WHEN TO START DISULFIRAM THERAPY?

Disulfiram should be started after detoxification from alcohol is completed and the patient is free of alcohol or alcohol-containing beverages for at least 12 hours before the start of disulfiram

Baseline investigations.

• Haemogram
• Liver function test: Attention should be paid to the liver enzymes (AST and ALT levels); Disulfiram should not be started if the AST and ALT levels are raised by more than 2-3 times above normal.

Beverages to be avoided with disulfiram therapy.

It should be advised that certain beverages should be avoided with disulfiram. These include: alcohol in any form (i.e. beer, wine, Indian made foreign liquor and locally brewed liquor), vinegars, sauces, cough mixtures,vitamin tonics and elixirs that contain alcohol, and even mouthwashes which may contain alcohol

  

What is the dose of disulfiram in starting ?

Disulfiram should be started as a single tablet containing 250 mg, once a day. It may take at least 4 - 5 days to reach a steady state level. The timing of the dose should be fixed, such that the patient takes the tablet at a particular time of the day. Some patients may experience sedation with morning use; in such cases the dose may be shifted to night time.

Supervised disulfiram ethanol reaction (DER).

In certain cases, supervised DER may be carried out in those patients who are willing for it, and who are sceptical of the effect of disulfiram in causing a DER. This should be carried out in specialized De-addiction Centres only.

Supervision of disulfiram therapy.

Disulfiram works best where a supervisor is involved in the administration of the medication. The supervisor may be a family member/ friend/ colleague with whom the patient is in daily contact. The supervisor should be chosen with the patients' consent. The supervisor should also be informed about the treatment and its implications. He/ she should ensure that the patient takes the medication and in front of him/ her.

Disulfiram identification card.

In the end, a disulfiram identification card should be made available to the patient, stating that he/ she is taking disulfiram, and also contains in brief, the beverages to be avoided with alcohol, the signs and symptoms of disulfiram alcohol reaction, and its treatment.

What are the points to remember during initiation of disulfiram ?

• Disulfiram therapy should be carried out after detoxification from alcohol
• Disulfiram to be started at least 12 hours after last alcohol use
• Disulfiram counselling should be carried out before the start of therapy
• Written consent should be obtained before the start of therapy
• A candidate may be chosen to supervise disulfiram therapy
• Disulfiram should be started at a dose of 250 mg

WHAT IS THE MECHANISM OF DISULFIRAM ACTION?

What is the Mechanism of Disulfiram action?

Disulfiram acts by binding irreversibly to the enzyme acetaldehyde dehydrogenase, (ALDH) leading to inactivation of the enzyme. When alcohol is consumed subsequent to disulfiram intake, there is an accumulation of acetaldehyde due to inhibition of the enzyme that metabolizes it. Elevated levels of acetaldehyde are responsible for the unpleasant effects experienced. This is termed as the Disulfiram- Ethanol Reaction (DER).

Pharmacokinetics

Absorption of disulfiram from the gastrointestinal tract is rapid but incomplete and approximately 20% is excreted in the feces. Because of its high lipid solubility, disulfiram is widely distributed and accumulated in various fat depots. Disulfiram is rapidly metabolized to diethyldithiocarbamate (DDC), which is partly excreted as carbon disulfide in the expired air and is partly metabolized in the liver to Me-DDC. Me-DDC is metabolized further to the active metabolite Me-DTC (diethylthiocarbaminic acid methyl ester). The concentration of Me-DTC reaches its maximum after about four hours, but the maximum enzyme inhibiting effect (aldehyde dehydrogenase [ALDH]) is first reached after three daily doses. The plasma half-life for Me-DTC is about ten hours, but the enzyme inhibiting effect of ALDH lasts considerably longer. The effect can thus persist for 7 to 14 days after discontinuation. In patients receiving disulfiram maintenance treatment, the ingestion of alcohol brings about a typical disulfiram-alcohol reaction within the course of five to ten minutes.

Metabolism is not appreciably affected by a mild to moderate decrease in hepatic function. The metabolites are chiefly excreted with the urine. A part is recovered in the expired air as carbon disulfide.

Toxicity.

Drowsiness followed by coma, persistent nausea, vomiting, aggressive and psychotic behavior, and ascending flaccid paralysis are manifestations of toxicity.

Drug Interactions.

Disulfiram inhibits enzyme induction and thus may interfere with the metabolism of drugs taken concomitantly. An increase in the levels of oral anticoagulants, phenytoin, and oral hypoglycaemic may occur.

Indication.

Disulfiram is recommended to persons suffering from alcohol dependence syndrome who are at risk of relapse.

Preparations of Disulfiram.

200/250 mg oral tablet in a package of 10 tablets.

Trade name : ESPERAL; DISULFIRAM; DIZONE.

Cost : Rs. 11 - 16 for 10 tablets depending on the brand.

FREQUENTLY ASKED QUESTIONS ABOUT THE USE OF DISULFIRAM.

Q 1. Can disulfiram be given surreptitiously (without the consent of the patient)?

Ans. Disulfiram cannot be given without the consent of the patient. It is necessary to educate the patient regarding the side effects of Disulfiram as well as the nature of 'Disulfiram Ethanol Reaction' (DER) before initiation of Disulfiram.

Q 2. Do deaths occur with Disulfiram?

Ans. Deaths with Disulfiram are very rare. The reported deaths in the literature are one in lakh users of disulfiram. Experience at our centre shows that disulfiram can be safely used in patients without fear of causing deaths.

Q 3. Should one stop Disulfiram during other common illness such as fever, diarrhea because of the fear of interaction with other commonly prescribed medicines?

Ans. No. One can safely continue Disulfiram during common illness without fear of interaction with commonly prescribed medications.

Q 4. The patient is having weakness after the start of Disulfiram and requests to stop Disulfiram. Should I stop it?

Ans. On most of the occasion, weakness is as a result of chronic effects of alcohol ingestion and NOT because of Disulfiram per se. One must check the patient's motivation if he is requesting to stop Disulfiram and conduct motivational enhancement therapy. Also LFT reports should be monitored.

Q 5. Since the effect of disulfiram lasts for 10 - 14 days, should I ask the patient to ingest Disulfiram once every 10 days?

Ans. Though the effect of Disulfiram lasts for 10 - 14 days, Disulfiram should be taken every day to maintain constant and adequate blood levels.

Q 6. The patient claims that he is addicted to whiskey only. He asks whether he can consume beer or wine. What should I do?

Ans. No alcohol containing beverages should be consumed when the patient is on disulfiram. For further details see the paragraph on Beverages to be avoided during Disulfiram therapy.

Q 7. The patient has been taking Disulfiram since 9 months. Would he continue to remain free of alcohol lifelong as a result of this therapy?

Ans. Disulfiram prolongs the duration of abstinence in an alcohol dependent individual. There is always a risk of relapse at a future date. The risk of relapse reduces with increase in duration of abstinence.

Q 8. What is the optimum dose of disulfiram in an individual patient?

Ans. Disulfiram should be started as a single tablet containing 250 mg, once a day. It may take at least 4 - 5 days to reach a steady state level. During follow up, if it is found that the patient is using alcohol while regularly compliant on disulfiram, then it is necessary to carry out a disulfiram ethanol reaction and increase the dosage to 500 mg OD if no reaction occurs.

Q 9. Can disulfiram be administered to a patient who is in a state of alcohol intoxication or without their full knowledge?

Ans. Disulfiram should never be administered to a patient who is in a state of alcohol intoxication or without their full knowledge. Under both the circumstances, patient will develop disulfiram-ethanol reaction (DER) which can be life threatening.

Q 10. What is disulfiram-ethanol reaction (DER)?

Ans. Disulfiram acts by binding irreversibly to the enzyme acetaldehyde dehydrogenase, (ALDH) leading to inactivation of the enzyme. When alcohol is consumed subsequent to disulfiram intake, there is an accumulation of acetaldehyde due to inhibition of the enzyme that metabolises it. Elevated levels of acetaldehyde are responsible for the unpleasant effects experienced. This is termed as the Disulfiram- Ethanol Reaction (DER). High levels of acetaldehyde produce nausea, substantial vomiting, hyperventilation, chest pain, flushing, throbbing headache, light-headedness, palpitation, blurred vision and other unpleasant symptoms. In rare cases arrhythmias, acute heart failure, convulsion and

death may occur. The patient's reaction will be proportional to the dosage of both disulfiram and alcohol, and will continue to occur as long as alcohol is being metabolized.

Q 11. How should disulfiram-ethanol reaction (DER) be treated?

Ans. The disulfiram-ethanol reaction is treated symptomatically. Patient will require monitoring of pulse and blood pressure. Vasopressors and antiarrythymic agents may have to be given in case hypotension or cardiac arrhythmias occur.

Q 12. How does disulfiram help in maintaining abstinence or preventing relapse?

Ans. The underlying principle for using disulfiram in treating alcoholism is that most alcoholics taking disulfiram will avoid drinking because they fear getting sick. Thus, disulfiram prevents impulsive drinking and allows the patient time to think about other ways to cope with acute cravings or stressful moments.

Q 13. When to start disulfiram in a patient using alcohol ?

Ans. Disulfiram should be started after detoxification from alcohol is completed and the patient is free of alcohol or alcohol containing beverages for at least 12 hours before the start of disulfiram.

Q 14. At which time of the day, disulfiram should be used daily?

Ans. The timing of the dose should be fixed, such that the patient takes the tablet at a particular time of the day.Some patients may experience sedation with morning use; in such cases the dose may be shifted to night time. It is always advisable to take the tablets in the morning following the breakfast under the supervision of a significant family member. This helps in two ways; Firstly, it takes away from the patient the thought of using alcohol for the whole day and secondly it helps in building the trust between the

patient and the significant family member.

Q 15. What should be done if a patient develops psychosis while on disulfiram?

Ans. Psychotic reactions are uncommon with disulfiram. However, it is usually noted when a patient is on disulfiram due to the following reasons: high dosage of disulfiram, combined toxicity (with metronidazole or isoniazid), or as a rare side-effect in some individual vulnerable for such reactions. Identification of the cause along with appropriate measures is required to be taken. To be on the safer side, it is always advisable to stop disulfiram first. If needed, anti-psychotic medications can be used for short-term basis as judged clinically.

Q 16. What is the optimum duration of therapy with disulfiram?

Ans. The optimal duration of disulfiram treatment is not known. The optimal duration of therapy varies with the individual patient and the agreed treatment goals. The patient will remain abstinent as long as he is compliant on disulfiram. It is advisable to give more emphasis on the agreed treatment goals of disulfiram treatment rather than setting an arbitrary duration of treatment.

Q 17. What should be the usual duration of treatment with disulfiram?

Ans. Usually disulfiram therapy should be continued for a period of 6 to 9 months till the time the patient feels confident to abstain from alcohol without medication, the risk for relapse has been reduced and patient is rehabilitated. However, in some patients, the therapy would have to continue for a longer period of time. Patients neither develop tolerance to disulfiram nor to the disulfiram ethanol reaction. During this time, the patient is expected to be able to master the coping strategies necessary to deal with difficult situations without resorting to alcohol.

WHAT IS DISULFIRAM THERAPY FOR ALCOHOLISM?

Introduction

Alcohol dependence has been recognized to be a chronic relapsing illness and the desired goal of long-term abstinence often remains elusive. The chances of relapse are more in the first few months of abstinence. Hence detoxification alone may not be enough and the treatment needs to be continued for an extended period to achieve long-term abstinence.

This phase of treatment, termed the 'maintenance phase' is often difficult and challenging. Several psychosocial and pharmacological modalities have been used in the maintenance phase. One of the most important pharmacological modality is the use of deterrent therapy. Disulfiram is the most widely used medication for such therapy.

The following protocol gives the guidelines to be followed during introducing patients to disulfiram and subsequent follow up.

Rationale for use.

Disulfiram is used as an aid in the management of alcohol dependent individuals who want to remain in a state of sobriety, but are unable to maintain an abstinent state. It acts as a deterrent and helps in delaying the decision to drink if motivation reduces temporarily. Disulfiram should be used in conjunction with supportive and psychotherapeutic interventions for the best results.

Substantial literature has been generated on the use of disulfiram in alcoholism, but the number of controlled clinical trials is limited. There is little evidence that disulfiram enhances abstinence, but there is evidence that disulfiram reduces drinking days especially in patients with supervised therapy. Studies have also suggested that the use of a 'disulfiram contract' is an effective approach to enhance adherence and maintain abstinence.

Used alone, without proper motivation and supportive therapy, disulfiram is unlikely to have more than a brief effect on the drinking pattern. The therapy is more successful if disulfiram is used for an extended period of time. Among several measures, compliance is a strong predictor of outcome.

What is the Side effects of Disulfiram?

 Common - Transient mild drowsiness, fatigue, impotence, headache, acneiform eruptions, allergic dermatitis and a metallic or garlic-like aftertaste may be experienced during the first 2 weeks of therapy. These complaints usually disappear later during therapy or with reduced dosage.

  

Induction

Setting - Disulfiram can be started in the outpatient as well as inpatient setting.

What is the duration of disulfiram therapy ?

Usually disulfiram therapy should be continued for a period of 6 to 9 months till the time the patient feels confident to abstain from alcohol without the need for treatment for the same, the risk for relapse has been reduced and patient is rehabilitated. However, in some patients, the therapy would have to continue for a longer period of time. Patients neither develop tolerance to disulfiram nor to the disulfiram ethanol reaction.

During this time, he is expected to be able to master the coping strategies necessary to deal with difficult situations without resorting to alcohol.

Disulfiram alcohol reaction .

Disulfiram plus alcohol may produce reactions. Even a small amount of

alcohol taken while on disulfiram may produce redness of the face, throbbing in the head and neck, headache,breathing difficulties, stomach distress, vomiting, sweating, thirst, chest pain, fast heartbeat, faintness,marked uneasiness, weakness, sensation of surroundings revolving around you, blurred vision, and confusion. Rarely in severe reactions, there may be a decrease in breathing, shock, acute heart failure,

unconsciousness, convulsions, and death.

What is the Side effects ?

 Side effects of disulfiram taken alone may include drowsiness, numbness in extremities,metallic taste, and/ or allergic skin reaction. Liver damage is an uncommon reaction.