Alexander DeLuca, M.D.
Does Disulfiram Have a Role in Alcoholism Treatment Today?
by Richard K. Fuller &
Enoch Gordis; Addiction; 99(1); 21-24; 2004.
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.
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.
SIDE EFFECTS AND ADVERSE
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.
ACAMPROSATE AND NALTREXONE
COMBINED WITH DISULFIRAM
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.
ANTIDEPRESSANTS AND DISULFIRAM
PARTICULAR PATIENTS WHO MIGHT
BENEFIT FROM DISULFIRAM
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.
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