Substitution therapy for alcoholism: time for a reappraisal?

A number of compounds already in use as medications for various indications substitute for ethanol at clinically relevant brain pathways, in particular, at gamma-aminobutyric acid (GABA) receptors. Nevertheless, although substitute medications have been recognized for heroin and tobacco dependence, patients with alcohol dependence are rarely offered an analogous approach. Benzodiazepines may have paradoxical effects, and abuse and dependence are known. Baclofen (GABA(B) agonist) has not been associated with dependence or misuse and has been effective in several trials in preventing relapse, although research is required to establish the optimal dosing regimen. GABA-ergic anticonvulsants, helpful in treating withdrawal, have yet to emerge as effective in relapse prevention. Clomethiazole and sodium oxybate, the latter having been shown to be effective in relapse prevention, have incurred a reputation for dependence and abuse. However, data have emerged showing that the risk of abuse of sodium oxybate is lower than many clinicians had foreseen. For a condition where existing therapies are only effective in a proportion of patients, and which has high morbidity and mortality, the time now seems right for reappraising the use of substitute prescribing for alcohol dependence.

Serum concentration of chlormethiazole and therapeutic effect in acute alcohol withdrawal syndrome: an open clinical trial.

It was the aim of this study to find a relationship between the serum concentration of chlormethiazole and its therapeutic effect in acute alcohol withdrawal syndrome. As a secondary subject, the concentration of chlormethiazole was investigated in relation to variables of treatment and variables of physical status of patients. In an open clinical trial, the clinical status of patients was rated by the Mainz Alcohol Withdrawal Scale (MAWS) and the Delirium Rating Scale (DRS). Chlormethiazole concentration was measured by gas-liquid chromatography. Patients were dichotomized according to minimum values of MAWS and DRS after 2 days of treatment (good response and retarded or no response). Chlormethiazole concentration and dose per body weight and MAWS and DRS scores before treatment were compared by the Student t test and the Mann-Whitney test. The two groups were also analyzed by logistic regression with chlormethiazole concentration, MAWS and DRS score before treatment, age, gender, body weight, years of alcoholism, and dose per body weight as independent variables. Chlormethiazole concentration was analyzed by multiple regression with dose, age, gender, smoking, initial alcohol, body weight, and liver dysfunction as independent variables. Forty-three patients were included in the study. Twenty-four patients reached a minimum time of investigation of 2 days. The chlormethiazole concentration was in the range of 0.3 to 5.4 microg/mL at doses of 10 to 24 capsules/d (1 capsule = 192 mg chlormethiazole). As the main result, significantly increased chlormethiazole concentrations were found in patients with retarded or no response; however, in addition the DRS score before treatment and dose per body weight were increased. In addition, the final models of logistic regression contained only DRS score before treatment. As a secondary result, the final model of multiple regression revealed an increased chlormethiazole concentration with dose of chlormethiazole and concentration of alcohol in blood and a decreased chlormethiazole concentration with body weight. This was the first study to investigate the relationship between the chlormethiazole concentration and therapeutic effect in alcohol withdrawal. No robust relationship could be detected that could be separated from the control of treatment by clinical variables. Rather, a poor therapeutic outcome is mainly predicted by an increased initial severity of symptoms, and higher doses are applied in more severely ill patients. Thus, pharmacokinetic control of treatment is not recommended.

Failure of IV atropine to abolish nasal irritation caused by chlormethiazole infusion in elderly patients undergoing spinal anaesthesia.

The efficacy of intravenous atropine in abolishing the nasal irritation of chlormethiazole was assessed. Forty elderly patients undergoing transurethral resection of prostate under spinal anaesthesia were studied. One ml of either atropine sulphate (0.6 mg) or normal saline was administered intravenously in a double-blind fashion 10 minutes prior to infusion of 0.8% chlormethiazole edisylate. A loading infusion of 5 ml X min-1 of the chlormethiazole solution was followed by a variable rate of infusion in order to maintain a predetermined state of sedation--i.e. where the patient lapsed into sleep but was easily awakened to obey commands. Sneezing was the commonest side-effect occurring in 45% and 70% of patients in atropine and saline groups respectively. This was not effectively abolished by IV atropine in incremental doses of 0.6 mg up to 1.8 mg. Because of the sneezing and restlessness, four patients in the atropine group required general anaesthesia to improve operating conditions. These side-effects of chlormethiazole may limit its use as a sedative for surgery in this elderly age group.

Clomethiazol tablets induce ulcers in the esophoagus.

A 55 year old woman developed severe retrosternal pain and odynophagia four hours after taking a tablet of clomethiazol. Endoscopy revealed extensive ulceration of the upper esophagus 19-23 cm from the incisors. Esophageal manometry showed reduced contraction amplitudes in this area. The lesions healed rapidly after the medication was stopped, and the motility disturbances of the esophagus improved. Thus, clomethiazol tablets have to be included in the list of drugs which can damage the esophageal mucosa. This damage is probably due to the acid salt ethanedisulfonate of the clomethiazol tablets. Clomethiazol capsules are preferable since they do not appear to be harmful to the esophagus.

[Therapy of alcoholism. The use of thiamine, ATP and magnesium and the control of clomethiazole sympathetic blockade (author's transl)]. / Therapie der Alkoholkrankheit. Anwendung von Thiamin, ATP und Magnesium sowie Bekämpfung einer durch Chlormethiazol entstandenen Sympathikus-Blockade.

Substitution therapy with thiamine, ATP and magnesium which, just like that with clomethiazole has a parasympathomimetic action, is based on the principle of suppression of the sympathetic system. If these patients are no longer capable for any reason of continuing to take the endogenous substances (thiamine, ATP and magnesium) by mouth, the treatment is continued with clomethiazole an an infusion. But since the intravenous administration of clomethiazole is not seldom accompanied by a parasympathetic coma with respiratory and cardiac depression and miosis, treatment of a sympathetic blockade with dextrose solution containing salt is proposed.