Disulfiram

Disulfiram primarily works by inhibiting the action of aldehyde dehydrogenase, the enzyme involved in the second step in the metabolism of alcohol, that converts acetaldehyde to acetate. This leads to the accumulation of acetaldehyde following consumption of alcohol while on disulfiram. The resulting symptoms are unpleasant including flushing, dizziness, nausea and vomiting, irregular heartbeat, breathlessness and headaches. Disulfiram acts as a deterrent to drinking because the patient expects to experience these negative consequences. 

Disulfiram has been associated with significantly greater rates of abstinence relative to control, primarily in open-label studies. Supervised intake of disulfiram to ensure treatment adherence has been associated with greater success.

Based on the results of the recent studies discussed above and previous clinical experience, disulfiram is an appropriate medication for patients who are motivated to abstain from alcohol. It should not be prescribed for patients who have a goal of reduced alcohol intake. It is beneficial for patients that accept a need for an external control on their drinking and are prepared to be supervised in the daily dosing of the medication. Since it is most effective with supervised administration, willingness of patient’s spouse, family member or a friend is an important factor. 

Disulfiram can cause significant toxicity if relapse occurs. It should only be prescribed to patients that display no medical or psychosocial contraindications as described below. 

The intensity of the disulfiram-alcohol reaction varies amongst patients and in rare cases may result in cardiovascular collapse, myocardial infarction, respiratory depression, convulsion and death.  

Accordingly, treatment is contraindicated for patients with significant cardiovascular, hepatic or pulmonary disease. Several of the patients most suited to disulfiram in other terms may suffer from these problems. A risk-benefit analysis of the treatment should therefore be undertaken by the treating clinician. The death rate due to the disulfiram-alcohol reaction is small (only 1 in 15,000 patients treated), whereas a substantial proportion would be expected to experience premature mortality and/or reduced quality of life if problems are untreated.  

Disulfiram is contraindicated in patients with liver disease because of the production of toxic drug metabolites, which may lead to potentially fatal hepatotoxicity. 

Careful monitoring of cardiac and liver condition is recommended if disulfiram treatment is started. Liver tests should be performed fortnightly for 2-3 months, particularly in those with abnormal tests at baseline.  

There is low grade evidence that disulfiram may result in an exacerbation of psychosis. Treatment in patients with potential risk should be monitored.  

Safe use of disulfiram during pregnancy has not been established. There are no well controlled studies of the safety of disulfiram during pregnancy or lactation. It is not definitive that disulfiram causes fatal abnormalities when administered during pregnancy although there have been rare case reports of congenital abnormalities following prenatal exposure in conjunction with other compounds. The drug is listed in category B2, meaning disulfiram has been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.

The most relevant interaction with other drugs concerns medicinal product containing alcohol (e.g. drop formulations) as this can trigger the disulfiram-ethanol reaction.

Disulfiram increases the blood concentration of benzodiazepines, caffeine, phenytoin, the active ingredient in marijuana, isoniazid, barbiturates, anticoagulants, tricyclic agents and paraldehyde. Disulfiram should not be given concomitantly with paraldehyde because paraldehyde is metabolized to acetaldehyde in the liver.

Moreover, disulfiram reinforces the action of coumarinic anticoagulants thus increasing the international normalised ratio (INR). Disulfiram augments warfarin hypoprothombinemia by chelating the metal cations necessary for the synthesis of active prothrombin. This combination is usually avoided.

Treatment should begin after detoxification, approximately 24-48 hours after drinking cessation. Medical history should be taken. It is important to discuss the effects of the drug when alcohol is taken, including potential severe, life threatening reaction. The patient’s anticipation of its effects will greatly enhance the drug’s effectiveness as a deterrent against drinking. Disulfiram should be seen as an aid that does not detract from the patient’s own responsibility in maintaining abstinence.

Based on the outcomes of the recent studies discussed above, disulfiram treatment is best suited to individuals with social supports (e.g. family) who will help supervise medication. Supervision has a marked effect on adherence and may greatly improve the effectiveness of this intervention.

A spouse/partner is an obvious choice for married/de facto patients. It is important to stress that the spouse cannot be expected to control the other person’s drinking. A written ‘disulfiram contract’ should be considered between a carer and patient. This contract should include an outline of the likely effects of drinking and products that may need to be avoided (e.g. facial products), the recognition that the patient will allow the medication to be supervised, that the carer will be the supervisor and that the supervisory role includes contacting the health professional if medication compliance becomes a problem.

Disulfiram is formulated in tablets of 200mg, with the recommended dose being 200- 400mg (1-2 tablets/day orally). Some patients can continue to drink on 200-400 mg without significant aversive effects, and the dose should be increased. The maintenance dosage should generally not exceed 600 mg a day. In many patients, two or three doses per week may be sufficient, and this approach may be more practical and easier to schedule with supervision.

Disulfiram is available in tablets. It is not subsidised by the Pharmaceutical Benefit Scheme (PBS).

Disulfiram is likely to be a useful treatment for the first 3-6 months of treatment. After that the benefits of continuing use are less clear and the patient should be reviewed before continuation. Some patients continue treatment for 12 months or more, particularly when effective and for severe AUD. Prolonged treatment is supported by published uncontrolled case series.

Some of the common adverse effects of disulfiram include drowsiness, nausea, headache and fatigue. Some patients may report taste disturbance (metallic or garlic-like). Rarely, jaundice, hepatitis (sometimes fatal), peripheral neuropathy, psychosis, confusion, optic neuritis, blood dyscrasias and rash may occur. These are more common when doses exceed 400mg daily. 

Clinicians should educate patients about expected side effects and duration; and should distinguish between prolonged alcohol withdrawal symptoms and side effects of disulfiram by beginning treatment once the more pronounced features of withdrawal have subsided (after the first 3 to 5 days). Patients should be advised to stop taking disulfiram at once and tell their doctor if they notice yellowing of their eyes or skin, dark urine. 

Even very small amounts of alcohol may cause unpleasant effects. Clinicians should advise patients to avoid using alcohol in cooking and choose skin and oral hygiene products (such as perfumes, body lotions, mouth washes) that do not contain alcohol. Some medicines contain alcohol and should also be avoided. However, the strength of the alcohol–disulfiram interaction varies between individuals. Some patients react to very small amounts of alcohol, others have little reaction when consuming large quantities of alcohol. 

Potentially fatal hepatoxicity can occur with disulfiram, although rare. The hepatoxicity is usually reversible if disulfiram is stopped before clinically evident liver disease is present. Therefore, monitoring of liver function is crucial. As the onset can be very rapid, it is important to inform patients of the risks and symptoms. If adverse symptoms are noted, disulfiram should be stopped. 

As per above, it is crucial to closely monitor liver functions tests due to the hepatotoxic effects, especially in patients with pre-existing elevated liver function tests prior to commencement of disulfiram treatment.  

Treatment should be suspended if the patient lapses; psychosocial relapse prevention techniques should be used to deal with the lapse or relapse (see Chapter 9). Disulfiram may be recommenced after 48 hours abstinence. 

Alcohol metabolism returns to normal between 7 and 10 days (sometimes three weeks) after stopping disulfiram, as new enzymes must be synthesised. Patients may experience adverse reaction if they drink alcohol within 7 days after stopping treatment. Psychosocial relapse prevention interventions should continue beyond the end of pharmacotherapy.