Current Scheduling Status
None
Year(s) and type of review / ECDD meetings
Drug Class
Recommendation (from TRS)
Substance identification
Clomethiazole (INN, CAS 533-45-9 for the base; CAS 1867-58-9 for the edisylate), chemically, the base is 5-(2-chloroethyl)-4-methylthiazole and the edisylate is the 1,2-ethanedisulfonate (2:1). Other names include chlormethiazole (BAN), chlormethiazole edisylate (BP 1980) and clomethiazolum (NFN). No isomeric forms are possible.
Similarity to known substances and effects on the CNS
Clomethiazole has been classified as an anticonvulsant, sedative and hypnotic, with some anti-anxiety effects. It is viewed as an effective agent in the treatment of alcoholic delirium tremens. It possesses minor pharmacological cross-tolerance to alcohol in animals. Its mode of action differs from both benzodiazepines and barbiturates. Its anticonvulsant activity is apparently mediated through chloride ion channels coupled to GABA-receptors and glycine-receptors. It is extensively metabolized and does not seem to induce as much liver microsomal enzyme production as do barbiturates, which may account for the less marked development of tolerance to it. Clomethiazole produces a dose-related protection from convulsions induced by a wide range of chemicals, in particular isoniazid. The anticonvulsant dose is much lower than sedative-hypnotic doses. Clomethiazole appears to activate beta rhythms, preferentially in subcortical regions and in the reticular formation.
Dependence potential
Controlled studies have shown that clomethiazole does not support barbiturate dependence or produce primary physical dependence in animals. In drug discrimination studies, clomethiazole was recognized as pentobarbital-like by the pigeon but not by the rhesus monkey. Rats and baboons did not discriminate clomethiazole as a benzodiazepine. Intravenous selfadministration studies in the codeine-trained rhesus monkey were negative but the substance was self-administered in pentobarbital- maintained animals. When given by the intracerebroventricular route in the rat it was not self-administered. In this model the standards, diazepam and amobarbital, were self-administered. There are no controlled human studies on the dependence. potential of clomethiazole. There are, however,-a number of case reports of tolerance and withdrawal signs following clomethiazole abuse.
Actual abuse and or/evidence of likelihood of abuse
A significant level of abuse has been reported in the Federal Republic of Germany. In addition, there have been cases reported from Finland, Poland, Sweden, and the United Kingdom. Most cases of abuse reported have been i in patients known to be dependent on alcohol or other substances. Abuse of the drug by the intravenous route has been reported from the Federal Republic of Germany. Of 80 countries reporting on the national control status of clomethiazole, 48 reported that it was registered and/or available on the market. The drug is available only on prescription in all countries where it is approved for marketing, purchased on government tenders, or available on an individual patient basis. Forty-eight countries reported no abuse, seizure, or clandestine laboratories. Four countries reported seizures of small amounts of the drug from 1983 to 1985. No diversions were reported.
Therapeutic usefulness
Clomethiazole has two major. therapeutic indications: (a) treatment of delirium tremens after alcohol withdrawal as well as after the withdrawal of certain other drugs, and (b) treatment of certain convulsive disorders such as eclampsia convulsions, status epilepticus, and myoclonic seizures. It is also indicated in gerontopsychiatric states of insomnia and restlessness, and in anaesthesia (as a hypnotic in patients. who require regional anaesthesia). It is an effective drug for inpatient treatment of delirium tremens. However, outpatient treatment of alcoholic cases with clomethiazole may lead to abuse. The Committee rated the therapeutic usefulness of clomethiazole in the treatment of delirium tremens associated with alcohol withdrawal and selective convulsive states as significant, while usefulness for other indications was rated as moderate.
Recommendation
On the basis of available data concerning its pharmacological profile, dependence potential, and actual abuse, the Committee rated the likelihood of abuse of clomethiazole as moderate. The Committee noted that any drug that is used extensively in the treatment of chemical dependency or its consequences is likely to be abused to a certain degree by patients. The degree of seriousness of the public health and social problems associated with the substance was found to be moderate and its therapeutic usefulness moderate to
high. The Committee found that there was insufficient evidence that clomethiazole is currently being, or is likely to be, abused so as to constitute a public health and social problem warranting the placing of the substance under international control. In light of this assessment, the Committee did not recommend the scheduling of clomethiazole. However, the Committee recognized that this substance may present future problems and recommended that it be monitored closely.
Clomethiazole (INN, CAS 533-45-9 for the base; CAS 1867-58-9 for the edisylate), chemically, the base is 5-(2-chloroethyl)-4-methylthiazole and the edisylate is the 1,2-ethanedisulfonate (2:1). Other names include chlormethiazole (BAN), chlormethiazole edisylate (BP 1980) and clomethiazolum (NFN). No isomeric forms are possible.
Similarity to known substances and effects on the CNS
Clomethiazole has been classified as an anticonvulsant, sedative and hypnotic, with some anti-anxiety effects. It is viewed as an effective agent in the treatment of alcoholic delirium tremens. It possesses minor pharmacological cross-tolerance to alcohol in animals. Its mode of action differs from both benzodiazepines and barbiturates. Its anticonvulsant activity is apparently mediated through chloride ion channels coupled to GABA-receptors and glycine-receptors. It is extensively metabolized and does not seem to induce as much liver microsomal enzyme production as do barbiturates, which may account for the less marked development of tolerance to it. Clomethiazole produces a dose-related protection from convulsions induced by a wide range of chemicals, in particular isoniazid. The anticonvulsant dose is much lower than sedative-hypnotic doses. Clomethiazole appears to activate beta rhythms, preferentially in subcortical regions and in the reticular formation.
Dependence potential
Controlled studies have shown that clomethiazole does not support barbiturate dependence or produce primary physical dependence in animals. In drug discrimination studies, clomethiazole was recognized as pentobarbital-like by the pigeon but not by the rhesus monkey. Rats and baboons did not discriminate clomethiazole as a benzodiazepine. Intravenous selfadministration studies in the codeine-trained rhesus monkey were negative but the substance was self-administered in pentobarbital- maintained animals. When given by the intracerebroventricular route in the rat it was not self-administered. In this model the standards, diazepam and amobarbital, were self-administered. There are no controlled human studies on the dependence. potential of clomethiazole. There are, however,-a number of case reports of tolerance and withdrawal signs following clomethiazole abuse.
Actual abuse and or/evidence of likelihood of abuse
A significant level of abuse has been reported in the Federal Republic of Germany. In addition, there have been cases reported from Finland, Poland, Sweden, and the United Kingdom. Most cases of abuse reported have been i in patients known to be dependent on alcohol or other substances. Abuse of the drug by the intravenous route has been reported from the Federal Republic of Germany. Of 80 countries reporting on the national control status of clomethiazole, 48 reported that it was registered and/or available on the market. The drug is available only on prescription in all countries where it is approved for marketing, purchased on government tenders, or available on an individual patient basis. Forty-eight countries reported no abuse, seizure, or clandestine laboratories. Four countries reported seizures of small amounts of the drug from 1983 to 1985. No diversions were reported.
Therapeutic usefulness
Clomethiazole has two major. therapeutic indications: (a) treatment of delirium tremens after alcohol withdrawal as well as after the withdrawal of certain other drugs, and (b) treatment of certain convulsive disorders such as eclampsia convulsions, status epilepticus, and myoclonic seizures. It is also indicated in gerontopsychiatric states of insomnia and restlessness, and in anaesthesia (as a hypnotic in patients. who require regional anaesthesia). It is an effective drug for inpatient treatment of delirium tremens. However, outpatient treatment of alcoholic cases with clomethiazole may lead to abuse. The Committee rated the therapeutic usefulness of clomethiazole in the treatment of delirium tremens associated with alcohol withdrawal and selective convulsive states as significant, while usefulness for other indications was rated as moderate.
Recommendation
On the basis of available data concerning its pharmacological profile, dependence potential, and actual abuse, the Committee rated the likelihood of abuse of clomethiazole as moderate. The Committee noted that any drug that is used extensively in the treatment of chemical dependency or its consequences is likely to be abused to a certain degree by patients. The degree of seriousness of the public health and social problems associated with the substance was found to be moderate and its therapeutic usefulness moderate to
high. The Committee found that there was insufficient evidence that clomethiazole is currently being, or is likely to be, abused so as to constitute a public health and social problem warranting the placing of the substance under international control. In light of this assessment, the Committee did not recommend the scheduling of clomethiazole. However, the Committee recognized that this substance may present future problems and recommended that it be monitored closely.
ECDD Recommendation
Placed under surveillance
Link to full TRS
who_trs_761.pdf1.41 MB