1. Taken daily; 2. Do not take within 12 hours of ingesting alcohol; 3.Do not drink alcohol during or for 14 days following Antabuse therapy; 4. Check all medications for alcohol as an ingredient; 5. Use caution when operating vehicles or performing tasks with dangerous equipment; 5. Report signs of hepatotoxicity. Related Questions
 Your entire career may be on the line. Don't risk wasting time and money on a repeat exam if you fail. With NCLEX Premium, you'll walk out of the testing center feeling like you just took a first grade spelling test. Chemical name: Bis(diethylthiocarbamoyl) disulfide. Trade name: Antabuse®. U.S. distributor: Odyssey Pharmaceuticals, Inc., East Hanover, NJ. U.S. Food and Drug Administration approval to treat alcohol dependence: 1951. Dosage/How taken: Tablet by mouth once daily (also may be crushed and mixed with water, coffee, tea, milk, soft drink, or fruit juice). How supplied: Bottles of 100 or 1,000 250 mg tablets or bottles of 50, 100, or 500 500 mg tablets. Storage: Keep out of reach of children; keep tightly closed in original container; store at room temperature, away from excess heat and moisture (not in the bathroom or near a sink); discard when outdated or no longer needed. Disulfiram was the first medication approved by the U.S. Food and Drug Administration (FDA) to treat chronic alcohol dependence. In its pure state, disulfiram is a white to off-white, odorless, almost tasteless powder, which is soluble in water and alcohol. Disulfiram, an alcohol-aversive or alcohol-sensitizing agent, causes an acutely toxic physical reaction when mixed with alcohol. Continuing research and clinical findings have clarified disulfiram's mode of action and established its safe and effective use in the treatment of alcohol use disorders (AUDs) in some patient groups. Exhibit 3-1 summarizes disulfiram's development history. View in own window
Unlike other medications approved to treat alcohol dependence, disulfiram does not affect brain opiate, γ-aminobutyric acid, or glutamate receptors directly. However, it does have some central nervous system effects, inhibiting enzyme dopamine β-hydroxylase and affecting serotonergic function. Whether disulfiram directly decreases the urge to drink remains uncertain. However, disulfiram definitely disrupts the metabolism of alcohol, causing a severe reaction when patients mix disulfiram and alcohol. Patient knowledge of a possible severe reaction to alcohol consumption is thought to increase the patient's motivation to remain abstinent. Some experts (e.g., Schuckit, 2006) question disulfiram's effectiveness because the time between alcohol ingestion and the reaction can be as long as 30 minutes and the intensity of the reaction is unpredictable. Normally, the enzyme alcohol dehydrogenase in the liver and brain transforms alcohol into acetaldehyde. The enzyme aldehyde dehydrogenase (ALDH), also in the liver and brain, oxidizes the acetaldehyde byproduct into acetic acid. Disulfiram blocks this oxidation by inhibiting ALDH, causing a rapid rise of acetaldehyde in the blood when alcohol is consumed. The result is called a disulfiram-alcohol reaction, and it may increase the acetaldehyde concentration in blood to 5 to 10 times that occurring without disulfiram. Disulfiram does not appear to affect the rate of alcohol elimination from the body. The disulfiram-alcohol reaction usually begins about 10 to 30 minutes after alcohol is ingested. Its adverse effects range from moderate to severe (Exhibit 3-2). Intensity varies with individual patient characteristics. The reaction is generally proportional to the amounts of disulfiram and alcohol ingested. Mild effects may occur at blood alcohol concentrations of 5 to 10 mg/100 mL. At 50 mg/100 mL, effects usually are fully developed. When the concentration reaches 125 to 150 mg/100 mL, unconsciousness may occur. Although disulfiram-alcohol reactions can be life threatening, as indicated in Exhibit 3-2, the reduced dosages and careful patient medical screening now in practice have made this outcome extremely rare. View in own window
Early researchers believed that patients needed to experience at least one supervised disulfiram-alcohol reaction to understand its effects. The practice of deliberately inducing a reaction by giving large doses of disulfiram in conjunction with “alcohol challenges” has been abandoned. A clear, convincing description of the reaction is considered sufficient for most patients. About 80 to 95 percent of ingested disulfiram is absorbed from the gastrointestinal tract and rapidly distributed to tissues and organs. It is then metabolized to various mixed disulfides. The unabsorbed fraction is excreted. Disulfiram is irreversibly bound to ALDH. It can take up to 2 weeks for the body to synthesize sufficient unbound enzyme to metabolize alcohol adequately. This is why alcohol ingestion may produce unpleasant symptoms for up to 2 weeks after a patient has taken the last dose of disulfiram. Disulfiram may work as an adjunct to psychosocial treatment to eliminate alcohol consumption for patients who can achieve initial abstinence of at least 12 hours, are committed to maintaining abstinence, agree to take the medication, and do not have contraindications to disulfiram. Findings on the efficacy of disulfiram treatment are mixed. (To review some reports, see the online annotated bibliography and literature review at http://www.kap.samhsa.gov.) Studies concluding that disulfiram is effective in treating AUDs frequently emphasize the circumstances in which it is administered to patients. In particular, the level and quality of supervision a patient receives while taking disulfiram are believed to be important elements in its success (e.g., Brewer, Meyers, & Johnsen, 2000; Kristenson, 1995). Some studies have found that court-ordered disulfiram therapy promotes efficacy by increasing adherence to the disulfiram regimen (Martin, Clapp, Alfers, & Beresford, 2004; Martin, Mangum, & Beresford, 2005). Use of incentives, contracting with the patient and a significant other to ensure adherence, providing regular reminders to the patient, and patient behavioral training and social support also may enhance disulfiram efficacy by increasing treatment adherence. Most experts (e.g., Schuckit, 2006) agree that an optimum disulfiram response requires its use in a specialty substance abuse treatment program. One study suggests that disulfiram might be more effective in promoting short-term abstinence and treatment retention after detoxification than in preventing long-term relapse (e.g., Chandrasekaran, Sivaprakash, & Chitraleka, 2001). Nevertheless, the most rigorous study of disulfiram therapy (Fuller et al., 1986) showed unequivocally that disulfiram (250 mg/day), compared with placebo (1 mg/day) or a vitamin, reduced the proportion of days of alcohol consumption for the duration of the study (1 year) in male veterans who reported some drinking. However, there were no differences between treatment groups in the percentage of veterans sustaining abstinence throughout the study period. Some experts dismiss disulfiram as a viable treatment option, particularly in primary care settings. This conclusion is based on mixed results with disulfiram in clinical trials and the severe adverse effects that may result from the disulfiram-alcohol reaction, as well as concerns about other potentially serious side effects and “problems with compliance” (Williams, 2005, pp. 1776–1777). The capacity to arrange ongoing supervision of disulfiram ingestion may be limited in a primary care setting. The consensus panel concludes that disulfiram is most effective for patients who have undergone detoxification or are in the initiation stage of abstinence, especially when they are committed to abstinence and receive adequate, ongoing supervision. Disulfiram may not reduce the urge to drink alcohol. However, it may assist in motivating the patient not to drink. As with other medications, general efficacy also increases when disulfiram is administered in conjunction with intensive behavioral interventions. Patients with severely impaired judgment or who are highly impulsive from a severe mental illness or cognitive impairment may be inappropriate candidates for treatment with disulfiram. Disulfiram has been used to treat AUDs for almost 60 years. Deaths from the disulfiram-alcohol reaction have become rare because lower dosages are used and patients with severe cardiac disease are excluded from disulfiram treatment (Chick, 1999). Its hepatotoxicity in some patients remains a concern (see Side Effects, Contraindications, and Cautions below). Side effects of disulfiram are usually minor (see Exhibit 3-4 below). Severe adverse reactions are uncommon (see Exhibit 3-8 below). However, patients receiving disulfiram should be monitored for hepatotoxicity (see Timing of Laboratory Work below). Disulfiram may cause hepatitis, but the risk is low. Estimates of disulfiram-induced hepatitis are between 1 in 25,000 (Wright, Vafier, & Lake, 1988) and 1 in 30,000 (Chick, 1999, p. 427) patients treated per year. A disproportionate number of these cases may be associated with use of disulfiram to treat nickel allergy (an unusual but known indication for use of disulfiram). A black-box warning about treatment with disulfiram is included in the Antabuse package insert. Before administering disulfiram, the clinician should inform patients and their families about the disulfiram-alcohol reaction, including that this reaction may occur for up to 14 days between the last ingested dose of disulfiram and alcohol consumption. Disulfiram should never be administered to a patient who is in a state of alcohol intoxication or without the patient's full knowledge. The physician should instruct relatives accordingly. Physicians should not administer disulfiram until the following steps have been taken:
There is strong evidence that supervised ingestion is necessary for disulfiram therapy compliance (e.g., Brewer et al., 2000; Kristenson, 1995; reviewed by Fuller & Gordis, 2004). Although not absolutely essential, supervised administration by a pharmacist, healthcare provider, or family member is preferred as a key component of the treatment plan. Exhibit 3-3 summarizes standard dosage information for disulfiram. Additional dosage information includes the following:
Disulfiram can cause minor side effects (Exhibit 3-4). The common side effects typically occur during the first 2 weeks of therapy and wane either spontaneously or after a decrease in the disulfiram dosage. View in own window
* Dermatologic side effects often can be managed with concomitant antihistamines. Hepatic toxicity including hepatic failure resulting in transplantation or death has been reported. Severe and sometimes fatal hepatitis associated with disulfiram therapy may develop even after many months of therapy. Hepatic toxicity has occurred in patients with or without a history of abnormal liver function. Patients should be instructed to call their physician immediately if they develop symptoms of possible hepatic impairment (Exhibit 3-5). View in own window
Exhibit 3-6 summarizes contraindications for disulfiram therapy, and Exhibit 3-7 summarizes cautions. Exhibit 3-8 lists severe adverse reactions that may occur with disulfiram and ways to manage them. These reactions are uncommon. View in own window
* Serious disulfiram-induced hepatic injury occurs rarely, and the precise etiology is unknown. Exhibit 3-9 describes the most common drug interactions with disulfiram and their clinical management. Exhibit 3-10 summarizes the recommended laboratory testing regimen for disulfiram therapy. In general, liver function requires ongoing monitoring because of disulfiram's occasional association with hepatic injury. In contrast to liver injury caused by alcohol, which typically shows a high aspartate aminotransferase-to-alanine aminotransferase ratio, disulfiram liver injury usually shows equivalent and very high elevations of both enzymes (Bjornsson, Nordlinder, & Olsson, 2006). Pregnant women should discontinue taking disulfiram immediately. Urine toxicology screening is not an ideal method of detecting alcohol use, although it sometimes can detect use that occurred within a few hours of test administration. View in own window
Severe cases of disulfiram poisoning have been reported, mainly in children who have ingested large amounts because of patients' negligent handling or storage of their medication. Symptoms of overdose include drowsiness followed by coma or persistent nausea, vomiting, aggressive or psychotic behavior, and ascending flaccid paralysis that can reach the cranial nerves. Treatment consists of administration of oxygen therapy, glucose (5 percent intravenously), and sodium ascorbate (1 gram intravenously). The patient should be kept in bed and as quiet as possible with appropriate symptomatic treatment. Patients seemingly on an adequate maintenance dosage of disulfiram who report that they can drink with impunity could be disposing of their tablets without taking them. Physicians should not conclude that disulfiram is ineffective until patients are proved to have been taking their daily tablets. Once patient adherence is confirmed, the physician should consider increasing the disulfiram dosage (see Exhibit 3-3) or changing the patient to another medication. Genetic factors may influence sensitivity to disulfiram in some patients (reviewed by Kenna, McGeary, & Swift, 2004a, 2004b). Wide individual differences exist in the activity of the target enzyme ALDH. Individuals with low intrinsic ALDH activity are more likely to exhibit high sensitivity to disulfiram, and those with high intrinsic ALDH are more likely to show little or no sensitivity to disulfiram. The duration of the disulfiram-alcohol reaction varies from 30 to 60 minutes in mild cases to several hours or until the alcohol is metabolized in more severe cases. When effects are severe, supportive measures may be needed to restore blood pressure and treat shock. Administration of oxygen or carbogen (95 percent oxygen, 5 percent carbon dioxide), large intravenous doses of vitamin C (1 g), ephedrine sulfate, or intravenous antihistamines may be indicated. Potassium levels should be monitored particularly in patients on digitalis because hypokalemia has been reported. Patients should receive thorough education about disulfiram. Use of disulfiram should include ongoing monitoring, medical management, and counseling. Used without proper patient education, motivation, and supportive intervention, disulfiram is unlikely to have more than a brief effect on drinking patterns, particularly in patients with poor medication compliance, more severe forms of alcohol dependence, or both. In addition to giving patients the general patient education discussed in Chapter 6, healthcare providers should educate patients about the following key points regarding disulfiram therapy:
Clinicians are advised to document that a patient has received and understands the information described above and to obtain the patient's informed written consent to treatment before prescribing disulfiram. Who Is Appropriate for Treatment With Disulfiram?
Prolonged disulfiram administration does not produce tolerance. Daily, uninterrupted dosing may be continued until the patient has established stable, long-term alcohol abstinence. Depending on the patient, disulfiram therapy may continue for months or years. A 9-year study of 180 patients with chronic alcohol dependence (Krampe et al., 2006) concluded that the beneficial action of long-term (12- to 20-month) supervised disulfiram therapy was psychological, not pharmacological, because placebo worked as well as disulfiram. Nevertheless, the study found that the likelihood that a patient would remain continuously abstinent years after termination of medication therapy was directly related to the length of time the patient continued supervised therapy with either disulfiram or placebo. For some patients who have completed successful treatment with disulfiram and who are facing anticipated high-risk relapse situations such as social events or travel, it may be appropriate to restart disulfiram along with behavioral interventions to help them cope with the high-risk situation and avoid relapse. No withdrawal syndrome is associated with discontinuing disulfiram, but patients must be warned that disulfiram-alcohol reactions may occur within 2 weeks of discontinuing the medication. Disulfiram appears to have modest clinical efficacy in maintaining alcohol abstinence in patients with AUDs, particularly when administered under supervision. Patients who are motivated for treatment, commit to abstinence, have supervised dose administration, and understand and participate in their treatment appear to derive the greatest benefits from disulfiram therapy. However, disulfiram does not appear to produce overall higher abstinence rates than placebo. Disulfiram therapy also has rare but serious risks of neurologic and hepatic toxicity. Patients require careful clinical and laboratory monitoring during disulfiram therapy. Disulfiram can be considered for any patient who is alcohol dependent, does not display contraindications, has a goal of total abstinence, and can comply with appropriate monitoring. Clinical visits in which the practitioner and patient discuss the risks and benefits of disulfiram therapy can motivate the patient to commit to alcohol abstinence. In addition to the pharmacologic actions of the medication, the patient's simply deciding to take the medication can enhance motivation for abstinence. The risks associated with disulfiram are well known and serious. However, patients can benefit from disulfiram as long as they receive careful clinical and laboratory monitoring to manage the risks associated with this therapy. |
A nurse is teaching a client who has alcohol use disorder about disulfiram
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