Novel Nonbenzodiazepine Hypnotic Drugs
Zolpidem: Zolpidem was marketed in the United States in the early 1990s as the first nonbenzodiazepine hypnotic with a specific effect on the omega-1 receptor. Due to its specificity, zolpidem lacks anticonvulsant, muscle relaxant, and anxiolytic effects, and has been shown to have less effect on sleep architecture and next-day performance compared to benzodiazepines. Its hypnotic efficacy is the same as that of benzodiazepine hypnotics. Rebound insomnia, memory impairment, dependence and withdrawal are uncommon. A 10 mg dose of zolpidem is recommended and has demonstrated hypnotic efficacy for five weeks without affecting sleep stages or producing tolerance, rebound, or detrimental effects on psychomotor performance. Nightly doses greater than 10 mg do not provide additional hypnotic effect and are associated with greater adverse effects. In the elderly, the recommended initial dose of zolpidem is 5 mg.
Because much of the clinical literature on triazolam is based on higher doses of 0.25 to 0.5 mg, its greater reports of rebound insomnia, memory and psychomotor impairment compared to zolpidem may be due to differences in dosage rather than any inherent differences in the two drugs. A review comparing zolpidem and triazolam concludes that the two drugs have similar pharmacokinetic and pharmacodynamic effects in humans. When given in usually recommended, equipotent doses, the drugs do not differ in efficacy, tolerability, residual effects, memory impairment, rebound insomnia, abuse potential, or other adverse effects. An evaluation of acute behavioral and subject-rated effects of different doses of zolpidem, triazolam and temazepam found dose-dependent differences but not significant differences among the three drugs. Expected adverse effects of zolpidem include dizziness, headache and gastrointestinal distress in 3%–5% of patients. Case reports of dependence and tolerance usually involve higher than recommended doses. Amnesia involving no recollection of telephone conversations when awakened within one hour of taking 5 or 10 mg of zolpidem has been reported.
Zaleplon: Although zaleplon has a pharmacologic profile similar to that of zolpidem, zaleplon offers a rapid absorption and onset of effect, no active metabolites, and an elimination half-life of one hour. This pharmacokinetic profile of very rapid onset and offset suggests zaleplon will be most useful for patients with sleep-onset insomnia but not those with early morning awakening. Zaleplon is also useful for patients who need to take a hypnotic agent for rapid effect but who have limited time before they must awaken. To date, hypnotic agents have primarily been used at bedtime in anticipation of sleep difficulty. Zaleplon is useful for treating insomnia when it occurs, even during the night and early morning, and for promoting naps at circadian times of heightened alertness. Clinical trials available thus far suggest that zaleplon 10 mg is an effective rapidly acting hypnotic without evidence of next-day residual sedation, memory impairment or rebound effects. Zaleplon, like zolpidem, has been studied in doses that are effective yet low enough not to be associated with the rebound insomnia seen with higher dose triazolam.
Zaleplon is rapidly absorbed, with peak plasma levels achieved within 1.1 hours after a 10 mg dose. In comparison, a 10 mg dose of zolpidem achieves peak plasma levels after 1.7 hours. The mean elimination half-life of zaleplon is one hour with a range of 0.8 to 1.4 hours. The pharmacokinetics and safety data do not differ significantly in younger adults and the elderly when given a 10 mg dose.
In several dose response studies evaluating single doses of zaleplon from 1 to 60 mg, zaleplon was generally well tolerated in doses up to 30 mg. The most frequent adverse effects associated with zaleplon included dizziness and headache. Symptoms began to appear approximately 30 minutes after dosing, peaked at one to two hours, and were no longer evident after four hours. No psychomotor impairment was seen with doses up to 15 mg. At 60 mg (six times the therapeutic dose), zaleplon produced clinically significant drowsiness, dizziness, and impaired coordination, but no effect on short-term memory.
A comparison of pharmacodynamic effects of different doses of zaleplon and zolpidem found that on many measures of cognitive and psychomotor effects, 20 mg of zaleplon was comparable to 10 mg of zolpidem. The order of agonist potency was found to be as follows: placebo < zaleplon 10 mg < zaleplon 20 mg < zolpidem
10 mg < zolpidem 20 mg. No rebound insomnia was observed in 106 patients discontinued from zaleplon 2–20 mg after five consecutive nights of use, and adverse effects were as common with placebo as with active drug.
Although zaleplon and zolpidem are similar in duration of sleep, they differ in residual side effects. After 10 mg doses, zolpidem has residual effects on performance and memory tests for up to five hours. Zaleplon has no such effects after two hours.
For adults, a bedtime dose of 10 mg is recommended; for elderly patients, an initial dose of 5 mg is recommended. Zaleplon can be given like other hypnotic drugs before bedtime, or it can be given in the middle of the night after a patient experiences difficulty falling asleep or staying asleep. Zaleplon’s very rapid onset and short duration of effect allows it the unique indication to be given anytime during the night as long as at least four hours of sleep time remain after dosing. Until zaleplon became available, hypnotic drugs had always been given in anticipation of sleep difficulty prior to bedtime. Hypnotic drugs could not be given during the night or repeated during the night for fear of residual hangover effects. Zaleplon is the first drug whose labeling allows for dosing during the night once sleep difficulty occurs because its short half-life minimizes the risk of morning hangover effects.