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
Disulfiram
Disulfiram
Definition
Disulfiram is an aldehyde dehydrogenase inhibitor. It prohibits the activity of aldehyde dehydrogenase, an enzyme found in the liver. In the United States, disulfiram is sold under brand name Antabuse.
Purpose
Disulfiram is used as a conditioning treatment for alcohol dependence. When taken with alcohol, disulfiram causes many unwanted and unpleasant effects, and the fear of these is meant to condition the patient to avoid alcohol.
Description
Two Danish physicians who were investigating disulfiram for its potential benefits to destroy parasitic worms took disulfiram and became sick at a cocktail party. After a series of pharmacological and clinical studies, it was determined that disulfiram interacts with alcohol.
Disulfiram by itself is not toxic. If taken with alcohol, however, it alters certain steps in the breakdown of alcohol. When alcohol is ingested, it is converted first to a chemical called acetaldehyde. Acetaldehyde is further broken down into acetate. In order for acetaldehyde to be broken down into acetate, aldehyde dehydrogenase needs to be active. Disulfiram is an aldehyde dehydrogenase inhibitor. Since disulfiram blocks the activity of aldehyde dehydrogenase, acetaldehyde cannot be broken down and the levels of acetaldehyde become five to ten times higher than the normal levels. This causes uncomfortable effects that encourage the person to avoid alcohol.
Disulfiram comes in a 250- and 500-mg tablet.
Recommended dosage
Disulfiram therapy should be started only after the patient has abstained from alcohol for at least 12 hours. The initial dose may be as high as 500 mg taken once daily. If the medication is sedating, the dose can be administered in the evening. Ideally, though, the daily dose should be taken in the morning—the time the resolve not to drink may be strongest. The initial dosing period can last for one to two weeks.
A maintenance dose can range anywhere from 125-500 mg daily with the average dose being 250 mg daily. Disulfiram therapy should continue until full recovery. This may take months to years, depending upon the patient’s response and motivation to stop using alcohol. The duration of disulfiram’s activity is 14 days after discontinuation, and patients need to avoid alcohol for this period of time.
Precautions
Before beginning therapy, patients should be carefully evaluated for their intellectual capacity to understand the goal of therapy, which can be described as behavioral modification with negative reinforcement. Patients with history of psychosis , severe myocardial disease, and coronary occlusion should not take disulfiram. People with diabetes taking disulfiram are at an increased risk for complications. Severe liver failure has been associated with the use of disulfiram in patients with or without a prior history of liver problems. People with advanced or severe liver disease should not take disulfiram. Disulfiram should never be given to patients who are in a state of alcohol intoxication or without the patient’s knowledge. Those patients with history of seizures , hypothyroidism, or nephritis need to use disulfiram with caution and close monitoring.
Besides avoiding alcohol, patients should also avoid any products containing alcohol. This includes many cold syrups, tonics, and mouthwashes. Patients
KEY TERMS
Coronary occlusion —Blockage of the arteries supplying the blood to the heart.
Hypothyroidism —Thyroid gland that is abnormally low-functioning. A lowered metabolic rate results.
Jaundice —A yellowing of the skin caused by excess bilirubin in the blood; a liver disorder.
MAO inhibitors —A group of antidepressant drugs that decrease the activity of monoamine oxidase, a neurotransmitter found in the brain that affects mood.
Myocardial disease —Disease of the muscular layer of the heart wall.
Nephritis —Inflammation of the kidney.
Psychosis —Severe state that is characterized by loss of contact with reality and deterioration in normal social functioning; examples are schizophrenia and paranoia. Psychosis is usually one feature of an overarching disorder, not a disorder in itself. (Plural: psychoses)
should not even use topical preparations that contain alcohol such as perfume and aftershave lotion.
Side effects
The most common side effect of disulfiram includes drowsiness and fatigue. Many patients experience metallic or garlic-like aftertaste, but most patients develop tolerance to this effect.
In addition, disulfiram is also associated with impotence. This is most common in doses of 500 mg daily. Disulfiram can also cause blurred vision, skin discoloration, inflammation of the skin, increased heart rate, and mental changes.
During the first three months of therapy, patients should have their liver function evaluated. Patients need to be monitored for the signs of jaundice, nausea, vomiting, abdominal pain, light stools, and dark urine as these may be the signs of liver damage due to disulfiram. The signs of alcohol ingestion include flushing, headache, nausea, vomiting and abdominal pain.
Interactions
Disulfiram can make cisapride, benzodiazepines , astemizole, cyclosporine, erythromycin, and cholesterol-lowering drugs called statins more toxic. Disulfiram in combination with isoniazid, monoamine oxidase inhibitors (MAOIs) (such as phenelzide and tranylcypromine ), metronidazole, omeprazole and tricyclic antidepressants may cause adverse central nervous system effects.
In addition, disulfiram may raise the concentrations of the medications theophylline and phenytoin in the body. Disulfiram may put patients on warfarin (a blood-thinning drug) at an increased risk of bleeding. Disulfiram should never be used with tranylcypromine and amprenavir oral solution.
Disulfiram may react even with small amounts of alcohol found in over-the-counter cough and cold preparations and any medication that comes in an elixir form.
Resources
BOOKS
Lacy, Charles. Drug Information Handbook. Hudson, OH: Lexi-Comp, 2002.
Taylor, David, Robert Kerwin, and Carol Paton. The Maudsley 2005-2006 Prescribing Guidelines. New York: Taylor and Francis, 2005.
PERIODICALS
Berglund, Mats. “A Better Widget? Three Lessons for Improving Addiction Treatment from a Meta-Analytical Study.” Addiction 100.6 (June 2005): 742–50.
Boothby, Lisa, A., and Paul L. Doering. “Acamprosate for the Treatment of Alcohol Dependence.” Clinical Therapeutics: The International Peer-Reviewed Journal of Drug Therapy 27.6 (June 2005): 695–714.
Buonopane, Alessandra, and Ismene L. Petrakis. “Pharmacotherapy of Alcohol Use Disorders.” Substance Use and Misuse 40.13-14 (2005): 2001–20.
Krampe, Henning, and others. “Follow-Up of 180 Alcoholic Patients for Up to 7 Years After Outpatient Treatment: Impact of Alcohol Deterrents on Outcome.” Alcoholism: Clinical and Experimental Research 30 (1) (Jan. 2006): 86–95.
Kulig, Clark C., and Thomas P. Beresford. “Hepatitis C in Alcohol Dependence: Drinking Versus Disulfiram.” Journal of Addictive Diseases 24.2 (2005): 77–89.
Nava, Felice, Stefania Premi, Ezio Manzato, and Alfio Lucchini. “Comparing Treatments of Alcoholism on Craving and Biochemical Measures of Alcohol Consumptions.” Journal of Psychoactive Drugs 38.3 (Sept. 2006): 211–17.
Petrakis, Ismene L., and others. “Naltrexone and Disulfiram in Patients with Alcohol Dependence and Comorbid Psychiatric Disorders.” Biological Psychiatry 57.10 (May 2005): 1128–37.
Sofuoglu, Mehmet, and Thomas R. Kosten. “Novel Approaches to the Treatment of Cocaine Addiction.” CNS Drugs 19.1 (2005): 13–25.
Suh, Jesse J., Helen M. Pettinati, Kyle M. Kampman, and Charles P. O’Brien. “The Status of Disulfiram: A Half of a Century Later.” Journal of Clinical Psychopharmacology 26.3 (June 2006): 290–302.
OTHER
Wyeth-Ayerst Laboratories Staff. “Product Information: Antabuse, Disulfiram Tablets.” Philadelphia: Wyeth-Ayerst Laboratories, 2000.
Ajna Hamidovic, Pharm.D.
Ruth A. Wienclaw, PhD
Disulfiram
Disulfiram
Definition
Disulfiram is an aldehyde dehydrogenase inhibitor. It prohibits the activity of aldehyde dehydrogenase, an enzyme found in the liver. In the United States, disulfiram is sold under brand name Antabuse.
Purpose
Disulfiram is used as a conditioning treatment for alcohol dependence. When taken with alcohol, disulfiram causes many unwanted and unpleasant effects, and the fear of these is meant to condition the patient to avoid alcohol.
Description
Two Danish physicians who were investigating disulfiram for its potential benefits to destroy parasitic worms took disulfiram and became sick at a cocktail party. After a series of pharmacological and clinical studies, it was determined that disulfiram interacts with alcohol.
Disulfiram by itself is not toxic. If taken with alcohol, however, it alters certain steps in the breakdown of alcohol. When alcohol is ingested, it is converted first to a chemical called acetaldehyde. Acetaldehyde is further broken down into acetate. In order for acetaldehyde to be broken down into acetate, aldehyde dehydrogenase needs to be active. Disulfiram is an aldehyde dehydrogenase inhibitor. Since disulfiram blocks the activity of aldehyde dehydrogenase, acetaldehyde cannot be broken down and the levels of acetaldehyde become five to ten times higher than the normal levels. This causes uncomfortable effects that encourage the person to avoid alcohol.
Disulfiram comes in a 250- and 500-mg tablet.
Recommended dosage
Disulfiram therapy should be started only after the patient has abstained from alcohol for at least 12 hours. The initial dose may be as high as 500 mg taken once daily. If the medication is sedating, the dose can be administered in the evening. Ideally, though, the daily dose should be taken in the morning—the time the resolve not to drink may be strongest. The initial dosing period can last for one to two weeks.
Maintenance dose can range anywhere from 125–500 mg daily with the average dose being 250 mg daily. Disulfiram therapy should continue until full recovery. This may take months to years, depending upon patient's response and motivation to stop using alcohol. The duration of disulfiram's activity is 14 days after discontinuation, and patients need to avoid alcohol for this period of time.
Precautions
Before beginning therapy, patients should be carefully evaluated for their intellectual capacity to understand the goal of therapy, behavioral modification with negative reinforcement . Patients with history of psychosis , severe myocardial disease, and coronary occlusion should not take disulfiram. People with diabetes taking disulfiram are at an increased risk for complications. Severe liver failure has been associated with the use of disulfiram in patients with or without a prior history of liver problems. People with advanced or severe liver disease should not take disulfiram. Disulfiram should never be given to patients who are in a state of alcohol intoxication or without the patient's knowledge. Those patients with history of seizures , hypothyroidism, or nephritis need to use disulfiram with caution and close monitoring.
Besides avoiding alcohol, patients should also avoid any products containing alcohol. This includes many cold syrups, tonics, and mouthwashes. Patients should not even use topical preparations that contain alcohol such as perfume and after-shave lotion.
Side effects
The most common side effect of disulfiram includes drowsiness and fatigue . Many patients experience metallic or garlic-like aftertaste, but most patients develop tolerance to this effect.
In addition, disulfiram is also associated with impotence. This is most common in doses of 500 mg daily. Disulfiram can also cause blurred vision, skin discoloration, inflammation of the skin, increased heart rate, and mental changes.
During the first three months of therapy, patients should have their liver function evaluated. Patients need to be monitored for the signs of jaundice, nausea, vomiting, abdominal pain, light stools and dark urine as these may be the signs of liver damage due to disulfiram. The signs of alcohol ingestion include flushing, headache, nausea, vomiting and abdominal pain.
Interactions
Disulfiram can make cisapride, benzodiazepines, astemizole, cyclosporine, erythromycin, and cholesterol-lowering drugs called statins more toxic. Disulfiram in combination with isoniazid, MAO inhibitors (such as phenelzide and tranylcypromine ), metronidazole, omeprazole and tricyclic antidepressants may cause adverse central nervous system effects.
In addition, disulfiram may raise the concentrations of the medications theophylline and phenytoin in the body. Disulfiram may put patients on warfarin (a blood-thinning drug) at an increased risk of bleeding. Disulfiram should never be used with tranylcypromine and amprenavir oral solution.
Disulfiram may react even with small amounts of alcohol found in over-the-counter cough and cold preparations and any medication that comes in an elixir form.
Resources
BOOKS
Gilman, Alfred G. The Pharmacological Basis of Therapeutics. New York, NY: McGraw-Hill, 1996.
Kay, Jerald. Psychiatry:Behavioral Science and Clinical Essentials. Philadelphia: W. B. Saunders Company, 2000.
Lacy, Charles. Drug Information Handbook. Hudson, OH: Lexi-Comp, Inc., 2002.
Wyeth-Ayerst Laboratories Staff. Product Information: Antabuse, disulfiram tablets. Philadelphia, PA: Wyeth-Ayerst Laboratories, 2000.
Ajna Hamidovic, Pharm.D.