Charcot-Marie-Tooth disease: CMT2, CMT4, and others
Sep. 10, 2023
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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, 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.
The effects of disulfiram in combination with ethanol were discovered by two 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 (14). 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 to deter cocaine addiction (05; 38). 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 (25; 29). A Cochrane review, however, concluded that the evidence supporting disulfiram use in cocaine abuse was low and that large trials were needed (31). A randomized trial of disulfiram also found a limited benefit supplementing buprenorphine treatment (35). 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 (15). Some have also suggested that disulfiram may be useful for pathologic gambling, but studies have not been performed (28). Disulfiram also shows some promise as an antifungal agent (37).
Disulfiram combined with copper is an emerging antitumor therapy in various settings, including solid and hematological cancers (06; 32; 09; 46). Glioblastoma stem cells and medulloblastoma cells are also potential targets (36; 48). The drug may act as a tumor sensitizer to other therapies, including conventional chemotherapy and immune modulators. It appears to affect the PD-L1 pathway (47). That pathway may also inhibit injury from severe acute pancreatitis and related lung Injury (45). There is evidence of inhibition of the cytokine and macrophage signal regulator FROUNT that may augment checkpoint inhibitor therapies (39). Most reported studies are in vitro models but human trials are ongoing. Expansion of usage might initiate an increase in neuropathy cases.
Disulfiram additionally shows strong activity against Lyme disease spirochetes in a high throughput search. A retrospective open-label review of “high-dose” (4 mg/kg/day or greater) and “low-dose” (less than 4 mg/kg/day) treatment was performed in 71 chronic Lyme disease patients; 67 completed the trial (13). Gao and colleagues reported that 92% had symptomatic improvement. Toxicity in the high-dose group included fatigue (66.7%), psychiatric symptoms (48.5%), peripheral neuropathy (27.3%), and mild-to-moderate elevation of liver enzymes (15.2%). Patients with preexisting neuropathy were preferentially in the low-dose group. They reported all but one patient had neuropathy symptoms resolve, but no neurologic or electrodiagnostic studies were mentioned (13). They suggested that randomized trials are warranted.
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