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Does Disulfiram Have a Role in Alcoholism Treatment Today?

by Richard K. Fuller & Enoch Gordis; Addiction; 99(1); 21-24; 2004.
Originally posted: 1/6/2005; [www.doctordeluca.com/Library/AddictionMeds/DisulfiramRoleInRxToday04.htm].
 
See also:
Commentaries about the above article regarding safety and psychological aspects of disulfiram therapy, from the same issue of Addiction, and a response by Fuller & Gordis:
 
 Commentaries (PDF); Addiction; 99(1); 25-28; 2004.
 

[PDF printer format]

FOR DEBATE - Does disulfiram have a role in alcoholism treatment today?

It is almost 60 years since disulfiram was introduced for the treatment of alcohol dependence. With the advent of newer medications which act directly on the biological processes influencing the addiction to alcohol, does a medication that acts indirectly to deter drinking have a role in contemporary alcoholism treatment? The decision to use any medication requires weighing the efficacy and toxicity of the drug. Both research studies and clinical experience during the past 55 years have given us valuable information about the efficacy and safety of disulfiram.

EFFICACY
Early clinical studies of disulfiram have, for the most part, reported excellent results. However, most of these studies had several serious study design flaws including lack of control groups and blinding. Almost 40 years elapsed from the time disulfiram became available before a multi-site randomized clinical trial of 605 participants meeting modern standards of clinical trial design was published (Fuller et al.1986). This study found that disulfiram did not result in more total abstinence, but there were fewer drinking days among a subset of men who received disulfiram and were slightly older and had more residential stability than the study participants as a whole. This study showed that disulfiram prescribed for patients to take at their discretion has limited effectiveness.

A major reason that disulfiram is ineffective is that compliance with the disulfiram regimen is poor when patients are given it to take on their own. This was the method of administration used in the multi-site study because that was common practice at the time. The study documented that compliance with unmonitored disulfiram was generally poor. The multi-site study was criticized on the grounds that it was known that adherence to disulfiram was poor if patients were allowed to take it at their discretion, and that the appropriate form of administration was for either the clinic staff or relatives to observe the ingestion of disulfiram (Brewer 1987). However, the evidence at that time that supervised administration of disulfiram was effective was based on observational studies, often of small sample size, and small sample randomized studies. In 1992 a randomized clinical trial (Chick et al. 1992) of 126 participants attending an alcohol dependence treatment clinic compared the supervised administration of 200 mg disulfiram to the supervised administration of 100 mg of vitamin C and found significantly less drinking with disulfiram. Recent reviews of disulfiram treatment (Hughes & Cook 1997; Anton 2001) have concluded that unsupervised disulfiram administration is of limited utility but endorse supervised disulfiram.

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DOSAGE
It has been argued that in addition to poor compliance, disulfiram is not effective because the currently used dose of 250 mg is not sufficient to cause a disulfiram-ethanol reaction in many patients (Brewer 1984). During the 60 years that disulfiram has been used, both clinical experience and research have provided information about the appropriate dose. When disulfiram was first used, higher doses (1000-3000 mg daily) were employed. Clinical practice has indicated that there is considerably less toxicity and little attenuation of the disulfiram-ethanol reaction (DER) with the 250 mg dose. At the 1-3-g doses deaths from the DER were reported. Deaths appear to be much more rare with the current dose. Toxicities such as psychotic reactions and neuropathy also appear to be dose-related. Brewer (1984) reported that 250-500-mg doses are insufficient to cause a DER in some patients. However, a dose-response study conducted in 52 healthy non-alcoholic volunteers showed that 200 mg or less of disulfiram and 0.15 g ethanol/kg body weight resulted in a fall of the diastolic blood pressure of 20 or more mmHg in 31 of the volunteers and an increase in the heart rate of 20 or more beats per minute in 40 of the volunteers (Christensen et al. 1991). Taking all their data into consideration, these authors concluded that the appropriate dose for half the subjects was 200 mg and for the other half was 300 mg. They stated that they could not recommend more than 300 mg because of the circulatory changes. The task for the practitioner is to balance a dose sufficient to cause a DER without unduly increasing the risk of toxicity. Weighing these factors, it is reasonable to begin with the 250 mg dose. If the patient drinks and does not experience a DER, the dose can be increased to 500 mg.

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SIDE EFFECTS AND ADVERSE REACTIONS
Side effects and possible adverse reactions should not be a barrier to its use. Two placebo-controlled studies have not found a greater incidence of side effects with disulfiram except for drowsiness (Christensen et al. 1984; Fuller et al. 1986). Drowsiness is usually of short duration. If it persists, it usually can be managed by having the patient take the dose in the evening. Poulsen et al. (1992) analyzed adverse drug reaction (ADR) reports submitted to the Danish Committee on Adverse Drug Reactions during a 22-year period. During this period (1968-90) 155 ADRs were reported. Hepatic was the most frequent (34%) followed by neurological (21%), cutaneous (15%), psychiatric (4%) and other (26%). This report does not state explicitly what doses were implicated in the adverse reactions. They estimate the rate to be one ADR per 200-2000 patients per year which they conclude is an intermediate rate of ADRs for a medication.

A concern is the rare and idiosyncratic but potentially fatal hepatotoxicity that can occur with disulfiram. In the Danish study 14 deaths were reported, 11 of which were due to liver failure. The authors estimate the rate of fatal disulfiram-induced hepatitis is 1 per 25 000 patients treated/year. The peak of hepatotoxicity, non-fatal or fatal, occurred at 60 days after beginning treatment. Because hepatotoxicity is usually reversible if disulfiram is stopped before clinically evident liver disease is present, Wright et al. (1988) recommend liver function tests to be obtained before treatment, at 2-week intervals for 2 months and 3-6-month intervals thereafter. Chick (1999), in his recent review of the safety of disulfiram, states that onset of hepatitis is usually very rapid and that frequent testing may not detect it. He recommends informing the patient, the patient's relatives and family physician of the risk and emphasizes that jaundice is usually preceded by fever and that the drug be stopped if adverse effects are noted. The prudent approach is to both inform the patient of the symptoms and signs of hepatotoxicity and also do frequent testing in the early months of treatment. The authors of a study which prescribed disulfiram to patients with modest elevations of transaminases (Saxon et al. 1998) concluded that this was feasible provided that frequent monitoring of the liver tests was performed. Nevertheless, a marked increase occurred much more frequently in those who had elevated transaminases than in those with normal values. Because of the seriousness of disulfiram hepatoxicity we recommend not prescribing disulfiram to those with abnormal liver tests.

Disulfiram should not be given to those with cardiovascular or cerebrovascular disease because hypotension can occur during the DER. Pregnant women should not be prescribed disulfiram because it has been reported to cause fetal abnormalities. Patients with an idiopathic seizure disorder should not take the drug. Anyone with a condition which impairs their ability to understand the risks associated with disulfiram should not be prescribed the drug.

It is important to remember when prescribing disulfiram that it may influence adversely the pharmacokinetics, and consequently the effects of medications metabolized by the cytochrome p450 system. Such drugs may have higher plasma levels and longer elimination half-lives if used concomitantly with disulfiram. Such medications include warfarin, phenytoin, amitriptyline and benzodiazepines, such as chlordiazepoxide and diazepam (but not lorazepam and oxazepam).

Is it ethical to prescribe a medication that has the risk of adverse events and is potentially lethal? This is a question that can be asked of any medication, because they all carry a risk of adverse events. It is a matter of weighing the efficacy of the medication and the seriousness of the illness versus the toxicity of the drug. We believe that it is important to emphasize that, as Chick (1999) has pointed out, disulfiram with a moderate record of adverse effects can be a helpful treatment for alcohol dependence, which is often lethal and has serious medical and social consequences.

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ACAMPROSATE AND NALTREXONE COMBINED WITH DISULFIRAM
The past decade has seen the introduction of newer pharmacotherapies such as acamprosate and naltrexone for treating alcohol dependence. Would disulfiram be efficacious if combined with these newer agents? One placebo-controlled trial of acamprosate prescribed disulfiram to those who requested it (Besson et al. 1998). Those patients on the disulfiram-acamprosate combination had significantly more abstinent days than those who received acamprosate only. However, those who wanted to take disulfiram may have been more motivated. Because patients were not assigned randomly to the disulfiram-acamprosate regimen, it is not possible to know whether the combination of disulfiram and acamprosate or motivation was responsible for the results. A randomized clinical trial is needed to test this combination. Regarding safety, Besson et al. (1998) reported no adverse interaction between acamprosate and disulfiram in 24 patients treated for 12 months. Saivan et al. (1998) cite a report that the pharmacokinetics of acamprosate were not affected by the administration of disulfiram in 12 healthy volunteers.

In a small study, 25 mg naltrexone with either disulfiram or calcium carbimide achieved markedly better results than disulfiram or calcium carbimide alone (Landabaso et al. 1999). In this study 30 patients who had been treated three or more times with either disulfiram or calcium carbimide ('aversion treatment') in the previous 3 years were assigned randomly to the naltrexone-aversion agent combination for 6 months versus aversion treatment alone for 12 months. It is not stated explicitly how many in the control group were on disulfiram. At the end of 6 months 73% of the combination group were abstinent compared to 34% of the control group. It is unfortunate that there was not a naltrexone-only group. If such a group had achieved results similar to the combination group, this would suggest that combining disulfiram with naltrexone provides no additional benefit to prescribing naltrexone alone. On the other hand, if the disulfiram-naltrexone group did better than a naltrexone only group, this would provide additional support for using this combination. There is no mention of adverse reactions in the combination group.

Most of the clinical trials evaluating naltrexone have usually required a period of abstinence (commonly 5 days to a week) before starting naltrexone. This was undertaken because naltrexone was conceptualized as a medication to prevent relapse and a period of abstinence was necessary to test this (S. O'Malley, personal communication). It is also of note that many of the acamprosate trials were done in alcoholics who were initially hospitalized and also had an initial period of abstinence. Would disulfiram be useful to assure an initial period of abstinence before beginning treatment with these medications? This is worthy of investigation. Although most clinical investigators have administered naltrexone after a period of abstinence, Sinclair (1998) has written that naltrexone can be initiated without detoxification from alcohol or a period of abstinence. Of course, in this alternative form of naltrexone administration disulfiram would be contraindicated.

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ANTIDEPRESSANTS AND DISULFIRAM
Some alcoholics are prescribed antidepressants for major depression. Is it safe to prescribe disulfiram and antidepressants concomitantly? There are animal (Smith & Muneo 1976) and human data (Blansjaar & Egberts 1995) to indicate that the concomitant use of MAO inhibitors and disulfiram is not safe. Disulfiram should not be used with the tricyclic antidepressants because it interferes with their pharmacokinetics (Ciraulo et al. 1985). Thase et al. (2001), in their review of the treatment of depression in alcoholics, discuss disulfiram as a treatment for alcohol dependence and endorse the use of selective serotonin receptor inhibitors but do not report if the combination has been safely used.

PARTICULAR PATIENTS WHO MIGHT BENEFIT FROM DISULFIRAM
Are there particular patients that benefit from disulfiram? Banys (1988) summarized this well when he wrote, '. . . disulfiram retains a place in standard alcoholism treatment programs because clinicians believe that this agent is useful for selected alcoholic patients. Until more studies are completed that compare outcomes for selected subgroups of alcoholic patients, the major justification for this conviction remain poorly controlled studies and clinical experience.' With these caveats in mind, patients who might do better with unsupervised disulfiram are older ones (Baekeland et al. 1971; Fuller et al. 1986), more socially stable patients (Fuller et al. 1986), impulsive patients (Banys 1988) and those higher in motivation (Baekeland et al. 1971). Observational studies of patients being treated with supervised disulfiram indicate that those who are doing poorly with treatment but want to remain in treatment (Sereny et al. 1986) will benefit with this mode of treatment.

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CONCLUSION
Does disulfiram still have a role in alcoholism treatment? The answer is a qualified yes. Disulfiram does not have to be used when a patient presents initially for treatment. However, if the patient is struggling to achieve sobriety, the supervised administration of disulfiram is warranted. The side effects are usually minor and serious adverse reactions are uncommon although monitoring for hepatotoxicity should be done.

To better inform us about the use of disulfiram today, randomized clinical trials are needed to determine whether (1) supervised disulfiram would be useful to assure sobriety for high risk groups, e.g. criminal offenders and those who have failed previous attempts at treatment; (2) the supervised ingestion of disulfiram is better performed by a clinic staff member or by a relative; and (3) supervised disulfiram would improve treatment outcome when combined with the newer pharmacotherapies. For the future, we need to move beyond disulfiram and continue to develop better pharmacotherapies that act directly on the neurobiological processes underlying alcohol dependence.

REFERENCES

• Anton, R. F. (2001) Pharmacological approaches to the management of alcoholism. Journal of Clinical Psychiatry, 62(supp 20), 11-17.

• Baekeland, F., Lundwall, L., Kissin, B. & Shanahan, T. (1971) The correlates of outcome in disulfiram treatment of alcoholism. Journal of Nervous and Mental Disease, 53, 1-9.

• Banys, P. (1988) The clinical use of disulfiram (Antabuse): a review. Journal of Psychoactive Drugs, 20, 243-260.

• Besson, J., Aeby, F., Kasas, A., Lehert, P. & Potgieter, A. (1998) Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study. Alcoholism: Clinical and Experimental Research, 22, 573-579.

• Blansjaar, B. A. & Egberts, T. C. (1995) Delerium in a patient treated with disulfiram and tranylcypromine [Letter]. American Journal of Psychiatry, 152, 296.

• Brewer, C. (1984) How effective is the standard dose of disulfiram? A review of the alcohol-disulfiram reaction in practice. British Journal of Psychiatry, 144, 200-202.

• Brewer, C. (1987) Disulfiram treatment of alcoholism [Letter]. Journal of the American Medical Association, 257, 926.CrossRef Abstract

• Chick, J., Gough, K., Wojciech, F., Kershaw, P., Hore, B., Mehta, B., Ritson, B., Ropner, R. & Torley, D. (1992) Disulfiram treatment of alcoholism. British Journal of Psychiatry, 161, 84-89.

• Chick, J. (1999) Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Safety, 20, 427-435.

• Christensen, J. K., Moller, I. W., Ronstad, P., Angelo, H. R. & Johansson, B. (1991) Dose-effect relationship of disulfiram in human volunteers. I: Clinical studies. Pharmacology and Toxicology, 68, 163-165.

• Christensen, J. K., Ronstad, P. & Vaag, U. H. (1984) Side effects after disulfiram. Comparison of disulfiram and placebo in a double blind multicentre study. Acta Psychiatrica Scandinavica, 69, 265-273.

• Ciraulo, D. A., Barnhill, J. & Boxenbaum, H. (1985) Pharmacokinetic interaction of disulfiram and antidepressants. American Journal of Psychiatry, 142, 1373-1374.

• Fuller, R. K., Branchey, L., Brightwell, D. R., Derman, R. M., Emrick, C. D., Iber, F. L., James, K. E., Lacoursiere, R. B., Lee, K. K., Lowenstam, I., Maany, I., Neiderheiser, D., Nocks, J. J. & Shaw, S. (1986) Disulfiram treatment of alcoholism: a Veterans Administration Cooperative Study. Journal of the American Medical Association, 256, 1449-1455.

• Hughes, J. C. & Cook, C. C. H. (1997) The efficacy of disulfiram: a review of outcome studies. Addiction, 92, 381-395.

• Landabaso, M. A., Iraurgi, I., Sanz, J., Calle, R., deApodaka, J. R., Jimenez-Lerma, J. M. & Guitierrez-Fraile, M. (1999) Naltrexone in the treatment of alcoholism: two year follow up results. European Journal of Psychiatry, 13, 97-105.

• Poulsen, H. E., Loft, S., Andersen, J. R. & Andersen, M. (1992) Disulfiram therapy-adverse drug reactions and intreractions. Acta Psychiatrica Scandinavica, 86, 59-66.

• Saivan, S., Hulot, T., Chabac, S., Potgieter, A., Durbin, P. & Houlin, G. (1998) Clinical pharmacokinetics of acamprosate. Clinical Pharmacokinetics, 35, 331-345.

• Saxon, A. J., Sloan, K. L., Reoux, J. & Haver, V. M. (1998) Disulfiram use in patients with abnormal liver function test results. Journal of Clinical Psychiatry, 59, 313-316.

• Sereny, G., Sharma, V., Holt, J. & Gordis, E. (1986) Mandatory supervised Antabuse therapy in an outpatient program: a pilot study. Alcoholism: Clinical and Experimental Research, 10, 290-292.

• Sinclair, J. D. (1998) New treatment options for substance abuse from a public health viewpoint. Annals of Medicine, 30, 406-411.

• Smith, D. F. & Muneo, S. (1976) Toxic interaction between disulfiram and tranylcypromine stereoisomers in rats [Letter]. Journal of Pharmacy and Pharmacology, 28, 858.

• Thase, M. E., Salloum, I. M. & Cornelius, J. D. (2001) Comorbid alcoholism and depression: treatment issues. Journal of Clinical Psychiatry, 62(supp 20), 32-41.

• Wright, C., Vafier, J. A. & Lake, C. R. (1988) Disulfiram-induced fulminating hepatitis: guidelines for liver-panel monitoring. Journal of Clinical Psychiatry, 49, 430-434.

[PDF printer format]

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See also:
Commentaries about the above article regarding safety and psychological aspects of disulfiram therapy, from the same issue of Addiction, and a response by Fuller & Gordis:
 
 Commentaries (PDF); Addiction; 99(1); 25-28; 2004.

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