Chapter 78: Disulfiram and Disulfiramlike Reactions

INTRODUCTION

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.¹⁰⁸ 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.^3,34 E.E 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.”³⁹ Subsequently, in 1951, the US Food and Drug Administration 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 several studies revealed no significant difference in drinking outcomes between unsupervised disulfiram administration and placebo.³³ Studies evaluating the efficacy of disulfiram that span nearly 60 years 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.^35,82,85 Disulfiram is being studied for its possible antineoplastic properties, which include the induction of oxidative stress, leading to cooper-dependent cytotoxicity, proteasome inhibition, and nuclear factor-kB inhibition.^15,38 Oxidative stress is enhanced by the presence of the disulfiram–copper chelation complex, and copper-binding drugs inhibit proteasome activity and generate reactive oxygen species.⁹⁰ Disulfiram is undergoing clinical trials for the treatment of various cancers, including melanoma and liver, lung, and prostate cancers.

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 acute or chronic poisoning. Although life-threatening effects associated with disulfiram are rare, clinicians should be aware of proper diagnosis and management of patients with disulfiram-associated toxicity.

Specific epidemiologic information about the 3 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 National Poison Data System from 2015 revealed 221 exposures to disulfiram, with the majority of cases being in adults and classified as unintentional. No deaths and ...