What are the side effects and adverse reactions of disulfiram?

Disulfiram Side Effects and Safety Profile

Most Critical Safety Concern: Hepatotoxicity

Disulfiram carries a significant risk of severe and sometimes fatal hepatotoxicity, which is the primary reason it is now rarely used and contraindicated in patients with any degree of liver disease. 1

Hepatic Toxicity Details

• Fatal hepatitis occurs in approximately 1 in 30,000 patients treated per year, though severe hepatotoxicity requiring transplantation or resulting in death has been documented even after many months of therapy 2, 1
• Hepatotoxicity is an idiosyncratic reaction that can develop at any time during treatment, regardless of prior liver function status 1, 3
• Absolute contraindication in patients with alcoholic liver disease, acute hepatitis, elevated liver enzymes, or any hepatic cirrhosis/insufficiency 1, 3, 4
• Patients must immediately report early hepatitis symptoms: fatigue, weakness, malaise, anorexia, nausea, vomiting, jaundice, or dark urine 1
• Baseline and follow-up liver function tests at 10-14 day intervals are required to detect hepatic dysfunction 1

Disulfiram-Alcohol Reaction

Cardiovascular Effects

• Flushing, throbbing in head and neck, chest pain, palpitations 1, 4
• Tachycardia, hypotension, syncope 1
• Severe reactions: cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure 1, 2

Gastrointestinal Effects

• Nausea and copious vomiting 1, 4
• Thirst 1

Neurological Effects

• Throbbing headache, dizziness, vertigo, blurred vision, confusion 1, 4
• Marked uneasiness, weakness 1
• Severe reactions: unconsciousness, convulsions, death 1

Respiratory Effects

• Respiratory difficulty, dyspnea, hyperventilation 1, 4
• Severe reactions: respiratory depression 1

Reaction Characteristics

• Reactions can occur with alcohol up to 14 days after last disulfiram dose 1
• Mild reactions occur at blood alcohol levels as low as 5-10 mg/dL in sensitive individuals 1
• Symptoms fully developed at 50 mg/dL; unconsciousness typically at 125-150 mg/dL 1
• Duration: 30-60 minutes in mild cases, several hours in severe cases, or as long as alcohol remains in blood 1
• Deaths from disulfiram-alcohol reactions are now rare, likely due to lower dosing (250-500 mg/day vs historical higher doses) and exclusion of cardiac patients 2, 5

Central Nervous System Toxicity (Direct Drug Effect)

Psychiatric and Neurological Effects

• Psychotic reactions, acute organic brain syndrome, confusional states, catatonia 6, 2
• Peripheral neuropathy and optic neuritis (dose-related) 2
• Psychiatric complications appear more common in Indian populations than Western countries 2
• Risk increased with: excessive dosing, pre-existing major psychiatric illness, or anatomical brain lesions 6
• CNS toxicity typically appears in first weeks of treatment and reverses after drug discontinuation 6

Mechanism of CNS Effects

• Disulfiram and its metabolite carbon disulfide inhibit dopamine beta-hydroxylase, increasing dopamine and reducing norepinephrine levels in the CNS 6, 7
• Brain catecholamine effects occur at doses higher than those inhibiting aldehyde dehydrogenase, suggesting therapeutic dosing (25 mg/kg or lower equivalent) may avoid neurotoxicity while maintaining efficacy 7

Common Non-Serious Side Effects

• Tiredness, headache, sleepiness are most frequent 2
• Rubber contact dermatitis (hypersensitivity to thiuram derivatives) - patients with this history should be evaluated before receiving disulfiram 1

Important Drug Interactions and Precautions

• Interactions with cytochrome P450 enzyme system compounds 2
• Should not be exposed to ethylene dibromide or its vapors - animal research suggests toxic interaction with higher tumor incidence and mortality 1
• Use with extreme caution in: diabetes mellitus, hypothyroidism, epilepsy, cerebral damage, chronic/acute nephritis 1

Clinical Efficacy Context

Despite these risks, disulfiram has poor evidence for efficacy - systematic reviews conclude there is little evidence it enhances abstinence, and its use has been largely supplanted by safer alternatives like acamprosate and naltrexone 8

Safer Alternative Medications

For Patients WITH Liver Disease:

• Acamprosate is the preferred agent - no hepatic metabolism, no hepatotoxicity risk, safe in liver disease 3, 9, 4
• Baclofen may be used in cirrhosis - doses up to 80 mg/day generally safe, though gradual titration recommended in severe liver disease 3, 4
• Naltrexone is contraindicated - causes hepatocellular injury 8, 3, 4

For Patients WITHOUT Liver Disease:

• Acamprosate - most evidence for maintaining abstinence (odds ratio 1.49), requires prior detoxification 8, 9
• Naltrexone - moderate evidence for efficacy (odds ratio 0.70 for dropout reduction) 8

Critical Patient Education Requirements

Patients must carry identification cards stating they are on disulfiram and describing reaction symptoms, with emergency contact information 1

Patients must be warned to avoid alcohol in all forms:

• Sauces, vinegars, cough mixtures 1
• Aftershave lotions and back rubs 1
• Any disguised alcohol sources 1

Never administer disulfiram to intoxicated patients or without their full knowledge 1