Triazolam: A Review of its Pharmacological Properties and Therapeutic Efficacy in Patients with Insomnia

Summary

Synopsis

Triazolam¹ is a triazolobenzodiazepine with hypnotic properties, advocated for use in acute or chronic insomnia, situational insomnia in hospitalised patients, and insomnia associated with other disease states. As triazolam has a relatively short half-life of about 2 to 3 hours in healthy subjects and has only 1 short acting active metabolite, α-hydroxytriazolam, it would seem more suitable as an hypnotic than longer acting drugs such as flurazepam, nitrazepam or flunitrazepam, particularly when residual sedative effects on the day after ingestion are undesirable. Thus, with usual hypnotic doses of triazolam (0.25 or 0.5mg) impairment of psychomotor and cognitive function is generally not carried over into the day after ingestion, although at doses of 1mg or greater, residual effects may appear. In short term comparative studies triazolam was clearly superior to a placebo, and was at least as effective as flurazepam, or other benzodiazepines such as nitrazepam or diazepam, in hastening sleep onset, reducing nocturnal awakenings, and increasing sleep duration. In other studies it was often superior to chloral hydrate, methyprylone or quinalbarbitone (secobarbital). In a small number of patients with chronic insomnia receiving extended treatment with triazolam in a clinical setting or in some sleep laboratory studies, no evidence of tolerance occurred; however, some evidence of reduced effect with repeated administration has been reported in one sleep laboratory study. Thus, a definitive statement about the likelihood of tolerance occurring on repeated administration is difficult to make at this time.

Pharmacodynamic Studies

Triazolam is a 1,4-benzodiazepine analogue. In hypnosis models in mice, triazolam was 2, 4 and 8 times more potent on a weight basis than flurazepam, nitrazepam and diazepam, respectively. In human sleep laboratory studies, triazolam, like other benzodiazepine hypnotics, caused dose-dependent effects on sleep stages in both healthy volunteers and insomniac patients, reducing stage ‘wake’ and stage 1 sleep, increasing stage 2 and usually having minimal effects on stages 3 and 4. Most sleep laboratory studies have not shown polygraphic evidence of tolerance (loss of initial stage ‘wake’ reduction) or rebound insomnia on abrupt withdrawal, but evidence of reduced effectiveness on repeated administration was reported in one such study. Further data on longer term use are thus needed before it can be clearly stated whether or not tolerance is likely to be a significant problem during chronic therapy. Like flurazepam 15mg, no or only slight depression of rapid eye movement (REM) sleep occurred after triazolam 0.25 or 0.5mg; however, a higher dose of 1mg may significantly reduce REM sleep, and cause REM rebound on withdrawal, as may occur with ‘higher’ doses of flurazepam.

In contrast to findings with flurazepam and nitrazepam, sleep stage alterations and EEG changes during short term administration of triazolam did not extend past the morning after ingestion. Similarly, impairment of performance of psychomotor and cognitive tests was significantly less in subjects 10 hours after taking triazolam 0.25 and 0.5mg than after flurazepam 15 and 30mg, nitrazepam 10mg, or quinalbarbitone 100mg.

Pharmacokinetics

Triazolam is rapidly absorbed following oral ingestion; after an oral dose of 0.88mg, peak plasma concentrations are reached after 1.3 hours. Triazolam is about 90 % bound to human plasma albumin. It is widely distributed to body tissues in monkeys. In man, triazolam is converted to 6 metabolites, of which one, a-hydroxytriazolam, has been stated to have 50 to 100% of the potency of the parent compound; however, the relative contribution of this minor metabolite to the clinical effects of the drug is unclear since this metabolite is present in the plasma primarily in its conjugated form. The plasma elimination half-life of triazolam is about 2.2 hours. After oral administration, triazolam is excreted in the urine (about 91%) and faeces (about 9 %), mainly as conjugates of the a-hydroxytriazolam and 4-hydroxy metabolites. There is no evidence that triazolam or any of its metabolites accumulate on repeated administration in patients with normal renal function.

Therapeutic Trials

A number of double-blind crossover controlled trials, involving mainly outpatient insomniacs taking triazolam 0.25 or 0.5mg for a single night, have shown triazolam to be superior to a placebo, often better than usual doses of chloral hydrate, methyprylone or quinalbarbitone, and at least as effective as flurazepam 15 or 30mg, nitrazepam or diazepam in hastening sleep onset, reducing nocturnal awakenings, and/or increasing sleep duration. In 3 longer term trials comparing triazolam with flurazepam, both drugs maintained their effectiveness for up to 84 nights of administration. In the only in-patient crossover study, comparing triazolam 0.5mg with flurazepam 30mg in psychiatric patients, both hypnotics were equally effective on all sleep parameters over 44 nights of use. In geriatric patients, triazolam 0.25 to 1 mg has produced sleep without the paradoxical agitation or impaired morning alertness that has sometimes been reported with flurazepam or nitrazepam. When compared with placebo in a 2-night double-blind crossover trial in elderly patients, triazolam 0.125mg appeared to induce faster sleep onset (15 minutes faster) and longer duration of sleep (0.5 hours longer), although nocturnal awakenings did not change. In an open 1-year study where triazolam 0.5 to 1mg was taken nightly by psychiatric patients, hypnotic efficacy was maintained with no evidence of tolerance, habituation, change in dream patterns, rebound insomnia, or apparent adverse drug interactions with antidepressant and antipsychotic drugs administered concomitantly. As in insomniac patients, in presurgical, postsurgical, and postpartum patients, triazolam 0.25 or 0.5mg was at least as effective for hypnotic use as flurazepam 30mg, nitrazepam 5mg or flunitrazepam 0.25 to 2mg. Thus, in presurgical patients, triazolam 0.5mg resulted in a sleep time of 6 to 8 hours in 8496 of patients, compared with 76%, 7296 and 3296 of those receiving flurazepam 30mg, nitrazepam 5mg, and placebo, respectively.

Side Effects

Triazolam has generally been well tolerated, and discontinuation of therapy has rarely been necessary. Residual drowsiness (‘hangover’) has been the most frequently reported side effect and, as is to be expected, it is dose-dependent, the incidence usually being no greater than with a placebo after a 0.25mg dose (5.7% for both), slightly higher after 0.5mg (8.1%), but about 4 times greater after 1 mg. Like flurazepam, other side effects, such as headache, dizziness, nervousness and dry mouth have occurred in less than 4% of patients on triazolam 0.25 and 0.5mg, and these have usually been mild. 2 cases of anterograde amnesia have been reported. Recent atypical reports in the Netherlands of a cluster of intolerable psychological changes has led the Dutch drug registry to temporarily suspend sale of triazolam in that country. However, further confirmation of these largely anecdotal reports will be needed before the side effect can be attributed solely to triazolam or to other causes. Such effects have not been reported in other countries.

Dosage

The usual dose range of triazolam is 0.25 to 0.5mg, taken at bedtime or shortly before. In chronic insomniacs transferred from long term therapy with other hypnotic agents, up to 1mg may be needed to produce satisfactory sleep. The 1mg dose usually should be reserved for hospitalised patients. In elderly patients, or those with a history of marked sensitivity, 0.125mg may suffice. Prior to receiving triazolam, as with all hypnotic agents, patients should be cautioned about the additive effects of other depressant drugs and alcohol, and the possibility of residual effects on performance the morning after ingestion.