Esperal

Esperal, an alcohol aversive or alcohol sensitizing agent, causes an acute toxic physical reaction when mixed with alcohol. Ongoing research and clinical results have clarified the drug's mechanism of action and established its safe and effective use in the treatment of alcohol use disorders in certain patient populations.[ 1 ]

Disulfiram was the first drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic alcohol dependence. In its pure form, disulfiram is a white to off-white powder, odorless and tasteless, soluble in water and alcohol.

Patient education

Patients should be given detailed information about Esperal. Use of this medicinal product should include ongoing monitoring, treatment and counselling. When used without appropriate patient education, motivation and supportive intervention, Esperal is unlikely to have more than a short-term effect on drinking patterns, particularly in patients with poor adherence to treatment, more severe forms of alcohol dependence or both.

In addition to providing patients with the general education described in Chapter 6, health care professionals should inform patients of the following key points regarding Esperal therapy:

• Advantages and limitations of this drug
• What to expect from Esperal and normal time to full effect
• Full details about the disulfiram-alcohol reaction
• Strong warnings regarding the consumption of alcoholic beverages while taking the drug.
• Warnings about using alcohol in disguised forms, such as in sauces, vinegars, cough mixtures, aftershave lotions or ointments.
• The importance of ongoing counseling and participation in a 12-step or self-help group during Esperal therapy
• The importance of informing the consultant and prescriber in case of an error or relapse
• The importance of telling doctors or dentists that the patient is taking this medicine when he or she is scheduled for surgery, including dental surgery.
• The importance of having a safety card indicating that the patient is taking Esperal, the symptoms of possible disulfiram-alcohol reactions, and the doctor or facility to contact in an emergency
• Report symptoms of potential neurological injury to your doctor immediately.
• Report any symptoms of possible liver damage to your doctor immediately.
• Clinicians are advised to document that the patient has received and understands the information described above and to obtain the patient's informed written consent for treatment before prescribing Esperal.

Indications Esperal

Disulfiram is one of three medications approved by the FDA for the treatment of alcohol dependence. It is a second-line option ( acamprosate and naltrexone are first-line agents) in patients with adequate physician supervision. Esperal is safe and effective in the supervised short-term and long-term treatment of individuals who are dependent on alcohol but are motivated to stop drinking. Ongoing research is ongoing in treating patients with comorbid alcohol dependence with PTSD, alcohol and cocaine dependence, and cocaine dependence alone. [ 2 ], [ 3 ], [ 4 ]

Recent studies of Esperal as a proteasome inhibitor and DNA demethylating agent show promising new potential therapeutic applications in malignancies and fungal infections. Esperal may play a primary or adjunctive role in the treatment of drug-resistant fungal infections (particularly candidiasis) and malignancies by inhibiting the ABC transport protein responsible for resistance. In addition, data show that disulfiram metabolites induce p53, mediating apoptosis and cell death. Research into the role of disulfiram as an anticancer agent is ongoing.

Release form

Vials of 20 pcs., 1 vial in a cardboard pack. Polypropylene vials of 20 tablets of 500 mg.

Pharmacodynamics

In the stomach, disulfiram is converted to the active metabolite diethyldithiocarbamate. In the blood, it is converted to diethyldithiocarbamic acid (DDC), which decomposes to form diethylamine and carbon disulfide. DDC undergoes phase II metabolism to form sulfoxide and sulfone metabolites. These S-oxidized compounds are the potent active metabolites that exert the action of Esperal. [ 5 ], [ 6 ]

Alcohol addiction

Disulfiram irreversibly inhibits aldehyde dehydrogenase (ALDH1A1) by competing with nicotinamide adenine dinucleotide (NAD) at the cysteine residue in the enzyme's active site. ALDH1A1 is a liver enzyme in the major oxidative pathway of alcohol metabolism that converts ethanol into acetaldehyde. At therapeutic doses of Esperal, alcohol consumption increases serum acetaldehyde levels, causing sweating, palpitations, flushing, nausea, dizziness, hypotension, and tachycardia. This constellation of symptoms is known as the disulfiram-alcohol reaction and discourages alcohol consumption. The reaction is proportional to the dose of the drug and alcohol. Thus, Esperal is not an anti-craving drug and does not modulate the neurobiological mechanism of addiction.

Cocaine addiction

Esperal also inhibits dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, causing dopamine accumulation. Increased dopamine levels correct the underlying deficit in cocaine-dependent patients. Recent studies have shown a reduction in the frequency and amount of cocaine use in patients treated with Esperal.

Unlike other medications approved for the treatment of alcohol dependence, Esperal does not directly affect opiate, gamma-aminobutyric acid, or glutamate receptors in the brain. However, it does have some effects on the central nervous system by inhibiting the enzyme dopamine β-hydroxylase and affecting serotonergic function. It remains unclear whether Esperal directly reduces the desire to drink. However, the drug definitely disrupts alcohol metabolism, causing a severe reaction when patients mix Esperal and alcohol. It is believed that patient awareness of a possible severe reaction to alcohol consumption increases the patient's motivation to abstain. Some experts (e.g., Schuckit, 2006) question the effectiveness of the drug because the time between alcohol intake and the reaction can be as long as 30 minutes, and the intensity of the reaction is unpredictable.

Effect on alcohol oxidation

Normally, the enzyme alcohol dehydrogenase in the liver and brain converts alcohol into acetaldehyde. The enzyme aldehyde dehydrogenase (ALDH), also in the liver and brain, oxidizes the byproduct acetaldehyde to acetic acid. Esperal blocks this oxidation by inhibiting ALDH, causing acetaldehyde levels in the blood to rise rapidly when alcohol is consumed. The result is called the disulfiram-alcohol reaction, and it can increase acetaldehyde levels in the blood by 5-10 times compared to without Esperal. The drug does not affect the rate at which alcohol is eliminated from the body.

Disulfiram-alcohol reaction

The disulfiram-alcohol reaction usually begins about 10-30 minutes after alcohol ingestion. Its side effects range from moderate to severe ( Appendix 3-2 ). The intensity depends on the individual characteristics of the patient. The reaction is usually proportional to the amount of Esperal and alcohol ingested. Mild effects may occur at blood alcohol concentrations of 5 to 10 mg/100 ml. At 50 mg/100 ml, the effects are usually fully developed. When the concentration reaches 125-150 mg/100 ml, loss of consciousness may occur. Although disulfiram-alcohol reactions can be life-threatening, the reduced dosages and careful medical examination of patients that are now common practice have made this outcome extremely rare.

Early investigators believed that patients should experience at least one controlled disulfiram-alcohol reaction to understand its effects. The practice of deliberately inducing a reaction by administering large doses of Esperal in combination with an "alcohol load" is abandoned. For most patients, a clear and convincing description of the reaction is sufficient.

Possible effects of disulfiram-alcohol reaction.

Affected body part	Moderate	Severe form
Skin of the body	Sweating and hot flashes, especially in the upper chest and face.	Nobody
Respiratory system	Hyperventilation Difficulty breathing/shortness of breath	Respiratory depression
Head, neck, throat	Acetaldehyde odor from the breath Blurred vision Throbbing in the head and neck Thirst	Nobody
Stomach, digestive system	Nausea/vomiting	Nobody
Chest, heart, circulatory system	Chest pain/palpitations Hypotension Tachycardia	Cardiovascular collapse Arrhythmia Myocardial infarction (in individuals with pre-existing coronary artery disease) Acute congestive heart failure (in individuals with pre-existing myocardial dysfunction)
Brain / nervous system	Dizziness Fainting Marked restlessness Confusion	Convulsions of the unconscious
Another	Weakness	Death

Early investigators believed that patients should experience at least one controlled disulfiram-alcohol reaction to understand its effects. The practice of deliberately inducing a reaction by administering large doses of Esperal in combination with an "alcohol load" is abandoned. For most patients, a clear and convincing description of the reaction is sufficient.

Pharmacokinetics

About 80-95 percent of Esperal taken orally is absorbed from the gastrointestinal tract and quickly distributed throughout tissues and organs. It is then metabolized to various mixed disulfides. The unabsorbed fraction is excreted from the body. Disulfiram is irreversibly bound to ALDH. It may take up to 2 weeks for the body to synthesize enough unbound enzyme to adequately metabolize alcohol. This is why alcohol intake may cause unpleasant symptoms for 2 weeks after the patient has taken the last dose of Esperal.

Dosing and administration

Doctors should not prescribe Esperal until the following steps have been taken:

• Tell the patient about Esperal and obtain informed consent.
• Wait until the patient has abstained from alcohol for at least 12 hours and/or the breath or blood alcohol level is zero.
• Perform a physical examination, basic liver and kidney function tests, and a pregnancy test for women. Perform an electrocardiogram if clinically indicated (eg, history of heart disease).
• Complete a medical and psychiatric history. Determine allergies to disulfiram or other drugs; prescription and over-the-counter medications, including vitamins; history of cardiovascular disease, diabetes, thyroid disease, seizure disorder, central nervous system disorder, or kidney or liver disease; and, for women, reproductive status, including current pregnancy or plans to become pregnant or breastfeed.

Dosage

Esperal is available for oral use only. Tablets are available in 500 mg form. Tablets can be crushed and mixed with liquids (water, coffee, milk, fruit juice) and should be taken once daily. The drug should not be started 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 Esperal, as there have been reports of disulfiram-alcohol reactions for up to 2 weeks after discontinuation. There is no benefit in increasing the dose of Esperal to more than 500 mg/day.

Initial dosage	250 mg/day in 1 morning or evening dose for 1-2 weeks.
Average maintenance dosage	250 mg/day
Dosage range	125–500 mg/day
Maximum dosage	500 mg/day

Additional dosage information includes the following:

• Instruct patients who experience sedation with Esperal to take it at bedtime. If daytime sedation persists, reduce the dose.
• If the patient can drink alcohol without problems while on the standard starting dose (which is rare), increase the dosage (the dose may be increased to 500 mg/day with careful monitoring). Never exceed 500 mg/day.
• Instruct patients who miss a dose to take it as soon as they remember. However, if it is almost time for the next dose, they should skip the missed dose.
• Tell patients never to take a double dose of Esperal.

Treatment control

There is strong evidence that supervised administration is essential for adherence to Esperal therapy (e.g., Brewer et al., 2000; Kristenson, 1995; reviewed by Fuller & Gordis, 2004 ). Although not absolutely necessary, supervised administration by a pharmacist, health care provider, or family member is preferred as a key component of the treatment plan.

The table shows the recommended laboratory testing regimens for Esperal therapy. In general, liver function requires constant monitoring because of the occasional association of Esperal with liver injury. Unlike alcohol-induced liver injury, which typically shows a high aspartate aminotransferase to alanine aminotransferase ratio, disulfiram-induced liver injury typically shows equivalent and very high elevations of both enzymes ( Bjornsson, Nordlinder & Olsson, 2006 ). Pregnant women should stop taking the drug immediately. Urine toxicology screening is not an ideal method for detecting alcohol use, although it can sometimes detect alcohol use within a few hours of testing.

Laboratory studies of Esperal therapy

Interval / Period	Test type
Before starting Esperal therapy to confirm abstinence and determine baseline values after stabilization	Breath or blood alcohol testing (if clinically indicated to confirm abstinence) Liver function tests: alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, lactate dehydrogenase, bilirubin, total protein, albumin, prothrombin time Complete blood count, routine chemistries (if clinically indicated) Renal function tests: standard blood urea nitrogen (BUN), creatinine Pregnancy test (women of childbearing potential)
10–14 days after initiation of therapy, then monthly (or more frequently) for the first 6 months of therapy; every 3 months thereafter	Liver function tests: alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, bilirubin.
Monthly during therapy	Pregnancy test (women of childbearing age)
As clinically indicated during therapy	Renal function tests: BUN, creatinine. Urine toxicology screen: performed only if there is concern about unreported alcohol or drug use.

Duration of treatment and withdrawal of Esperal

Long-term use of Esperal does not cause tolerance. Daily continuous dosing can be continued until the patient has established stable long-term alcohol abstinence. Depending on the patient, therapy with this drug can continue for several months or years. A 9-year study of 180 patients with chronic alcohol dependence (Krampe et al., 2006) concluded that the positive effect of long-term (12 to 20 months) supervised therapy with the drug was psychological rather than pharmacological, since placebo worked as well as Esperal. However, the study showed that the likelihood that a patient will continue to abstain for several years after stopping drug therapy is directly related to the duration of supervised therapy with Esperal or placebo.

For some patients who have successfully completed Esperal treatment and who are faced with expected high-risk relapse situations, such as social events or travel, it may be appropriate to continue therapy along with behavioral interventions to help them cope with the high-risk situation and avoid relapse.

There is no withdrawal syndrome with discontinuation of Esperal, but patients should be warned that disulfiram-alcohol reactions may occur within 2 weeks after discontinuation of the drug.

Use Esperal during pregnancy

Although Esperal is not absolutely contraindicated, it should be avoided because the risk to the fetus is unknown. (Pregnant patients should receive behavioral therapy, if necessary in a hospital setting.) Do not give Esperal to nursing mothers. Patients should stop breastfeeding before taking this drug.

Contraindications

Esperal is not a safe option for everyone. This drug is absolutely contraindicated 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 starting the drug. Esperal is contraindicated in psychosis, as it may worsen the patient's psychosis. Caution is necessary in patients with a history of liver disease, and the physician must weigh the risks and benefits. Patients receiving metronidazole, paraldehyde, alcohol, or alcohol-containing products (sauces, cough mixtures, vinegar) should not receive this drug and should be taught in advance to avoid a disulfiram-alcohol reaction. Never administer to a patient with or without suspected alcohol ingestion. consent and understanding of the disulfiram-alcohol reaction. Esperal may be a therapeutic option with caution in patients with seizures, diabetes, thyroid disease, traumatic brain injury, and kidney disease due to the possibility of an accidental disulfiram-alcohol reaction.

Disulfiram Warnings

Patient's condition or circumstances	Treatment recommendations
History of heart disease, diabetes mellitus, hypothyroidism, epilepsy, cerebral damage, chronic or acute nephritis, liver cirrhosis or liver failure	Use with caution. There is no evidence that patients with pre-existing liver disease are more prone to severe hepatotoxicity from Esperal therapy.
Patients with hepatitis C	Based on currently available data, if baseline transaminase levels are normal or only moderately elevated (less than five times the upper limit of normal), use with close monitoring of liver function.
Children and teenagers	Safety and effectiveness in children have not been established. One study suggests that Esperal may be safe and effective in adolescents ( Niederhofer & Staffen, 2003 ). Use with caution.
Patients receiving or who have recently received metronidazole, paraldehyde, alcohol or alcohol-containing products (eg, cough syrups, tonics); also patients exposed to ethylene dibromide or its vapors (eg, in paint, paint thinner, varnish, shellac)	Do not use Esperal until the substances have left the patient's body.
Patients using products containing alcohol in disguised forms (eg, vinegars, sauces, aftershave lotions, ointments)	Ask patients to test any alcohol-containing product before using it by applying it to a small area of skin for 1-2 hours. If there is no redness, itching, or adverse effects, the product is safe to use.
Age 61 and over	Dosage reduction may be required.

Side effects Esperal

Esperal has an acceptable risk profile. However, it is associated with many side effects and drug interactions, including death. The most common and less serious side effects include headache, drowsiness, fatigue, and bad breath (or metallic taste). [ 7 ], [ 8 ], [ 9 ]

Dermatological, neurological, psychiatric and cardiac events have been reported. Serious adverse events include hepatitis, hepatotoxicity, psychosis, seizures, peripheral neuropathy and optic neuritis. Dermatological adverse events are rare and include exfoliative dermatitis, rash and pruritus. Liver failure may develop after many months of therapy. Cases of fulminant liver failure with fatal outcome have been reported despite drug discontinuation (1 case per 30,000 patients treated per year).

Psychiatric side effects are rare. Psychosis, confusional states, mutism, head shaking, memory impairment and, rarely, stupor have been reported and the effects are dose-related. Symptoms usually resolve with discontinuation of the drug and a short course of antipsychotic medication. Psychosis may result from an interaction between Esperal and cannabis. Adverse neurological effects may occur as early as 10 days after onset. Axonal polyneuropathy is a rare side effect. Some cases of severe sensorimotor polyneuropathy involving cranial nerves have been reported within a few weeks of starting Esperal at a dose of 500 mg. Neuropathy occurs in 1 case per 1000 patients taking Esperal per year.

Drug interactions occur with compounds that utilize the cytochrome P450 enzyme system for oxidative metabolism. This interaction may occur with the following drugs: amitriptyline, imipramine, phenytoin, chlordiazepoxide, diazepam, omeprazole, and acetaminophen. Drug interactions may occur with other drugs not listed. Slow elimination of Esperal may cause a disulfiram-alcohol reaction within fourteen days of discontinuation.

Side effects of Esperal and their treatment

Optic neuritis	Usually diagnosed after patient complains of visual impairment. Stop taking the drug and perform an ophthalmological examination.
Peripheral neuritis, polyneuritis, peripheral neuropathy	Usually diagnosed after the patient complains of paresthesia (numbness or tingling). Stop taking Esperal and observe the patient or order a neurological examination.
Hepatitis, including cholestatic and fulminant hepatitis, and liver failure*	When symptoms of liver dysfunction appear or are observed, perform a medical history and physical examination, and obtain follow-up liver function tests. If clinical or laboratory evidence of liver dysfunction is detected, discontinue Esperal immediately. Maintain clinical monitoring of symptoms and liver function. Follow findings until resolution.
Psychosis	Psychotic reactions to Esperal have been reported, usually associated with high dosage of the drug, associated toxicity to other drugs (e.g., metronidazole, isoniazid) or unmasking of underlying psychoses in patients experiencing the stress of alcohol withdrawal. If psychosis is diagnosed and other interacting drugs are present, reduce or discontinue the drug and treat underlying psychoses as indicated.

* Serious liver damage caused by Esperal is rare and its exact etiology is unknown.

Overdose

In case of overdose, contact your local poison control center. There is no information on the treatment of Esperal overdose and no antidote. Supportive care with supplemental oxygen, cardiac monitoring, and intravenous fluids may be needed. If symptoms are severe, consult a physician. Cases of ingestion of 5 g or more have resulted in parkinsonism, choreoathetosis, and thalamic syndrome. Doses should not exceed 500 mg/day for the treatment of alcohol dependence, and doses for the treatment of malignancies have not yet been determined.

Interactions with other drugs

Preparation, remedy, medicine	The Esperal Effect	Recommended action
Benzodiazepines Chlordiazepoxide (Librium ® ) Diazepam (Valium ® )	Decreases plasma clearance of chlordiazepoxide or diazepam.	Substitute for Oxazepam (Serax ® ) or lorazepam (Ativan ® )
Isoniazid	May cause unsteady gait, changes in mental status	Stop taking Esperal if any effect occurs.
Rifampicin (Rifadin ®, Rimactan ® )	If used with isoniazid to treat tuberculosis, see Effects of isoniazid above.	Adjust dosage if necessary.
Metronidazole ( Flagyl® )	Increases the likelihood of confusion or psychosis.	Esperal and metronidazole should not be prescribed simultaneously.
Oral anticoagulant (eg, warfarin [Coumadin ® ])	Inhibits the metabolism of warfarin	Adjust dosage if necessary.
Oral hypoglycemic	Forms disulfiram-like reactions with alcohol.	Carefully monitor the concomitant administration of oral hypoglycemic agents and Esperal.
Phenytoin (Dilantin ® )	Increases serum levels by inhibiting CYP 450 2C9	Obtain baseline serum phenytoin level before Esperal therapy; re-evaluate level during therapy; adjust dosage if phenytoin level increases
Theophylline	Increases serum levels by inhibiting CYP 450 1A2	Obtain baseline serum theophylline level before Esperal therapy; reassess level during therapy; adjust dosage if serum theophylline level increases
Tricyclic antidepressants, amitriptyline (Elavil ® )	May cause delirium when used concomitantly	Adjust the dosage, stop taking Esperal, or switch to another class of antidepressants.
Desipramine (Norpramin ® ), imipramine (Tofranil ® )	Decreases total body clearance and increases the half-life and peak plasma levels of desipramine or imipramine.	Monitor closely; adjust dosage if necessary.

Storage conditions

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 out of date or no longer needed.

Analogues

Analogues of the drug are Antakson, Naltrexin, Lidevin with Biotredin, Teturam and Vivitrol with Medichronal and Disulfiram, as well as Colme and Naltrex.

Esperal may work as an adjunct to psychosocial treatment for alcohol cessation for patients who can achieve initial abstinence of at least 12 hours, are committed to maintaining abstinence, agree to take medication, and have no contraindications to the drug.

Efficiency

The evidence for the effectiveness of Esperal treatment is mixed. (To review some of the reports, see the Annotated Bibliography and Literature Review at www.kap.samhsa.gov.)

Positive results

Studies that find Esperal effective in the treatment of alcohol dependence often emphasize the circumstances under which it is administered to patients. In particular, the level and quality of patient supervision while taking the medication are thought to be important elements of its success (e.g., Brewer, Meyers, & Johnsen, 2000; Kristenson, 1995 ). Some studies have shown that court-ordered Esperal increases effectiveness by increasing adherence to the medication ( Martin, Clapp, Alfers, & Beresford, 2004; Martin, Mangum, & Beresford, 2005 ). The use of incentives, contracting with the patient and significant other to ensure adherence, regular patient reminders, and patient behavioral education and social support may also enhance the effectiveness of Esperal by increasing adherence.

Most experts (e.g., Schuckit, 2006 ) agree that Esperal requires its use in a dedicated drug treatment program to achieve an optimal response. One study suggests that it may be more effective in promoting short-term abstinence and maintaining treatment after detoxification than in preventing long-term relapse (e.g., Chandrasekaran, Sivaprakash, & Chitraleka, 2001 ). However, the most rigorous study of disulfiram therapy ( Fuller et al., 1986 ) consistently showed that Esperal (250 mg/day), compared with placebo (1 mg/day) or the vitamin, reduced the proportion of drinking days over the course of the study (1 year) in male veterans who reported drinking. However, there was no difference between treatment groups in the percentage of veterans who remained abstinent for the entire study period.

Negative findings

Some experts reject Esperal as a viable treatment option, particularly in primary care settings. This conclusion is based on mixed results from Esperal clinical trials and serious side effects that can result from the disulfiram-alcohol reaction, as well as concerns about other potentially serious side effects and “adherence issues” ( Williams, 2005, pp. 1776–1777). The ability to provide ongoing supervision of Esperal may be limited in primary care settings.

Eligible patients

The consensus group concluded that disulfiram is most effective for patients who have undergone detoxification or are in the early stages of abstinence, especially when they are committed to abstinence and are adequately monitored on an ongoing basis. Esperal may not reduce the desire to drink alcohol. However, it may help motivate the patient to abstain. As with other medications, overall effectiveness is also increased when Esperal is administered in combination with intensive behavioral interventions.

Patients with severely impaired judgment or high impulsivity due to severe mental illness or cognitive impairment may not be suitable candidates for treatment with this drug.

Safety

Disulfiram has been used to treat alcohol dependence for nearly 60 years. Fatalities from disulfiram-alcohol reactions have become rare because lower doses are used and patients with severe heart disease are excluded from treatment with Esperal ( Chick, 1999 ). Its hepatotoxicity remains a problem in some patients.

Side effects are generally minor. Serious adverse reactions are rare. However, patients receiving disulfiram should be monitored for hepatotoxicity. Esperal may cause hepatitis, but the risk is small. Disulfiram-induced hepatitis is estimated to occur in 1 in 25,000 ( Wright, Vafier, & Lake, 1988 ) to 1 in 30,000 ( Chick, 1999, p. 427) patients treated per year. A disproportionate number of these cases may be due to Esperal's use to treat nickel allergy (an uncommon but known indication for disulfiram use).

Warning about the pitfalls of Esperal

Esperal should never be administered to a patient who is intoxicated or without his/her full knowledge. The physician should instruct relatives accordingly. Before starting therapy, the physician should inform patients and their families about the disulfiram-alcohol reaction, including that this reaction may occur within 14 days between the last dose of the drug and alcohol consumption.