Continuing Education Activity

Disulfiram is one of three drugs approved by the Federal Drug Administration (FDA) to treat alcohol dependence. It is a second-line option (acamprosate and naltrexone are first-line treatments) in patients with sufficient clinical supervision. Disulfiram is safe and efficient in supervised short-term and long-term treatment of individuals dependent on alcohol but motivated to discontinue alcohol use. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of disulfiram, pertinent for members of the interprofessional team in the treatment of patients with misuse syndromes that will respond to such therapy.

Objectives:

• Review the approved indications for disulfiram therapy.
• Identify the mechanism of action of disulfiram based on the indication for which it is used.
• Outline the adverse effects of disulfiram.
• Summarize the importance of interprofessional communication, improving care coordination among the interprofessional team when initiating disulfiram therapy.

Indications

Disulfiram is one of three drugs approved by the FDA for the treatment of alcohol dependence. It is a second-line option (acamprosate and naltrexone are first-line treatments) in patients with sufficient physician supervision. Disulfiram is safe and efficient in supervised short-term and long-term treatment of individuals dependant on alcohol but who are motivated to discontinue alcohol use. Current studies for treating patients with comorbid alcohol dependence with post-traumatic stress disorder, alcohol and cocaine dependence, and cocaine dependence alone are underway.[1][2][3]

Recent studies of disulfiram as a proteasome inhibitor and DNA demethylating agent show promise for new potential therapeutic uses for malignancy and fungal infections. Disulfiram may have a primary or adjuvant role in treating drug-resistant fungal infections (particular candida) and malignancy by inhibiting ABC drug transport protein responsible for resistance. In addition, evidence shows metabolites of disulfiram induce p53, mediating apoptosis and cell death. Investigations of the role of disulfiram as an anti-cancer agent are ongoing.

Mechanism of Action

Disulfiram converts to an active metabolite, diethyldithiocarbamate, in the stomach. In the blood, it changes to diethyldithiocarbamic acid(DDC), which is degraded to form diethylamine and carbon disulfide. DDC undergoes phase II metabolism forming sulfoxide and sulfone metabolites. These S-oxidized compounds are potent active metabolites producing the effects of disulfiram.[4][5][6]

Alcohol Dependence

Disulfiram irreversibly inhibits aldehyde dehydrogenase (ALDH1A1) by competing with nicotinamide adenine dinucleotide (NAD) at the cysteine residue in the active site of the enzyme. ALDH1A1 is a hepatic enzyme of the major oxidative pathway of alcohol metabolism, converting acetaldehyde to acetate. At therapeutic doses of disulfiram, alcohol consumption results in increased serum acetaldehyde, causing diaphoresis, palpitations, facial flushing, nausea, vertigo, hypotension, and tachycardia. This aggregation of symptoms is known as the disulfiram-alcohol reaction and discourages alcohol intake. The reaction is proportional to both the dose of disulfiram and alcohol. Thus, Disulfiram is not an anti-craving drug and does not modulate the neurobiological mechanism of addiction.

Cocaine Dependence

Disulfiram also inhibits dopamine beta-hydroxylase (DBH), an enzyme that converts dopamine to noradrenaline, causing an accumulation of dopamine. Increased dopamine corrects the underlying deficit in patients addicted to cocaine. Recent studies have shown reduced frequency and amount of cocaine use in patients treated with disulfiram.

Administration

Disulfiram is available only via oral administration. Tablets are available in 250 mg to 500 mg forms. Tablets may be crushed and mixed with liquids (water, coffee, milk, fruit juice) and should be taken once per day. Disulfiram administration should never take place until the patient has abstained from alcohol for at least 12 hours. Patients should avoid alcohol and alcohol-containing products for at least 14 days after discontinuing disulfiram, as there are reports of disulfiram-alcohol reactions within 2 weeks of discontinuation. There is no benefit to increasing the dose of disulfiram to greater than 500 mg/day.

A trial of disulfiram and alcohol to produce a disulfiram-alcohol reaction is no longer a recommendation. However, the patient should receive extensive education on symptoms of disulfiram-alcohol reaction before administration.

Adverse Effects

Disulfiram has an acceptable risk profile. However, it is associated with many adverse events and drug-drug interactions, including death. The most common and less serious adverse effects include headache, sleepiness, tiredness, and halitosis (or metallic taste).[5][7][8][9]

Reports exist of dermatological, neurological, psychiatric, and cardiac events. Serious side effects include hepatitis, hepatotoxicity, psychosis, seizures, peripheral neuropathy, and optic neuritis. Dermatological adverse effects are rare and include exfoliative dermatitis, rash, and pruritis. Hepatic failure may develop after many months of therapy. There have been cases of fatal fulminant hepatic failure that have been reported despite discontinuation of medication (1 case in 30000 patients treated per year). Psychiatric adverse effects are rare. Psychosis, confusional states, mutism, headbanging, memory impairment, and rarely stupor have been reported, and effects are dose-dependent. Symptoms usually resolve after discontinuation of disulfiram and a short course of antipsychotic medication. Psychosis may occur as a result of an interaction between disulfiram and cannabis. Neurological adverse effects may occur as early as 10 days after initiation. Axonal polyneuropathy is a rare adverse effect. Some cases of severe sensory-motor polyneuropathy with the involvement of cranial nerves have been reported within weeks of initiation of disulfiram 500 mg. Neuropathy occurs in 1 case per 1000 patients treated with disulfiram per year.

Drug interactions occur with compounds utilizing the cytochrome P450 enzyme system for oxidative metabolism. This interaction can occur with the following medications: amitriptyline, imipramine, phenytoin, chlordiazepoxide, diazepam, omeprazole, and acetaminophen. Drug-drug interactions may occur with other medications not listed. Slow elimination of disulfiram may give rise to the disulfiram-alcohol reaction up to fourteen days after the discontinuation. Disulfiram-alcohol reactions have been reported in patients exposed to environmental chemical compounds containing alcohol.

Contraindications

Disulfiram is not a safe option for everyone. Disulfiram is contraindicated absolutely in patients with significant coronary artery disease or heart failure. Cases of heart failure and death have occurred in patients with severe myocardial disease shortly after the initiation of disulfiram. Disulfiram is contraindicated with psychosis as it may worsen the patient's psychosis. Caution is necessary for patients with a history of liver disease, and the physician must weigh the risks versus benefits. Patients receiving metronidazole, paraldehyde, alcohol, or alcohol-containing preparations (sauces, cough mixtures, vinegar) should not receive disulfiram and should be educated in advance to avoid a disulfiram-alcohol reaction. Never administer to a patient if alcohol use is suspected or without the patient's consent and understanding of disulfiram-alcohol reaction. Disulfiram may be a therapeutic option with caution in patients with seizures, diabetes, thyroid disorders, traumatic brain injury, and renal disease due to the possibility of an accidental disulfiram-alcohol reaction.

Monitoring

Close monitoring of adverse events is necessary, in particular, in patients with polysubstance abuse. Patients taking disulfiram require monitoring for signs and symptoms of hepatitis, including fatigue, weakness, anorexia, nausea, vomiting, jaundice, malaise, and dark urine. Baseline and follow-up liver function tests should be monitored ten days to one month following initiation of disulfiram. Complete blood count and serum chemistries should also require routine monitoring.

Toxicity

Contact the local Poison Control Center in case of overdose. No information is available on the treatment of disulfiram overdose, and there is no antidote available. Supportive care via supplemental oxygen, cardiac monitoring, and intravenous fluids may be necessary. Consult a physician if symptoms are severe. Cases of ingestion equal to or greater than 5 gm resulted in parkinsonism, choreoathetosis, and thalamic syndrome. Doses should not exceed 500 mg/day for treatment of alcohol dependence, and doses for malignancy remain as yet undetermined.

Enhancing Healthcare Team Outcomes

Disulfiram may be prescribed by the nurse practitioner, physician assistant, primary care provider, emergency department physician, or internist. However, all healthcare workers, including the nursing staff and pharmacist, must be familiar with its adverse effect profile. The agent is not well tolerated, and when consumed with alcohol, can produce severe side effects that can even lead to a heart attack. Today, this drug is not used to treat alcoholism because it is not deemed to be safe.[10]

When using disulfiram requires an interprofessional team approach. Prescribing was covered in the previous paragraph, and the pharmacist should have input regarding dosing as well as drug-drug interactions by performing complete medication reconciliation, reporting any concerns to the prescribing clinician. Nursing should monitor for treatment effectiveness and adverse reactions to disulfiram, also alerting the team should anything significant present. Only with an interprofessional team approach can disulfiram therapy have the potential for success. [Level 5]