Clobazam: A Review of its Pharmacological Properties and Therapeutic Use in Anxiety

Summary

Synopsis: Clobazam¹ is a 1,5-benzodiazepine with antianxiety and anticonvulsant properties, advocated for the treatment of primary anxiety and that associated with organic or functional disorders. Clobazam itself has a half-life of 18 hours, but that of the principal metabolite, N-desmethylclobazam, is about 50 hours. Although the metabolite is pharmacologically less active than the parent drug, steady-state plasma concentrations of the metabolite are 8 times higher than those of the unchanged drug. Therapeutic trials indicate that the antianxiety effect of clobazam 30 to 80mg daily is comparable with that of half its dose of diazepam. Clobazam has minimal muscle relaxant and hypnotic activity. Although subjective drowsiness has occurred with similar frequency with clobazam and diazepam in some studies, clobazam causes less objectively measured sedation or psychomotor impairment in experimental studies. Results of studies of vigilance and psychomotor performance during therapeutic use in patients are less conclusive, but clobazam may be useful in anxious patients who experience such impairment with other benzodiazepines.

Pharmacology: Clobazam is a 1,5-benzodiazepine with the nitrogen atoms in the 1,5 positions of the heterocyclic ring as opposed to in the 1,4 positions in diazepam. In standard screening tests for antianxiety activity in animals, clobazam is active in suppressing aggression induced by isolation or footshock and in decreasing the frequency of rearing action in a novel environment.

In mice, clobazam inhibited convulsions induced by pentylenetetrazol, nicotine, strychnine and picrotoxin. In these studies clobazam was comparable in efficacy with diazepam and more active than chlordiazepoxide. Clobazam seems to be initially effective against all varieties of epilepsy in about 75% of epileptic patients, but it loses all or part of its efficacy in over one-third of those who benefited from its effect. The usefulness of clobazam in epilepsy still has to be investigated.

Doses of clobazam required to impair motor coordination and produce muscle relaxation and hypo-reflexia in animals are considerably higher than those which produce anticonvulsant or antianxiety activity.

Human studies of the effects of certain benzodiazepines on objective measurements of arousal and psychomotor performance indicate that, in general, moderate doses of clobazam (10 or 20mg) have less adverse effect on tests of psychomotor performance than therapeutically equivalent doses of diazepam, chlordiazepoxide or lorazepam. In experimental studies, as in therapeutic trials, general alertness may be reduced subjectively, but this is often not reflected in objective measurements of arousal and psychomotor performance. The effects of clobazam on driving have been studied in a simulator, on a test track and in actual traffic conditions in a dual controlled car. Clobazam generally produced less impairment of driving performance than half its dose of diazepam, but performance was impaired by clobazam in a few subjects and performance tended to be impaired by combined alcohol and clobazam ingestion.

Pharmacokinetics: Clobazam is readily absorbed after oral administration and bioavailability does not vary significantly when administered as tablets, capsules or in solution. Peak serum concentrations of unchanged drug which are attained 1 to 4 hours after oral administration, are about 244ng/ml after 20mg, 430ng/ml after 30mg and 527ng/ml after 40mg. After repeated doses, steady-state concentration of unchanged clobazam is achieved within 1 week. Steady-state levels of the active metabolite N-desmethylclobazam appear to be about 8 times higher than those of the unchanged drug. Combined administration of single doses of clobazam 20mg and alcohol results in a 50% increase in bioavailability of clobazam, but the mechanism involved is not certain.

The two most important chemical changes that clobazam undergoes during metabolism are dealkylation and hydroxylation. Clobazam, unlike the 1,4-benzodiazepines, does not undergo hydroxylation at the 3 position of the heterocyclic ring. The main metabolites in serum after a single dose are N-desmethylclobazam and 4′-hydroxyclobazam in addition to the parent compound. In the urine, 9 metabolites plus clobazam were identified. In mice the anticonvulsant and antiaggressive effects of N-desmethylclobazam are 2.4 and 7-fold less respectively, than those of clobazam itself. 81 to 97% of an oral dose is recovered in the urine. The average half-life of clobazam (parent drug plus metabolites) is about 50 hours, whilst that of the unchanged drug is about 18 hours.

Therapeutic Trials: Controlled therapeutic trials, characterised by a high placebo response rate, have shown clobazam to be superior to placebo. Double-blind comparisons of clobazam 20 to 80mg daily with diazepam 10 to 40mg daily have generally not been able to demonstrate any significant difference between the antianxiety effect of the drugs in patients with moderate to mild anxiety neurosis or anxiety associated with organic or functional disease.

The Hamilton Anxiety Scale and a clinical global impression have been employed alone or in conjunction with various other methods of assessment in all comparative studies, but few such studies have included a placebo group to demonstrate the efficacy of the standard drug. However, those studies that have included a placebo, have shown clobazam to be superior in at least some assessment criteria. In one 3-month study, a fixed dose of 30mg daily of clobazam tended to be more effective than diazepam 15mg daily in alleviating anxious mood, whereas the reverse tendency was found with regard to muscular symptoms and tension.

In a comparison with a single daily dose of clorazepate 15mg in a small number of patients, clobazam 20 or 30mg (as a single daily dose) was statistically indistinguishable, but tended to cause a lower incidence of drowsiness.

Comparative and open studies in patients with anxiety associated with organic or functional illness indicate that clobazam alleviates anxiety and psychosomatic complaints in patients with acute myocardial infarction, cardiovascular symptoms without demonstrable organic disease, radiologically confirmed peptic ulcer and genitourinary and menopausal symptoms.

In patients with alcohol withdrawal symptoms no significant difference between diazepam 15mg and clobazam 30mg could be detected with the Hamilton Anxiety Scale, but the global assessment found clobazam 30mg superior to diazepam 15mg and clobazam 20mg.

A study in gynaecological patients about to undergo minor surgery was unable to distinguish between clobazam 20mg, diazepam 10mg or placebo as a premedicant. Similarly, clobazam 20mg was not significantly different from placebo in young hospitalised patients requiring a hypnotic. However, clobazam has been reported to improve insomnia, probably as a result of its alleviating anxiety.

Open studies in children suggest that clobazam 5 to 15mg daily is effective in alleviating primary anxiety and that associated with school, hospitalisation and various organic diseases.

Side Effects: Clobazam has generally been well tolerated, discontinuation of therapy having seldom been necessary. Drowsiness has been the most frequently reported side effect, but most studies have failed to differentiate between this subjective symptom and ‘sedation’ which signifies the subjective feeling associated with decreased motor activity. Drowsiness, sedation or ‘hangover’ have occurred more frequently with clobazam than with placebo and have generally been reported to occur with similar frequency with both clobazam and therapeutically equivalent doses of diazepam. However, studies which have also measured psychomotor function have found clobazam to have less adverse effect than diazepam. Thus, it might be expected that some individuals, at least, may spontaneously report drowsiness, but not exhibit sedation as reflected in decreased psychomotor activity. Other side effects reported in 10 to 40% of patients in controlled trials include dizziness, weakness and lightheadedness, whilst weight gain, hypotension syncope, incoordination, irritability and headache have been reported in 5 to 10% of patients.