Which type of drug preparation is contraindicated for a patient taking Disulfiram Antabuse?

Cardiovascular

Disulfiram in a dose of 250–300 mg/day does not affect pulse rate, blood pressure, or plasma noradrenaline concentrations, but 500 mg/day causes an increase in plasma noradrenaline, increased systolic blood pressure both recumbent and erect, and an increased erect pulse rate. The raised blood pressure does not reach hypertensive values, but the results suggest increased sympathetic nervous system activity in patients who take disulfiram. Caution should therefore be exercised in using disulfiram in hypertensive patients. Close monitoring of blood pressure is advised, and the dose of disulfiram should preferably be reduced to 250 mg/day [5].

Cardiac dysrhythmias occurred during a disulfiram + alcohol test in a 48-year-old man who had been an alcoholic for 5 years [6]. After drinking a test amount of alcohol, he developed flushing, nausea, vomiting, sweating, dyspnea, and hyperventilation, palpitation, tremor, confusion, and syncope. The electrocardiogram showed atrial fibrillation and non-sustained bouts of ventricular tachycardia of 7–8/minute. He also had severe hypotension.

A 27-year-old man took disulfiram and ethanol and developed significant hypotension and ischemic electrocardiographic changes [7]. He was treated with intravenous fluids and noradrenaline, which has been advocated as the pressor agent of choice.

Acute and Short-Term Toxicity (Animal/Human)

Disulfiram

Disulfiram is a form of aversive therapy that has been available since the 1940s. Disulfiram interferes with the metabolism of alcohol by irreversibly inhibiting aldehyde dehydrogenase, leading to the accumulation of acetaldehyde, which results in flushing, sweating, nausea, and tachycardia. Secondary mechanism of disulfiram is on the central nervous system to inhibit dopamine-β-hydroxylase from converting dopamine to norepinephrine, which potentially increases dopamine levels and may decrease cravings.

Serious adverse reactions include hepatotoxicity, optic neuritis, peripheral neuropathy, and psychotic reactions. Common side effects include metallic aftertaste, dermatitis, and transient sedation.

The efficacy of disulfiram is limited due to generally poor compliance when patients take it at their own discretion. Disulfiram is more effective when given in a monitored or witnessed setting for a highly motivated individual. Preliminary evidence shows that disulfiram may reduce alcohol cravings and increase consecutive days of abstinence among patients with alcohol dependence and comorbid psychiatric disorders.

Contraindications to disulfiram include use of alcohol-containing products or metronidazole. Relative contraindications include coronary artery disease, severe myocardial disease, and hypersensitivity to rubber (thiuram) derivatives.

Use disulfiram with caution in patients with hepatic cirrhosis or insufficiency, cerebrovascular disease or cerebral damage, psychoses (present or past), diabetes mellitus, epilepsy, hypothyroidism, and renal impairment. Disulfiram belongs to pregnancy category C. Patients must be reminded to carry a card to alert medical personnel in emergencies.

Disulfiram is available in oral daily dosing form at 250 mg daily (range 125–500 mg day−1). Potential drug interactions of disulfiram include warfarin, isoniazid, phenytoin, and any nonprescription medication containing alcohol. Prior to prescribing disulfiram, the patient’s liver function should be evaluated and subsequently monitored. Due to possible disulfiram–alcohol reaction, disulfiram should not be taken for at least 12 h and ideally 2 weeks after drinking alcohol. Patient needs to be instructed to avoid alcohol in the diet (vinegars and sauces), over-the-counter medications, and toiletries.

Disulfiram (Antabuse®)

Disulfiram was the first medication FDA approved for the treatment of AUDs in 1951. Disulfiram is an alcohol-aversive medication that causes a severe physical reaction when mixed with alcohol. If a patient consumes disulfiram and then ingests alcohol, a disulfiram–alcohol reaction is produced. The reaction begins 10–30 min after the alcohol is ingested and the adverse effects may include nausea, vomiting, headache, chest pain, weakness, blurred vision, mental confusion, sweating, and difficulty breathing. However, effects vary by individual patient. Disulfiram is available in tablet form and the recommended dosage ranges from 250 to 500 mg day−1.

Findings from clinical trials on the efficacy of disulfiram therapy are mixed. Results emphasize the importance of treatment setting and ongoing supervision of patients. The National Institute on Alcohol Abuse and Alcoholism TIP 49 states that both the level and the quality of supervision received by a patient are important elements in the success of disulfiram therapy and optimum response to the medication requires its use in specialty SUD treatment settings.

DISULFIRAM

Disulfiram is an aversion-based therapy that produces sensitivity to alcohol, resulting in a highly unpleasant reaction even when small amounts of alcohol are consumed. Disulfiram alters the normal metabolism of alcohol by inhibiting the enzyme aldehyde dehydrogenase and increases the levels of the toxic alcohol metabolite acetaldehyde. Clinical manifestations include flushing, tachycardia, hypotension, nausea, vomiting, diarrhea, and headache (Swift, 2007). These effects provide a strong deterrent for alcohol use.

Although disulfiram has been available since the late 1950s, there have been few well-controlled studies on the effectiveness of disulfiram treatment. The largest treatment study compared 1 year of 250 mg daily disulfiram, 1 mg disulfiram (placebo), and a multivitamin in 605 male alcohol-dependent subjects (Fuller et al., 1986). Results showed no differences in abstinence rates or time to first drink among the groups. More recent studies have suggested that disulfiram may be efficacious for some alcohol-dependent patients. A 6-month, double-blind study in 126 British patients found that those who received 200 mg disulfiram daily had more total days abstinent, reduced weekly drinking, and lower levels of γ-glutamyltransferase (a blood protein used commonly as a biomarker for heavy alcohol use) compared with those who received a vitamin placebo (Chick et al., 1992). In a 12-week treatment study of 122 patients with combined cocaine and alcohol dependence receiving psychotherapy and either disulfiram or no medication, those receiving disulfiram were found to have better treatment retention, as well as a longer duration of abstinence for both cocaine and alcohol use. Importantly, the treatment benefits were retained at the 1-year follow-up (Carroll et al., 2000).

Direct supervision of disulfiram ingestion and involvement in psychosocial treatment have been shown to increase its effectiveness. O’Farrell studied couples receiving behavioral marital therapy with and without a contract for spousal supervision of disulfiram compliance and found that the disulfiram contract reduced drinking compared to therapy alone (O’Farrell, Allen, & Litten, 1995).

Although the evidence for efficacy of disulfiram therapy is limited, disulfiram is still used, especially when a patient needs “external” control to maintain long-term abstinence. Enhancing medication adherence with direct supervision and involvement in psychosocial therapies that support medication use improve the effectiveness of disulfiram greatly (Suh, Pettinati, Kampman, & O’Brien, 2006). Patients receiving disulfiram must receive education about the consequences of drinking alcohol while taking the drug and must be committed to complete abstinence.

Disulfiram is available in 250-mg tablets. The usual oral dose is 250 mg once daily, although doses range from 125 to 500 mg, depending on side effects and patient response. Some researchers recommend higher doses, as a significant proportion of patients may not experience a disulfiram-alcohol reaction at the usual 250-mg daily dose (Brewer, 1993). However, side effects are increased at doses greater than 250 mg.

Disulfiram

Disulfiram has been utilized as a treatment for alcoholism for over 60 years. It functions as an aldehyde dehydrogenase inhibitor. The impaired metabolism of alcohol and increased concentration of acetaldehyde creates unpleasant subjective effects that deter alcohol consumption. As cocaine and alcohol are co-abused, one plausible mechanism by which disulfiram might exert effects is through a reduction of alcohol and its cueing effect for cocaine usage. Yet a more likely mechanism to explain disulfiram efficacy in cocaine-dependent populations involves inhibition of dopamine beta-hydroxylase. Recent work that disentangled disulfiram effects on cocaine abstinence initiation from its ability to support relapse prevention has demonstrated that disulfiram blocks cocaine-induced reinstatement in laboratory animals through disruption of the conversion of dopamine and the resultant altered ratio of dopamine to norepinephrine. This strong evidence points to inhibition of the enzyme dopamine beta-hydroxylase as the mechanism of action for disulfiram action in reducing cocaine use.

Several randomized, placebo-controlled trials support disulfiram as a cocaine pharmacotherapy. The interpretation of data on the clinical utility of disulfiram for cocaine dependence, however, is complicated by much of the human work being completed using subjects who are comorbid opioid dependent or comorbid alcohol dependent in the clinical trials. No major clinical trial of disulfiram has been conducted for patients with primary cocaine dependence as their sole diagnosis. The presence of a second chemical dependency may index a higher level addictive process and thus complicates interpretation of these data.

In a recent Cochrane review, seven trials of disulfiram that involved 492 subjects each included individuals with two substance dependencies – five included patients with cocaine dependence and alcohol abuse or dependence; two enrolled individuals with cocaine dependence with concurrent opioid dependence who were maintained on methadone or buprenorphine. Four direct comparisons between disulfiram and placebo were made, while other arms tested disulfiram against naltrexone or a nonpharmacologic treatment. In the comparisons with placebo, there was no significant effect of the medication on treatment retention. Though variability across the studies in the measurement of cocaine use precluded meta-analytic comparisons, the available evidence failed to identify a strong general effect of disulfiram over placebo. Disulfiram, however, demonstrated superior effects over naltrexone.

Subgroup analyses of disulfiram effects in the review showed interesting findings. In two randomized clinical trials, secondary analyses showed gender to moderate treatment responsiveness, whereby men benefitted from disulfiram and women did not. In one trial, the benefits of disulfiram accrued only to those who were abstinent from alcohol during the course of the treatment. Specifically, for those who abstained, disulfiram, cognitive behavioral therapy, and their combination were effective in reducing cocaine use and these outcomes improved over the course of the 12-week treatment period. In contrast, for those reporting a single drink or more during treatment, medication or therapy showed no benefits in terms of cocaine usage. This finding suggests two conclusions: insofar as disulfiram positively affects cocaine usage, this effect is not fully mediated by a reduction in alcohol consumption; second, it is possible that individuals with comorbid alcohol abuse may be medication nonadherent or that comorbid alcoholism dampens the therapeutic utility of the medication (as observed in the large modafinil trial).

A recent report by Oliveto’s group found a nonlinear dose–response relationship for disulfiram as a cocaine treatment. After a period of stabilization on methadone, cocaine and opioid-dependent participants were randomized to placebo or 62.5 mg, 125 mg, or 250 mg of disulfiram for 12 weeks. Participants were included in the analyses only if they completed the first 2 weeks of treatment. Over the full course of treatment, disulfiram did not impact opioid use, compliance with methadone treatment, nor did it exert an effect on drinking, although this may have been due to a very low level of drinking in the sample. In terms of the percentage of urine samples negative for benzoylecgonine, generalized linear mixed effects models showed that both the 250 mg and the placebo condition significantly reduced cocaine use. By contrast, the midrange dosage conditions for disulfiram increased cocaine consumption. The “inverted U” effects on cocaine use observed in this trial are difficult to explain and may be best understood as a function of the complex pharmacology and behavioral effects of disulfiram. The authors conclude that disulfiram in doses lower than 250 mg may be contraindicated for cocaine and opioid-dependent individuals. The viability of 250 mg compared to a higher dose (e.g. 500 mg) remains unclear.

Neurological

Disulfiram (tetraethylthiuram disulfide) is a quaternary ammonium compound used for treating alcohol dependency for over 60 years. It is an inhibitor of dopamine-β-hydroxylase causing an increase in the concentration of dopamine in the brain. Initially, when disulfiram was being used, the doses were much higher (1000–3000 mg) than today (250–500 mg) due to reports of neurotoxicity, delirium, and psychosis.

Alves et al. reports a case of a rare complication when using disulfiram for alcoholism treatment in a patient in alcoholic abstinence [29A]. A 42-year-old male developed psychotic symptoms 3 weeks after initiating treatment with disulfiram for alcohol dependency. The patient had a history of chronic alcoholism for 12 years and was under disulfiram treatment (250 mg/day) for 1 month, with no other past history of psychiatric illness. The symptoms worsened after he initiated alcohol consumption, while taking disulfiram. When he was admitted at the emergency room he presented symptoms of alcohol disulfiram reaction with tachycardia, sweating, and vomiting. Serological examination showed hepatic alterations (GGT-124, ALT-92); alcohol was positive—0.07. After the patient was hospitalized disulfiram was suspended the patient became asymptomatic in 4 days remained asymptomatic after 6 weeks. Treatment with disulfiram can lead to the appearance of psychosis, which can be related to alcohol-induced psychotic disorder based on symptoms, such as delusions and auditory and visual hallucinations. In clinical practice, psychosis in the context of alcoholism with disulfiram therapy is often neglected and should be taken into account. Patients with a family history of psychosis are more vulnerable to precipitants of psychosis than others due to genetic predisposition. The patient's father was previously diagnosed with chronic alcoholism when he presented with psychotic symptoms. Because of this family history, this patient may have low levels of dopamine-β-hydroxylase; so, when disulfiram blocks it, there is a greater predisposition to the development of psychosis. Other recent studies reported have alluded to side-effects of disulfiram ingestion including hepatic failure [30A] and risks of myocardial infarction [31A].

Disulfiram

Disulfiram irreversibly inhibits acetaldehyde dehydrogenase and causes acetaldehyde to accumulate following ingestion of alcohol. Elevated blood acetaldehyde causes facial flushing, severe headache, palpitations, tachycardia, hypertension, respiratory distress, nausea and vomiting. These symptoms commence within 15–30 min of ingesting alcohol and persist for several hours. Tachyarrhythmias, hypotension, collapse and occasional deaths occur if large quantities of alcohol are consumed. Alcohol challenge in which the effects of disulfiram are demonstrated to a patient taking disulfiram by administering a small quantity of alcohol is strongly discouraged.

Patients must be alcohol-free for at least 24 h before disulfiram is administered (and for at least 7 days after it is discontinued). It is usually prescribed in an initial dose of 800 mg daily. This is gradually reduced over 5–7 days to a maintenance dose of 100–200 mg daily. Patients must be warned that a disulfiram/alcohol interaction may be triggered by alcohol in some foods, in cough remedies and in toiletries such as aftershave lotions. They should also be encouraged to carry a card advising that they are being treated with disulfiram.

The adverse effects of disulfiram in the absence of alcohol include nausea, vomiting, drowsiness, halitosis, metallic taste and reduced libido. Dermatitis, hepatitis, peripheral neuritis and encephalopathy may also rarely occur. Disulfiram inhibits dopamine β-hydroxylase and elevates brain concentrations of DA. This may exacerbate schizophrenia and may rarely cause psychosis in otherwise healthy individuals.

Disulfiram in Alcohol Use Disorders

Disulfiram (Antabuse) was approved by the US Food and Drug Administration (FDA) for the treatment of alcohol dependence in 1951 and was the first medication to be given this indication. It remained the only FDA-approved medication for the treatment of alcohol dependence for several decades, until the approval of oral naltrexone in 1994. Disulfiram’s utility in the treatment of alcohol use disorders primarily relies on “psychological deterrence,” with patients ceasing consumption of alcohol in order to avoid the unpleasant disulfiram–ethanol reaction. Disulfiram is considered an “antidipsotropic” agent (one that prevents drinking) and is still referred to as an “aversive” agent. Though no longer done in current clinical practice, patients receiving disulfiram many years ago were initially administered both disulfiram and alcohol, creating an in vivo experience of aversive conditioning with the intent to eliminate drinking. This was not particularly successful, so more recently disulfiram is prescribed to help individuals avoid consuming alcohol. While taking disulfiram, its potential to foster complete abstinence from alcohol is unique among agents used to treat alcoholism and confers both great strength and weakness to the medication.

Numerous studies examining the clinical use of disulfiram have been published over a span of several decades. Early studies largely reported quite positive results. Unfortunately, many suffered from significant limitations, including lack of blinding, no monitoring of treatment adherence, inadequate follow-up periods, lack of comprehensive treatment plans, and nonrandomization. The majority of studies did not include control groups, and only very limited conclusions could be drawn from the first decades of study.

Taken as a whole, the accumulation of published literature has been equivocal in its support for disulfiram as an effective treatment for alcohol dependence. The largest and most frequently cited trial was a multi-site, Veterans Affairs (VA) cooperative study which included 605 veterans. Participants were randomly assigned to receive (1) 250 mg of disulfiram with 50 mg of riboflavin, (2) blinded 1 mg of disulfiram with 50 mg of riboflavin, or (3) no disulfiram with 50 mg of riboflavin. The inclusion of riboflavin was utilized to measure medication adherence. The second group, who received only 1 mg of disulfiram in a blinded fashion, was included in order to confer the psychological threat of a disulfiram–ethanol reaction, without occurrence of the actual experience. All subjects in the study were given counseling.

Disappointingly, all three groups in the study showed similar outcomes, including total abstinence and time to first drink. Among those who drank and had a complete set of assessment interviews, those in the 250-mg disulfiram group, reported significantly fewer drinking days than either of the other two groups, which led to the suggestion that disulfiram may help reduce drinking frequency after relapse. Compliance with the drug regimen (in all three groups) was the best predictor of positive outcome (abstinence). However, only 20% of patients who completed the study were medication compliant. Though impressive in its scope, this study was limited by its lack of any systematic procedures known to enhance medication compliance, such as supervised use, administration by a significant other, or behavioral contracting.

Data from several smaller trials utilizing supervised disulfiram administration have produced some positive results. In a randomized, placebo (vitamin C)-controlled trial involving 126 alcohol-dependent patients, the disulfiram-treated group had a significantly higher number of abstinent days, decreased mean weekly alcohol intake, and lower total alcohol consumption over a 6-month period compared to the vitamin C group. Two-thirds of the disulfiram group requested to continue the treatment at the end of the study. Other studies have found increased rates of abstinence and “significant periods of sobriety” in the context of supervised disulfiram use.

It has been repeatedly shown that techniques known to improve medication compliance, such as incentive-driven interventions and supervised disulfiram treatment, are associated with improved outcomes, including decreased alcohol consumption and achievement of abstinence. Based on these findings, it is strongly recommended that disulfiram use should be supervised and prescribed within a comprehensive treatment program. A small body of literature suggests that court mandates may also improve adherence with disulfiram therapy.

In attempting to address issues with compliance, investigations have been conducted on the use of disulfiram implants. The technique of subcutaneous disulfiram implantation was first introduced in the 1960s. Implants were intended to release disulfiram at a consistent rate and sufficient dose to invoke the disulfiram–ethanol reaction if the patient consumed alcohol. However, the effectiveness of disulfiram implants remains in doubt. Many studies utilizing disulfiram implants have suffered from methodological flaws. Furthermore, significant concerns regarding the implants themselves have arisen, including insignificant absorption and/or inadequate release of drug, infections, and other adverse physiological consequences. Disulfiram implants are not currently licensed for use in the United States.

The relationship between medication compliance and the effectiveness of disulfiram treatment is admittedly complex. It has been suggested that patients who are able to maintain compliance with disulfiram likely represent a more motivated, treatment-adherent subset of individuals whose success in achieving abstinence may not be attributable to the drug itself. These patients are hypothesized to be more likely to achieve positive outcomes, regardless of the treatment prescribed. Furthermore, a patient’s willingness to take a medication, such as disulfiram, which confers the risk of a significantly unpleasant bodily experience, is likely indicative of a heightened level of determination.

It is possible that disulfiram may be more useful in patients with certain characteristics. Though the literature on this topic has been unable to draw definite conclusions, patients who are older (over 40), socially stable, highly motivated, and able to tolerate treatment relationships have been shown to be more likely to benefit from disulfiram treatment. Additional predictors of positive response include longer drinking histories and Alcoholics Anonymous (AA) involvement.

Disulfiram may be particularly useful in the abstinence initiation phase of treatment, given its likelihood of eliminating impulsive drinking. However, it is not useful in preventing alcohol consumption planned in advance (allowing for premeditated nonadherence with the medication). The total prohibition of drinking fostered by disulfiram may also reduce preoccupation with alcohol, as craving has been shown to be related to perceived availability of substances.

In summary, the use of disulfiram in the treatment of alcohol dependence has garnered mixed results to date. However, there is evidence that disulfiram can be useful in reducing alcohol consumption and increasing rates of abstinence, particularly in the context of supervised use and among motivated individuals. Despite its potential utility, however, disulfiram is infrequently prescribed and, even then, often used for brief periods of time only. The exact reasons for this are unclear, though likely multifactorial. Patient acceptance can be hampered by fear of side effects or the disulfiram–ethanol reaction itself. Many patients are ambivalent about taking medication which dictates abstinence rather than allowing for occasional consumption. Physicians may be uncomfortable prescribing disulfiram due to lack of knowledge and experience with the medication, and many lack sufficient time/resources to comprehensively manage these patients. Additional factors include doubts about pharmacotherapeutic effectiveness, concern that medication might reduce motivation for psychosocial treatment and mutual-help group attendance, and cost. In spite of the high prevalence of alcohol dependence and its consequences, disulfiram remains underutilized.

9.2.6.1 Disulfiram (Antabuse)

Disulfiram was the first approved medication for AUD in 1951 (Mason and Heyser, 2021) that works primarily by blocking the metabolism of alcohol by the body. The goal for individuals taking disulfiram is complete abstinence, as any alcohol intake induces a rapid-onset aversive physical reaction. By irreversibly inhibiting ALDH, disulfiram induces acetaldehyde accumulation resulting in a physical reaction consisting of flushing, nausea, and vomiting which can last hours depending on how much alcohol is consumed. In this manner, Disulfiram acts directly on the binge/intoxication cycle to reduce the reinforcing properties of alcohol and prevent any amount of alcohol consumption.

Because disulfiram is metabolized by the liver, individuals must have regular blood tests to monitor liver function. It is taken as one pill daily, and the treatment cost per month is estimated to be $48 (Mason and Heyser, 2021). One major problem with disulfiram is medication non-compliance—individuals know that if they take the drug and drink, the result will be an extremely unpleasant physical reaction. Thus, by avoiding taking the medication, they avoid the aversive reaction. Unfortunately, this is not always true—disulfiram is an irreversible ALDH inhibitor, and its actions can last up to 14 days following the last dose. Individuals taking disulfiram need to be careful to avoid cooking wine, vinegar, kombucha and ethanol-containing mouthwash—as these products may trigger the disulfiram reaction (Fairbanks et al., 2020). Adverse events include neuropathy, hepatic failure, drowsiness, fatigue, impotence, headache, acne, and allergic dermatitis (Mason and Heyser, 2021). Disulfiram can also inhibit DBH, thus increasing dopamine levels which may result in psychosis (Fairbanks et al., 2020). Because of all the potential and serious side effects, disulfiram is best administered to patients under strict supervision—making it the second line treatment for patients in a controlled environment (Fairbanks et al., 2020). Contraindications include the use of metronidazole, paraldehyde, alcohol-containing preparations, severe myocardial disease, coronary occlusions and psychosis (Mason and Heyser, 2021).