79: Disulfiram and Disulfiramlike Reactions

HISTORY AND EPIDEMIOLOGY

Disulfiram tetraethylthiuram disulfide (TETD) was synthesized from thiocarbamide in the 1880s to accelerate the vulcanization (stabilization) of rubber by the addition of sulfur.¹⁰⁴ Sixty years later it was the first western medication used to treat alcohol dependence. By the turn of the 20th ­century, most rubber factory workers exposed to disulfiram found that they were intolerant to alcohol.^2,32 Williams, a rubber factory occupational physician, wrote, “If the chemical compound disulfiram is not harmful to man, one wonders if one has discovered a cure for alcoholism.” Apart from its use in the rubber industry, beginning in the early 1940s disulfiram was also used in medicine as a scabicide. Two scientists, Hald and Jacobsen, were exploring the antiparasitic effects of disulfiram when they made the rediscovery that ingesting alcohol after loading doses of disulfiram was quite unpleasant.³⁶ Subsequently, in 1951 the US Food and Drug Administration (FDA) approved disulfiram for the treatment for alcoholism. Disulfiram is typically prescribed at an initial dose of 500 mg/day for 1 to 2 weeks, followed by a maintenance dose of 125 to 500 mg/day.

Disulfiram was never widely used clinically, and its use further declined after the several studies revealed no significant difference in drinking outcomes between unsupervised disulfiram administration and placebo.³¹ Studies evaluating the efficacy of disulfiram span nearly 60 years and yield mixed results, with many studies having small sample sizes, nonrandomization, unblinded conditions, short follow-up periods, and no measurement of treatment adherence. With the worldwide approval of naltrexone in 1993, and later acamprosate, the clinical use of disulfiram declined. More recent interest in disulfiram for treating cocaine and other stimulant dependence has provided some renewed clinical interest.^33,79,82,99

Specific epidemiologic information about the three different forms of disulfiram toxicity is difficult to elucidate, even from an analysis of the American Association of Poison Control Centers (AAPCC). Data from the Annual Reports of the AAPCC National Poison Data System from 2007 to 2011 revealed 368 exposures to disulfiram, with the majority of cases being in adults and classified as unintentional. No deaths and only two major adverse outcomes were reported. Since 1982, 14 deaths associated with disulfiram have been reported to the AAPCC, most involving a disulfiram–ethanol reaction (Chap. 136). Serious adverse effects associated with both therapeutic use of disulfiram and with disulfiram overdose continue to be reported mostly in the form of case reports and case series. As such, these reports are difficult to interpret because of complications and comorbidities associated with alcohol use, the potential effects of polypharmacy, and the difficulty in relating the adverse effect to disulfiram, alcohol or a disulfiram–ethanol reaction.

In considering disulfiram toxicity, a distinction must be made between the clinical manifestations of a disulfiram–ethanol reaction and the toxic effects of disulfiram itself. Direct disulfiram toxicity can be further classified as ...