Disulfiram

DISULFIRAM

The registered trademark name for disulfiram is Antabuse—it is the most commonly used medication for the treatment of Alcoholism and the only one of two medications (the other being naltrexone) approved for this use in the United States, as of 2000. It is not intended as a substitute for the counseling alcoholics receive while in treatment; it is meant to be an aid in keeping alcoholics sober, so that they may benefit from counseling. Although disulfiram has been in clinical use since the late 1940s, only since the 1980s has its efficacy been studied by appropriate scientific methodology.

Disulfiram is used to deter drinking by causing an unpleasant reaction if a medicated person drinks Alcohol (ethanol). This reaction is called the disulfiram-ethanol reaction (DER); the symptoms include flushing, dizziness, rapid heartbeat, nausea, vomiting, and headache. The DER is of varying severity, and the degree of severity often depends on the dose of disulfiram being taken plus the amount of alcohol that was consumed. A DER can cause hypotension (low blood pressure) and can be so severe that death occurrs, although with adjusted dosage regimens this is very rare.

Disulfiram blocks the action of several of the body's enzymes, including aldehyde dehydrogenase (ALDH). The inhibition of ALDH is responsible for the DER; this occurs because ethanol (drinking alcohol) is metabolized in the liver to acetaldehyde. Acetaldehyde, in turn, is converted to acetic acid, which is catabolized to water and carbon dioxide.

Aldehyde dehydrogenase is the enzyme that facilitates the catabolism of acetaldehyde to acetate acid. When the action of ALDH is inhibited by disulfiram, acetaldehyde is not converted to acetate but accumulates in the blood. Most of the symptoms of the DER are due to the increased circulating acetaldehyde. Since the inhibition of ALDH by disulfiram is irreversible, a person taking disulfiram cannot stop taking it one day and begin drinking the next—several days (usually 4 to 7) must go by, because this is the amount of time necessary for the body to produce new enzyme.

OTHER MEDICATIONS

Certain other medications cause a mild DER, including such antibiotics as metronidazole (Flagyl). A medication available in Canada but not in the United States is citrated Calcium Carbimide (Temposil), which inhibits ALDH in a mixed reversible-irreversible fashion. When citrated calcium carbimide is discontinued, 80 percent of ALDH activity is restored within 24 hours. Hence, one can drink alcohol as soon as a day after stopping the use of citrated calcium carbimide without having a reaction.

In addition to disulfiram, there are other medications with different mechanisms of action that are now approved for use in helping recovering alcoholics maintain sobriety. The most promising of these newer drugs is naltrexone hydrochloride (ReVia), an opioid agonist that was found in 1992 to reduce the incidence of relapse in alcoholics in outpatient treatment programs. Since approval of the drug by the U.S. Food and Drug Administration (FDA), a number of additional studies of naltrexone have been published. In addition, a large number of studies are underway, with support from the National Institute on Alcohol Abuse & Alcoholism (NIAAA). Although, most studies of naltrexone have shown it to be helpful for relapse prevention, not all studies have been positive.

ADMINISTRATION AND DOSAGE

Disulfiram should be administered only by a physician and is given by mouth in tablet form. It should never be given until the patient has abstained from alcohol for at least 12 hours, and preferably for 48 hours. The dose is usually 250 or 500 milligrams daily. Some patients report not experiencing a DER with smaller doses, so larger doses may be required. Clinical experience indicates, however, that doses larger than 500 milligrams are accompanied by a greater risk of serious side effects. A problem that limits the effectiveness of disulfiram is that patients frequently stop taking the medication. To prevent this, disulfiram tablets sometimes have been implanted just below the skin of the abdominal wall. This technique, however, has been shown to be ineffective (Johnsen et al., 1987) because the absorption of the implanted disulfiram is erratic and poor, resulting in very low blood levels of disulfiram and a weak or no DER.

Patients should take disulfiram only under careful medical and nursing supervision. They should be warned that as long as they are taking the drug, ingesting alcohol in any form will make them sick and may endanger their life. Patients should be taught to recognize and avoid disguised forms of alcohol such as cough syrups, mouthwashes, some sauces, fermented vinegar, and even aftershave lotion or rubbing alcohol. In addition, patients should be taught to recognize the signs of disturbed liver function (jaundiced eyeballs or skin, nausea or pain in the upper right quadrant of the abdomen, dark urine, clay-colored stool) and report them at once to their doctor.

SIDE EFFECTS

The use of disulfiram may be accompanied by side effects. The most common one is drowsiness; for this reason, the medication is usually taken at bedtime. Timing is usually sufficient to take care of this problem, but if not, the medication may have to be discontinued, especially for those who drive or work in hazardous environments. Idiosyncratic liver toxicity can occur from taking disulfiram. For this reason, liver function must be monitored closely during the first several months of treatment, and if blood tests indicate possible liver damage, disulfiram must be discontinued immediately.

A 1986 Swedish study found that disulfiram enhances the absorption and toxicity of lead in rats. Recovering alcoholics who must work in environments containing lead or lead products are advised not to use disulfiram to maintain sobriety.

In addition, serious psychotic reactions and depressive episodes have occurred in patients taking disulfiram. In a multisite study of 605 men, admissions for psychiatric problems were uncommon; as many admissions of this type occurred in men taking the placebo or not receiving disulfiram as in those receiving a 250-milligram dose (Branchey et al., 1987). The risk of serious psychoses or of major affective illnesses occurring appears to be worse with higher doses.

INTERACTIONS WITH OTHER DRUGS

Disulfiram should not be given to patients who are taking metronidazole (Flagyl) or paraldehyde (Paral), as these drugs will produce a DER. Patients taking isoniazid (INH, Laniazid) may develop neurological symptoms if given disulfiram. Lastly, disulfiram may increase the blood levels and toxicity of warfarin (Coumadin), barbiturates, and phenytoin (Dilantin).

(See also: Naltrexone ; Relapse ; Treatment: Alcohol ; Treatment Types: Aversion Therapy )

BIBLIOGRAPHY

Branchey, L., et al. (1987). Psychiatric complications following disulfiram treatment. American Journal of Psychiatry, 144, 1310-1312.

Fuller, R. K., et al. (1986). Disulfiram treatment of alcoholism: A Veterans Administration cooperative study. Journal of the American Medical Association, 256, 1449-1455.

Fuller, R. K., Lee, K. K., & Gordis, E. (1988). Validity of self-report in alcoholism research: Results of a Veterans Administration cooperative study. Alcoholism: Clinical and Experimental Research, 12, 201-205.

Hardman, J.G., & Limbird, L. E. (Eds.) (1996). Goodman and Gilman's the pharmacological basis of therapeutics, 9th ed. New York: McGraw-Hill.

Johnsen, J., et al. (1987). A double-blind placebo controlled study of male alcoholics given a subcutaneous disulfiram implantation. British Journal of Addiction, 82, 607-613.

Wilson, B. A., Shannon, M. T., & Stang, C. L. (Eds.) (1995). Nurses drug guide, 3rd ed. Norwalk, CT: Appleton & Lange.

Richard K. Fuller

Raye Z. Litten

Revised by Rebecca J. Frey