Disulfiram

Disulfiram is an alcohol-sensitising agent used as an adjunct in alcohol dependence in patients who are motivated to stay abstinent. It blocks aldehyde dehydrogenase, so alcohol causes an unpleasant and potentially dangerous reaction. It works best when taken under supervision (for example by a family member or clinic). The reaction can be triggered by hidden alcohol in medicines, mouthwashes, perfumes, hand sanitisers, food, and some local brews and herbal preparations, so patients need clear counselling.

Classification. Aldehyde dehydrogenase inhibitor, alcohol-sensitising agent.

Mechanism. Irreversible inhibition of aldehyde dehydrogenase, which causes acetaldehyde to accumulate after alcohol intake (the disulfiram-alcohol reaction).

Pharmacokinetics. Well absorbed orally. Rapidly reduced to diethyldithiocarbamate and metabolised by the liver. Enzyme inhibition lasts 7 to 14 days after the last dose because new enzyme must be synthesised, so alcohol sensitivity remains for up to 2 weeks after stopping. Inhibits several CYP enzymes (CYP2E1, CYP2C9, CYP1A2).

All regimens are oral with no loading dose.

Alcohol dependence, adults (adjunct to psychosocial support).

• Start only after at least 24 hours of abstinence from alcohol (some labels allow 12 hours).
• Initial dose 500 mg to 800 mg once on day 1, then reduce over 5 days (for example 600 mg, 400 mg, 200 mg).
• Maintenance 100 to 200 mg once daily (up to 500 mg in some labels).
• Duration: continue until self-control is established, with review every 6 months; usually 6 to 12 months.

Supervised dosing. Give under direct observation where possible, three times weekly in some regimens, with the dose divided to match.

Dose limits. Liver impairment: avoid in severe disease. Kidney impairment: use with caution. Older adults: start low.

Contraindications. Alcohol intoxication or alcohol in the blood, severe cardiac disease (ischaemic heart disease, heart failure, arrhythmia), cerebrovascular disease, hypertension, psychosis, severe depression or suicidal risk, severe liver or kidney disease, pregnancy, hypersensitivity, concurrent metronidazole or paraldehyde.

Serious adverse effects. Severe disulfiram-alcohol reaction (flushing, palpitations, chest pain, hypotension, vomiting, breathlessness, collapse, arrhythmia, myocardial infarction, seizures, death), hepatotoxicity including fulminant liver failure, peripheral and optic neuropathy, psychosis, confusion, delirium.

Common adverse effects. Drowsiness, fatigue, headache, metallic or garlic taste, reduced libido, skin rash, mild nausea.

Interactions. Metronidazole causes psychosis and confusion. Isoniazid can cause ataxia, behaviour change and neurotoxicity, which is relevant to tuberculosis treatment. Phenytoin levels rise (toxicity). Warfarin effect is increased, so monitor INR. Benzodiazepines (diazepam, chlordiazepoxide), tricyclic antidepressants and theophylline levels rise. Alcohol in cough syrups, tonics, mouthwashes and herbal or traditional preparations triggers a reaction.

Common prescribing errors. Starting without full counselling about hidden alcohol; starting too soon after alcohol; not checking liver function; prescribing in cardiac disease; giving without supervised adherence; combining with metronidazole.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: not advised.
• Older adults: start low; higher risk of cardiac complications.
• Kidney impairment: use with caution.
• Liver impairment: avoid in severe disease.

Formulations. Tablets 200 mg, 250 mg and 500 mg; dispersible tablets 200 mg in some regions. Dissolve in water or swallow with food; take in the morning to reduce sedation. Give the patient a warning card.

Baseline. Informed consent with a clear explanation of the reaction, liver function tests, blood pressure, ECG if there is cardiac risk, mental state and suicide risk, medicines list, pregnancy status, a negative alcohol breath or blood test.

Monitoring. Repeat liver function tests at 2 weeks, monthly for 3 months and then every 6 months. Check blood pressure and mental state at each visit. Ask about neuropathy and visual change. Review alcohol use and adherence.

Stopping. No taper is needed. Warn that alcohol sensitivity continues for up to 14 days after the last dose.

Referral and escalation. Refer to addiction services for relapse or severe dependence. Jaundice, dark urine, severe abdominal pain, confusion, visual loss or psychosis needs the drug stopped and urgent review. A severe reaction (chest pain, hypotension, collapse) is a medical emergency.