Disulfiram is a long-established agent for the treatment of chronic alcoholism, and there has been interest in this agent to combat chronic cocaine abuse. The author discusses current knowledge of the associated peripheral neuropathy that primarily affects large fiber sensory and motor fibers. In some cases the neuropathy can be confused with alcoholic polyneuropathy or thiamine deficiency neuropathy in alcoholics, but the clinical features differ to some degree. Recognition of the phenomenon is critical prior to significant nerve injury.
• Disulfiram produces a dose- and length-dependent axonal sensorimotor neuropathy.
• Disulfiram use is expanding from ethanol to cocaine dependence.
• Motor and large fiber sensory nerve involvement from disulfiram differs from typical chronic alcohol-induced sensory neuropathy.
Historical note and terminology
The effects of disulfiram in combination with ethanol were discovered by 2 Danish physicians investigating the agent's use as an anthelminthic after they had accidentally induced a disulfiram-alcohol reaction in themselves. The drug was subsequently approved by the FDA in 1951 for the treatment of alcoholism and remains in use despite other effective agents, such as naltrexone and acamprosate (Grover and Basu 2004). Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage. During alcohol metabolism following disulfiram intake, the concentration of acetaldehyde occurring in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. This accumulation of acetaldehyde produces sensitivity to alcohol, resulting in a highly unpleasant disulfiram-alcohol reaction when the patient, under treatment, ingests relatively small amounts of ethanol. Disulfiram is still in use as a deterrent to drinking ethanol in the United States, Europe, and other places around the world. The drug is court mandated in some situations, but evidence suggests that compliance is poor in this setting.
The drug has been studied for the deterrence of cocaine addiction (Carroll et al 2004; Sofuoglu and Kosten 2005). Disulfiram has demonstrated efficacy in numerous randomized clinical trials for the treatment of cocaine dependence, but it is rarely used in clinical settings because of safety concerns (Malcolm et al 2008; Oliveto et al 2011). A Cochrane review, however, concluded that the evidence supporting disulfiram use in cocaine abuse was low and that large trials were needed (Pani et al 2010). A randomized trial of disulfiram also found a limited benefit supplementing buprenorphine treatment (Schottenfeld et al 2014). However, neuropathy appears to be much less common in this population. A single nucleotide polymorphism (SNP; C-1021T) in the dopamine beta-hydroxylase gene is relevant to paranoia associated with disulfiram pharmacotherapy for cocaine addiction (Haile et al 2009). Some have also suggested that disulfiram may be useful for pathologic gambling, but studies have not been performed (Mutschler et al 2010). Disulfiram also shows some promise as an antifungal agent but has yet to be tried on humans (Shukla et al 2004). The drug is also potentially active against cancer cells in vitro (Chiba et al 2014; Paranjpe et al 2014). Disulfiram may have efficacy against refractory glioblastoma in combination with temozolomide. Twelve patients underwent a dose-escalation phase 1 study; some developed neuropathy said to be reversible (Huang et al 2016).
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