Temazepam: A Review of its Pharmacological Properties and Therapeutic Efficacy as an Hypnotic

Summary

Synopsis: Temazepam1 is a benzodiazepine drug which is a minor metabolite of diazepam. In clinical studies using subjective evaluation methods it was effective for maintaining sleep and increasing total sleep time. However, sleep laboratory studies did not show a significant effect on some sleep parameters, especially sleep induction.

Temazepam has a relatively short half-life (about 5 to 11 hours, longer in some subjects and in the elderly), and no active metabolites of clinical importance, and thus may be considered more suitable for use as an hypnotic than longer acting drugs such as diazepam, nitrazepam or flurazepam when residual sedative effects the next day are not desirable. Indeed, few residual effects on morning performance appear to occur with usual single doses of temazepam, although at the upper end of the recommended dosage range (30mg or more) some evidence of impaired psychomotor and cognitive function in the morning has been reported. Whether or not temazepam is likely to produce ‘hangover’ with repeated night-time administration needs further clarification.

While a call for a large number of controlled trials may not be justifiable in evaluating a new hypnotic, a few well designed additional comparative studies in insomniac subjects are needed to assess adequately the relative merits of temazepam (particularly with regard to sleep onset) compared with other benzodiazepine hypnotics, especially those which are short- or intermediate-acting.

Pharmacodynamic Studies: Temazepam, a 1,4-benzodiazepine, is a minor metabolite of diazepam. It has a short elimination half-life (see below) and has been studied mainly as an hypnotic. In healthy subjects bedtime doses of temazepam of up to 30mg improved sleep maintenance and sometimes shortened sleep onset, although the effects were variable between studies. In a sleep laboratory study of insomniac subjects temazepam 30mg at bedtime for 35 consecutive nights significantly increased total sleep time and reduced wake time, but a significant effect on sleep onset latency was not demonstrated. Temazepam does not reduce the proportion of rapid eye movement (REM) sleep, but like many benzodiazepines it does delay the onset of the first REM period, thus producing a shift of REM sleep toward the latter part of the night. Like all benzodiazepine drugs it reduces stages 3 and 4 (slow wave) sleep. In studies testing psychomotor or cognitive performance the morning after a single bedtime dose, and in 2 studies following several night-time doses, temazepam 10, 15 or 20mg was usually free of important residual effects, but findings with a dose of 30mg were variable, some studies reporting no residual effects and others showing some evidence of impaired function in the morning. In a study designed to assess effects in the elderly, a single bedtime dose of temazepam 20mg had no effect on cognitive function measured by a letter ‘e’ deletion test, on sway on standing or on the EEG 4 and/or 11 hours after administration. However, whether or not temazepam is likely to produce important residual daytime effects after repeated night-time doses in the elderly needs further clarification. Following longer term use (several weeks) small sleep laboratory studies showed a trend toward ‘rebound effects’ on discontinuing therapy, with increased sleep latency, or changes in other indices, beyond baseline values.

Pharmacokinetic Studies: Temazepam is available commercially both as a ‘usual’ hard gelatin capsule dosage form and as a solution of the drug in polyethylene glycol within a soft gelatin capsule. The 2 dosage forms appear to have different absorption characteristics, peak plasma concentrations occurring more rapidly with the soft capsule form in 1 study in healthy subjects (peak concentration at 45 and 86 minutes, respectively, with a 20mg dose in the soft and hard capsules). Whether such kinetic differences between the dosage forms are of clinical importance, particularly with regard to effect on sleep onset latency, needs further clarification. Temazepam is excreted primarily in the urine as inactive conjugates, less than 2 % being excreted unchanged. The elimination half-life has usually been reported as within the range of 5 to 11 hours in healthy subjects, but was longer (15 to 20 hours) in an early study in healthy volunteers. In the elderly the elimination half-life was about 14 hours in 1 study and 15 to 30 hours in another, suggesting that accumulation could occur in some such patients with repeated doses.

Side Effects: Temazepam is well tolerated in most patients; about 90 % of patients remain free of adverse effects with usual doses. Gastrointestinal complaints, headache, dreams or nightmares and residual sedation have been the most frequently reported adverse effects in open studies. In individual cases paraesthesia, tachycardia, panic or nystagmus have occurred.

Therapeutic Trials: The clinical use of temazepam in general practice has been documented through large open studies or postmarketing surveillance reports covering more than 20,000 patients, but there are few well designed controlled comparative studies with the drug. In open studies results were reportedly ‘good’ or ‘very good’ or the drug was ‘effective’ in 70 to 90% of general practice patients receiving a dose of 10 to 30mg nightly for up to 3 months, or in patients with ‘resistant’ insomnia receiving doses of up to 80mg (usually 40mg). In a few comparative studies temazepam 10mg was about as effective as nitrazepam 5mg in psychiatric outpatients or chlormethiazole 384mg (base) in elderly inpatients. Temazepam and flurazepam in equal dosage (30mg) were of comparable effectiveness in geriatric or middleaged insomniacs. Similarly, temazepam 30mg and glutethimide 500mg or amylobarbitone (amobarbital) 200mg were about equally effective in general practice patients with insomnia or during hospitalisation. However, temazepam produced less subjectively assessed ‘hangover’ than flurazepam, chlormethiazole or amylobarbitone.

Dosage and Administration: The usual dose range of temazepam is 15 to 30mg in some countries or 10 to 60mg in others, taken at bedtime or shortly before. Precautions necessary with any depressant agent should be followed, including a warning to patients about the likely additive effects of alcohol and other depressant drugs, and the possibility of residual effects on performance in the morning.