Disulfiram

Indications

• FDA-approved as an aversive adjunct in carefully selected, cooperative adults with alcohol use disorder who want enforced sobriety plus psychosocial treatment.
• Third-line after naltrexone and acamprosate in the APA 2018 and VA/DoD 2021 guidelines, reserved for patients committed to total abstinence.
• Blinded trials show no advantage over placebo; open supervised administration by a partner, clinic or pharmacy is what produces benefit.
• Has no role in managing alcohol withdrawal and does nothing for craving; it deters drinking only through anticipated punishment.
• Studied off-label for cocaine use disorder through dopamine beta-hydroxylase inhibition, with mixed and largely disappointing results.
• Requires informed consent and a patient who understands the reaction; covert administration is prohibited by the boxed warning.

Mechanism of action

• Irreversibly inhibits aldehyde dehydrogenase, so acetaldehyde from ethanol accumulates to five to ten times normal and produces the aversive reaction.
• The reaction brings flushing, throbbing headache, nausea, vomiting, tachycardia, hypotension, dyspnea and chest pain within minutes of drinking.
• Because inhibition is irreversible, effect persists until new enzyme is synthesized, which takes up to 14 days after the last dose.
• Also inhibits dopamine beta-hydroxylase, raising dopamine and lowering norepinephrine, which explains the psychosis risk and the cocaine trials.
• Provides no craving reduction and no reward blockade, so it works only while the patient keeps taking it under observation.

Pharmacokinetics

• About 80-95% of an oral dose is absorbed and rapidly reduced to diethyldithiocarbamate and further to active and inactive metabolites.
• Highly lipophilic with accumulation in fat, so roughly a fifth of a dose remains in the body one to two weeks after stopping.
• Inhibits CYP2E1 and CYP1A2 and impairs oxidative metabolism broadly, raising concentrations of warfarin, phenytoin and oxidized benzodiazepines.
• Full enzyme inhibition takes about 12 h to develop, which is why the first dose is delayed until the patient is alcohol-free.
• Metabolites are excreted in urine and some carbon disulfide is exhaled, giving the characteristic garlic-like or metallic aftertaste.

Dosing

• Never give the first dose until at least 12 h after the last drink and the patient is fully sober; a zero breath alcohol reading is ideal.
• Start 500 mg once daily for one to two weeks, then maintain on 250 mg daily; the usual range is 125-500 mg and the max is 500 mg/day.
• Dose at bedtime if sedation is a problem, or in the morning if it disturbs sleep; a single daily dose is all that is needed.
• Arrange observed dosing by a spouse, family member, pharmacy or clinic, since supervision is the single strongest predictor of benefit.
• Counsel about hidden alcohol in mouthwash, cough and cold syrups, hand sanitizer, aftershave, vinegars, sauces, desserts and some topical preparations.
• Treatment typically continues one to two years; no taper is required, but warn that drinking can trigger a reaction for two weeks after stopping.

Adverse effects

• Drowsiness, fatigue, headache, a metallic or garlic-like aftertaste, acneiform rash and impotence are common in the first weeks of treatment.
• Hepatotoxicity ranging from transaminase elevation to fulminant hepatic failure can appear at any time, including after months of stable therapy.
• Peripheral neuropathy and optic neuritis occur with prolonged use and are the usual reasons to stop after the first year of treatment.
• Psychosis, confusion, delirium and catatonia are dose-related, more likely above 500 mg/day and in patients with a psychotic disorder.
• The disulfiram-alcohol reaction itself can be fatal, causing arrhythmia, myocardial infarction, respiratory depression, seizure and cardiovascular collapse.
• Hypersensitivity dermatitis is more frequent in people previously sensitized to thiuram derivatives, such as rubber industry workers.

Monitoring

• Baseline liver function tests, then repeat at 2 weeks, monthly for the first 3 months, and every 3 to 6 months thereafter.
• Baseline complete blood count, basic chemistry and thyroid status; consider an ECG in anyone with cardiac history or risk factors.
• Ask at every visit about numbness, tingling, gait change and visual blurring to catch neuropathy or optic neuritis early.
• Screen for confusion, paranoia or hallucinations, particularly after any dose increase above 250 mg daily.
• Reconfirm consent, motivation and the supervision arrangement at each visit, since unobserved dosing predicts loss of benefit.

Interactions

• Alcohol in any form is contraindicated, including intravenous drug diluents, elixirs, topical preparations and alcohol-containing food products.
• Metronidazole is contraindicated because the combination can precipitate confusion, psychosis and a severe acute organic brain syndrome.
• Inhibits warfarin metabolism and raises the INR, so anticoagulated patients need INR checks after starting and after any dose change.
• Substantially raises phenytoin concentrations, and increases levels of oxidized benzodiazepines such as diazepam and chlordiazepoxide.
• Contraindicated in severe myocardial disease, coronary occlusion and psychosis; combine cautiously with isoniazid, which can add ataxia and confusion.

Special populations

• Pregnancy: avoid, as human data are limited, case reports describe limb anomalies, and a reaction would expose the fetus to acetaldehyde.
• Lactation: excretion into human milk is unknown and no safety data exist, so alternative pharmacotherapy is preferred while breastfeeding.
• Pediatric safety and effectiveness have not been established and there is no recommended dose for patients under 18 years.
• Geriatric patients are more vulnerable to confusion, neuropathy and cardiovascular consequences of a reaction, so use with particular caution.
• Hepatic: avoid in significant liver disease or cirrhosis; also use caution in diabetes, hypothyroidism, seizure disorder and renal impairment.

Clinical pearls

• It only works observed; unsupervised disulfiram performs no better than placebo in blinded trials.
• Wait 12 h after the last drink to start, and warn that a reaction is possible 14 days after stopping.
• Check LFTs at baseline and 2 weeks; hepatitis can appear even after months of stable dosing.