Current Status of the 1,4‐ and 1,5‐Benzodiazepines in the Treatment of Epilepsy: The Place of Clobazam

Abstract

The 1,4-benzodiazepines have a recognised place in the treatment of epilepsy. Thus, diazepam, clonazepam, and, more recently, lorazepam are used intravenously for status epilepticus. Oral clonazepam has proved useful as adjunctive therapy in generalised absence seizures, myoclonic seizures, and partial seizures. Oral nitrazepam is well known for its use in the treatment of infantile spasms with hypsarrhythmia and in the myoclonic epilepsies of childhood. Clobazam, a 1,5-benzodiazepine, has been shown in controlled studies to be superior to placebo, and in open studies it has produced an overall reduction in seizure frequency of 65%. The main indication for its use is as oral adjunctive therapy in refractory epilepsy. It has a rapid onset of action, is well tolerated, and many studies indicate it has a psychotropic action and produces minimal or no cognitive impairment. The most common side-effect reported was sedation, while the overall incidence of side-effects in the open studies was 38%. In all studies reviewed, 4% of patients had to be withdrawn because of adverse reactions. In general, there are no significant interactions with other anticonvulsants, although changes in a few have been described. Withdrawal seizures can occur and require gradual termination of clobazam. The main disadvantage of clobazam is the development of tolerance, which develops in approximately 36% of patients, and there is no way of predicting in which patients or when the phenomenon is likely to occur. A dose of 20 to 30 mg at night is recommended, possibly commencing at 10 mg.

Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats

“…Though benzodiazepines (BZDs) possess excellent anticonvulsant activity and tolerability, their usefulness is limited in maintenance therapy of epilepsy because tolerance develops to their anticonvulsant effects following chronic treatment (Robertson, 1986;Schmidt et al, 1986;Haigh & Feely, 1988a). It has been recently suggested that partial agonists at the BZD receptor may have advantages over the more conventional full agonists regarding both their spectrum of action and their relative tolerance/dependence-inducing potential (Haefely et al, 1990).…”

Efficacy of low-dose, add-on therapy of clobazam (CLB) is produced by its major metabolite, N-desmethyl-CLB

“…The relatively high incidence of tolerance is another drawback in long-term administration [3,[5][6][7], and thus, lower dosage has been recommended to minimize the development of tolerance [7]. However, in previous studies of adult patients, the starting dose was usually set to more than 10 mg/day [2]. In recent Japanese clinical study including 234 adult patients, 185 patients showed improvement, and 14 out of them improved by the minimal dose of 5 mg/day but the standard dose ranged from 10 to 40 mg/day [8].…”

“…Clobazam (CLB) is a 1,5-benzodiazepine, proved to have antiepileptic properties both in adults and children with various types of epilepsy, mainly as an add-on therapy [2][3][4][5][6]. And yet, its sedative effect is one of the most common reasons for withdrawal [3,4,7,8], although it is milder than that of 1,4-benzodiazepines [6].…”

Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy

“…In an add-on trial, CLB administration was proven to be effective as an adjuvant therapy for epilepsy [2]. CLB has been used mainly as an add-on drug throughout the world [5][6][7].…”