs, lost productivity, incarceration, and property destruction.
The search for effective pharmacologic treatments has long been a focus of research. Disulfiram, which causes an aversive reaction when combined with alcohol, was for many years the only medication in use. More recently, the opiate antagonist naltrexone has also been used to treat alcohol-dependent patients.
The homotaurine derivative, acamprosate, has recently shown great promise. Though used widely in Europe,3 it is not approved for use in this country.
This article will therefore focus on disulfiram and naltrexone: their pharmacology, efficacy, side effects, and dosing strategies. We also will present guidelines for discussing each medication with patients and for deciding which, if either, to prescribe.
Differences in pharmacology
Disulfiram Since the serendipitous discovery of its reactive property with alcohol in the 1940s, disulfiram has been used in the pharmacological treatment of alcoholism. The agent disrupts alcohol metabolism by inhibiting the action of aldehyde dehydrogenase, thus blocking the conversion of acetaldehyde to acetate. Accumulation of acetaldehyde, the first metabolite of ethanol, causes numerous unpleasant effects, including flushing, weakness, and nausea.4 In addition to acting on aldehyde dehydrogenase, disulfiram inhibits dopamine-β-hydroxylase.5
Disulfiram is absorbed from the gastrointestinal tract and is rapidly distributed to tissues and organs. It begins to affect alcohol metabolism within 1 to 2 hours, with a peak at 12 hours. It is slowly excreted from the body over the next 2 weeks, although its effects may be lost sooner as the body secretes new enzyme.4
The ethanol-disulfiram reaction is characterized by flushing, throbbing in the head and neck, respiratory difficulty, vomiting, sweating, thirst, weakness, and hypotension ( Table 1). In some cases, the reaction can be fatal.
Naltrexone Following its approval for use in treating opioid dependence in the mid-1980s, the opiate antagonist naltrexone was approved nearly a decade ago for use in treating individuals with alcohol dependence. Research interest in the use of naltrexone for this purpose grew from theories that the endogenous opiate system may be involved in the development of alcohol dependence.6 Two simultaneously published studies in 1992 showed the benefit of naltrexone in alcohol dependence;7-8 this led to its approval by the Food and Drug Administration.
Naltrexone is metabolized to its major metabolite, 6-β-naltrexol, and is then excreted in the urine as both the original compound and this metabolite.9 The half-life of naltrexone in chronic administration is approximately 10 hours; the half-life of 6-β-naltrexol is 12 to 16 hours.
Comparison of efficacy
Disulfiram Results concerning efficacy have been mixed. Initial studies showed promising effects but were limited to anecdotal evidence and case studies. More recent studies have addressed issues relating to proper control groups, compliance, and motivation in evaluating disulfiram’s effect on alcohol consumption. Early studies used placebo groups to control for the effects of counseling or regular medical monitoring. However, no controls were employed to distinguish between the psychological effects of disulfiram (e.g., fear of a reaction) and its pharmacologic effects.
SYMPTOMS OF AN ETHANOL-DISULFIRAM REACTION
|• Flushing||• Sweating|
|• Throbbing in head and neck||• Thirst|
|• Respiratory difficulty||• Weakness|
|• Vomiting||• Hypotension|
|The intensity of the reaction is generally related to the amount of alcohol and disulfiram consumed. Because even small amounts of alcohol may cause a reaction, individuals taking disulfiram should avoid all forms of alcohol, including certain mouthwashes and cough syrups. Patients also should be instructed to read the ingredients of foods and medications they consume.|
|While the recommended daily dose for disulfiram ranges from 125 mg to 500 mg, individuals can vary widely in their reactions. Dosages below 250 mg/d have failed to produce aversive reactions in some individuals who drink alcohol. Dosages of 250 mg/d or higher, however, may cause toxic side effects, including a more severe reaction with alcohol. Clinicians should be aware that in a few patients, the dosage needed to produce an aversive reaction may be higher than the dosage that produces toxicity.4|
|The authors generally prescribe 125 mg/d, which is at the low end of the usual dose range, since the fear of a reaction—not the reaction itself—is the major therapeutic action of disulfiram. Moreover, a lower dosage diminishes (but by no means eliminates) the likelihood of a highly dangerous alcohol-disulfiram reaction.|