Loprazolam

Summary

Synopsis: Loprazolam¹ is a 1,4-benzodiazepine with hypnotic properties, advocated for use in acute or chronic insomnia. As loprazolam has a half-life of 7 to 8 hours in healthy adults it may have advantages over longer-acting hypnotics, particularly when residual sedative effects on the day after ingestion are undesirable, although at doses greater than 1mg residual sedation may occur. In addition, it may reduce daytime anxiety, following a hypnotic dose the night before, more effectively than the short-acting drug, triazolam. In short term comparative studies loprazolam was clearly superior to placebo, and was at least as effective as triazolam, flurazepam, nitrazepam, flunitrazepam or temazepam in hastening sleep onset, reducing nocturnal awakenings and increasing total sleep duration and quality. In the small number of patients with chronic insomnia who have received extended treatment with loprazolam, no evidence of tolerance has occurred, although rebound insomnia was evident 3 days after drug withdrawal in several studies.

Thus, with its ‘intermediate’ elimination half-life, loprazolam would appear to have some potential advantages over both long- and short-acting hypnotics in selected patients, although further studies are needed to fully elucidate its place in therapy.

Pharmacodynamic Studies: In human sleep laboratory studies, loprazolam causes dose-dependent effects on some sleep stages in both healthy volunteers and insomniacs. Loprazolam characteristically increases total sleep time. It also reduces the ‘wake’ stage and stage 1 sleep, increases stage 2 sleep and has minimal effects on stage 3 and 4 sleep. Most studies show no polygraphic evidence of tolerance (loss of initial ‘wake’ stage effects) or rebound insomnia after abrupt withdrawal. Further data on longer term use are needed before it can be clearly demonstrated whether or not tolerance is likely to be a specific problem during long term therapy. It is not yet clear whether loprazolam has any significant effects on rapid eye movement sleep.

Loprazolam 1mg impairs tests of manual dexterity, memory, tracking and mental arithmetic. However, impairment of psychomotor and cognitive function the morning after loprazolam is usually minimal (unless 2mg doses are used), in contrast to flurazepam 15mg which causes significant depression of these functions. Concomitant administration of alcohol appears to cause little if any additional psychomotor or cognitive impairment to that caused by loprazolam.

Pharmacokinetic Studies: Loprazolam is slowly and variably absorbed following oral ingestion, peak plasma concentrations usually being reached at 2 to 5 hours in non-fasting subjects. It is widely distributed to body tissues in animals, and is about 80% bound to plasma proteins. In man, loprazolam is converted to several metabolites, of which one, the piperazine-N-oxide (which accounts for 18% of total metabolites) may have a similar half-life to the parent compound although the pharmacological activity of metabolites is less than that of loprazolam. The relative contribution of this metabolite to the clinical effects of the drug is unclear. The plasma elimination half-life of loprazolam is usually about 7 to 8 hours although some studies report higher values. After oral administration, loprazolam is excreted primarily in the urine as conjugates, with only negligible amounts excreted unchanged. There is no evidence that loprazolam 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 single or repeated night-time doses of 0.5, 1 or 2mg, have shown loprazolam 1mg to be superior to placebo. A smaller number of studies have shown loprazolam to be better than flunitrazepam 1mg and at least as effective as flurazepam 15mg, temazepam 20mg, triazolam 0.25 to 1mg, or nitrazepam 5mg in hastening sleep onset, reducing nocturnal awakenings, and/or increasing total sleep duration. In the only long term placebo-controlled trial in outpatients, loprazolam was superior to placebo the first 3 weeks of use. In 2 long term trials comparing triazolam 0.5mg with loprazolam 0.5 and 1mg, both drugs maintained their effectiveness for 21 nights of administration. In geriatric patients, loprazolam 1mg has produced sleep without the paradoxical agitation or impaired morning alertness that has sometimes been reported with flurazepam or nitrazepam. When compared with nitrazepam 5mg in two double-blind studies in institutionalised elderly patients, loprazolam 1mg appeared to induce longer duration of sleep than nitrazepam, although the number of nocturnal awakenings did not change. In two open studies of 6 months and 1 year duration, loprazolam 1mg appeared to maintain its efficacy with no evidence of tolerance, habituation, change in dream patterns, rebound insomnia, or apparent adverse drug interactions with other psychotropic medications administered concomitantly. As in insomniac patients, in presurgical and medical patients, loprazolam 1mg was at least as effective as nitrazepam 5mg or triazolam 0.25mg and loprazolam 2mg was superior to nitrazepam 5mg in improving sleep onset, depth of sleep, nightly awakenings, and duration of sleep.

Side Effects: Loprazolam has generally been well tolerated and discontinuation of therapy has rarely been necessary. Residual drowsiness (‘hangover’) has been the most frequently reported side effect. Like flurazepam 15mg, nitrazepam 5mg and temazepam 20mg, loprazolam 1mg was associated with headache no more often than placebo. Dizziness with loprazolam 2mg occurred in 17% of patients compared with 3.4% and 0.9% for the 0.5 and 1mg dose or placebo (1%).

Dosage: The usual dose range is 0.5 to 2mg taken at bedtime or shortly before. The 1mg dose will usually produce satisfactory results, even in elderly subjects. The 2mg dose should usually be reserved for hospitalised severe insomniac patients and may be associated with a higher frequency of unwanted effects. In frail or debilitated elderly patients, 0.5mg may suffice. Prior to receiving loprazolam, as with all hypnotic agents, patients should be cautioned about the possible effects of other depressant drugs and alcohol.