Zolpidem

Abstract

Zolpidem is an imidazopyridine, a chemically novel nonbenzodiazepine hypnotic agent which acts at the benzodiazepine ω₁-receptor subtype in the brain. With a rapid onset of action and short elimination half-life, it reduces the latency to and prolongs the duration of sleep in patients with insomnia, yet has no major effects on sleep stages when given in dosages of 5 to 20mg nightly. Rebound effects on withdrawal of the drug have not been observed. Unlike benzodiazepines, zolpidem has no myorelaxant or anticonvulsant effects and its effects on anxiety appear to be minor. While zolpidem aids sedation, and may reduce memory or psychomotor function within the first 2 hours after administration of single oral doses, its use as a surgical premedicant remains to be established. Adverse effects are predominantly CNS and gastrointestinal in nature. Altered pharmacokinetics may lead to an increase in dose-proportionate adverse effects in the elderly and in patients with renal dysfunction. Limited evidence to date suggests that the dependence liability of zolpidem is minimal. Thus, zolpidem is an interesting alternative to benzodiazepines in the treatment of insomnia, with properties that potentially offer worthwhile advantages in this therapeutic area if they are confirmed with wider clinical experience. Zolpidem is a nonbenzodiazepine sedative-hypnotic agent which binds selectively to the benzodiazepine ω₁-receptor subtype in the central nervous system but possesses low affinities for ω₂-or ω₃-receptor subtypes. It reduces the time to onset and increases the duration of sleep in healthy volunteers when administered in doses as low as 5 to 7.5mg at bedtime. In volunteers and patients with sleep disorders, zolpidem did not alter sleep stages until given in doses of 10 to 20mg or more, when it increased stage 2 sleep, slow wave sleep (stages 3 and 4) and latency to rapid eye movement (REM) sleep, and decreased the duration of REM sleep. Zolpidem does not appear to cause rebound insomnia or other withdrawal reactions after short term administration. The psychomotor effects of zolpidem are minor and transient, with slight impairment of function observed during the first 2 hours after administration and no significant changes noted the next day. Memory may also be impaired during the first 2 hours after administration of zolpidem as a surgical premedicant, a time during which anterograde amnesia has been observed, but memory deficits appear to be unusual in the morning following administration to humans. In rats, the strong sedative effects of zolpidem appear to mask any anxiolytic responses. Adequate anxiolysis has not been consistently observed in patients receiving zolpidem as a presurgical medication, and this effect has not been sufficiently well studied in humans to recommend zolpidem as an anxiolytic. Relatively little tolerance to zolpidem developed in rats, but tolerance was evident with midazolam, and while zolpidem did not sensitise rats to midazolam, the response to zolpidem was reduced after long term midazolam administration. No evidence of tolerance or dependence was observed in at least 138 geriatric and general practice patients with insomnia treated for up to 1 year; however, few studies have systematically investigated the dependence liability of the drug. Dose increases tended to occur early in therapy (within 30 days) and were usually the result of initial poor efficacy. Indeed, the efficacy of static dosages of zolpidem appeared to increase during the first 4 weeks of therapy. Zolpidem did not produce adverse respiratory effects in hospitalised patients with transient insomnia or chronic obstructive pulmonary disease or in patients receiving the drug as a surgical premedicant. However, zolpidem may reduce oxygen intake in patients with sleep apnoea. Studies in baboons have shown that the drug may reduce cerebral blood flow and oxygen consumption. Zolpidem does not possess significant anticonvulsant or myorelaxant properties. Zolpidem is rapidly absorbed after oral administration, with peak plasma concentrations of about 200 μg/L attained approximately 2.2 hours after single oral 20mg doses and after 15 days of bedtime administration. First-pass metabolism occurs, resulting in a bioavailability of 70%. Although highly bound to plasma proteins, zolpidem concentrates initially in glandular and fatty tissues, but is rapidly eliminated, with only residual radioactivity observed in nonsecretory tissues 3 hours after administration. The drug is secreted in small amounts into breast milk. There are 3 major metabolites of zolpidem, which are all pharmacologically inactive. Unchanged zolpidem has been detected in only minute amounts (< 1%) in human ex-creta. The elimination half-life ranged from 1.5 to 2.4 hours in healthy volunteers; systemic clearance was 0.26 L/h/kg and the volume of distribution was 0.54 L/kg. Liver cirrhosis and renal disease both tend to reduce elimination of zolpidem and may necessitate dosage reductions. The drug is not removed by dialysis. Preliminary data suggest that zolpidem has a longer half-life in the elderly and shorter half-life in children; these changes may alter the duration of activity in these age groups. Gender may also affect zolpidem pharmacokinetics, as higher plasma concentrations and AUCs have been seen in women than in men and these may influence the incidence of adverse effects. Conversely, zolpidem pharmacokinetics appear to be unaffected by food, alcohol or caffeine consumption, or by race or ethnic origin. Zolpidem has been tested in the treatment of insomnia and as a sedative/anxiolytic administered before surgery. A noncomparative trial has shown that zolpidem is well tolerated and effective in elderly and general practice patients with insomnia when given for up to 6 months. Dose-ranging studies in patients with insomnia have found a nightly dosage of 10 to 20mg achieved good results with optimum tolerability. At these dosages, zolpidem is superior to placebo and is generally similar to the benzodiazepines flurazepam, flunitrazepam, oxazepam and triazolam in inducing and maintaining sleep, minimising awakenings and maximising the duration of sleep in elderly, general practice or psychiatric patients with insomnia. The subjective quality of sleep and morning condition of patients with insomnia tended to be improved by zolpidem compared with placebo, and were similar or superior to improvements achieved by benzodiazepines. When used in 10 or 20mg nightly dosages to treat insomnia, zolpidem did not result in impairment of memory or motor skills on awakening. As an oral premedicant before surgery, zolpidem 10 or 20mg was significantly superior to placebo in causing sedation, and was preferred to placebo by both patients and anaesthetists. It reduced the anaesthetic dose required but tended to prolong recovery relative to placebo. Zolpidem produced only minor interference with psychomotor skills in the 3 hours post-recovery. When compared with midazolam 15mg or lorazepam 1 or 2.5mg, zolpidem 10 to 20mg produced a similar degree of sedation, although midazolam 15mg was a more powerful anxiolytic. Some anterograde amnesia was observed in each study group but it was significantly more common in recipients of lorazepam 25mg. Neither zolpidem dose prolonged the recovery of responses to visual and auditory stimuli, unlike lorazepam 2.5mg. When given in a nightly dosage of up to 20mg zolpidem is generally well tolerated by patients with insomnia. The most common adverse effects occurring in clinical trials were dizziness and lightheadedness (5.2%), somnolence (5.2%), headache (3.0%) and gastrointestinal upset (3.6%). Adverse events appeared to be more frequent in recipients of zolpidem 10 or 20mg than in patients administered triazolam 0.5mg or flunitrazepam 1mg, and although dependence, tolerance and withdrawal effects may be less common with zolpidem these factors have not been adequately studied. Falls and confusion occurred almost exclusively in elderly patients, especially those receiving higher dosages (>20 mg/day) of the drug. Falls have not been reported in patients treated with zolpidem 5mg daily, although the population studied so far at this dosage is small. The incidence of amnesia was unrelated to age or dosage. Zolpidem resulted in double vision prior to anaesthesia induction in a small number of patients and tended to reduce blood pressure in patients administered the drug as a preoperative sedative. Initial zolpidem dosage in patients ‘< 65 years experiencing acute insomnia is 10mg nightly, increased to 15 or 20mg nightly if the response is inadequate. For patients >65 years experiencing insomnia, an initial 5mg dose may be increased to a 10mg maximum if needed. The lowest effective dose should be used. Dosage reduction is recommended in patients with renal or liver damage. Prolonged use is not recommended, and zolpidem recipients should be cautious when operating motor vehicles or machinery.