Zaleplon: a review of its use in the treatment of insomnia

Zaleplon is a pyrazolopyrimidine hypnotic agent which is indicated for the short term (2 to 4 weeks) management of insomnia. Zaleplon 5 and 10 mg at bedtime (usual recommended doses) significantly reduced sleep latency compared with placebo in clinical trials in nonelderly and elderly patients with insomnia. In general, sleep maintenance (sleep duration and number of awakenings) and sleep quality were not significantly different from placebo with zaleplon 5 and 10 mg/night. Zaleplon 20 mg/night significantly improved sleep latency and duration in nonelderly patients, but effects on number of awakenings were inconsistent and sleep quality generally did not improve. The relative hypnotic efficacy of zaleplon compared with that of triazolam and zolpidem is not yet clearly established. Tolerance to the hypnotic effects of zaleplon generally did not occur during 5 weeks' treatment, or during long term treatment (6 or 12 months) according to a small number of studies presented as abstracts. Zaleplon was well tolerated in clinical trials. The most common event was headache but the incidence was similar to that observed with placebo. Zaleplon 5 and 10 mg did not impair psychomotor function or memory even immediately after the dose in studies in volunteers or patients with insomnia. Zaleplon 20 mg, however, impaired psychomotor function and memory immediately after the dose but next-day effects were not observed. The psychomotor profile of zaleplon appears to be better than that of comparator agents. Rebound insomnia was not observed after sudden discontinuation of up to 12 months' treatment with zaleplon 5 and 10 mg/night and up to 4 weeks' treatment with zaleplon 20 mg/night. In addition, the potential for withdrawal syndrome with zaleplon appears to be low according to limited data. In conclusion, zaleplon 5, 10 and 20 mg administered at bedtime, or later if patients have difficulty sleeping, is an effective and well tolerated hypnotic agent. There was no evidence of next-day residual effects with the 5 and 10 mg dosages, and the incidence of withdrawal effects with zaleplon 5, 10 and 20 mg did not differ significantly to that observed with placebo. In addition, tolerance to the effects of zaleplon is unlikely to develop when administered for the recommended treatment period. The comparative efficacy and tolerability of zaleplon with other short acting nonbenzodiazepine hypnotics is difficult to establish. However, on the basis of current efficacy evidence and the lower incidence of residual effects with zaleplon 5 and 10 mg relative to comparator agents, this drug represents a useful option in the management of patients with insomnia who have difficulties initiating sleep.     

Twelve months of nightly zolpidem does not lead to rebound insomnia or withdrawal symptoms: a prospective placebo-controlled study

Rebound insomnia, worsened sleep when discontinuing use of a hypnotic, is reported in some short-term studies. No study has prospectively assessed, using patient reports or nocturnal polysomnography (NPSG), the likelihood of rebound insomnia with chronic hypnotic use. The objectives of this study was to assess in primary insomniacs the likelihood of experiencing rebound insomnia and a withdrawal syndrome on repeated placebo substitutions over 12 months of nightly zolpidem use. A group of 33 primary insomniacs, without psychiatric disorders or drug and alcohol abuse, 32-65 years old, 15 men and 18 women, were randomized to take zolpidem 10 mg (n = 17) or placebo (n = 16) nightly for 12 months. In probes during months 1, 4, and 12, placebo was substituted for 7 consecutive nights in both the zolpidem and placebo groups. NPSGs were collected and Tyrer Bezodiazepine Withdrawal Symptom Questionnaires were completed on the first two discontinuation nights. Rebound insomnia was not observed on the first two and the seventh discontinuation nights and its likelihood did not increase over the 12 months of nightly zolpidem use. Some individuals did show rebound insomnia, approximately 30-40% of participants, but the percentage of 'rebounders' did not differ between the placebo and zolpidem groups and did not increase across 12 months. No clinically significant withdrawal symptoms on the Tyrer were observed on the discontinuation nights over the 12 months of nightly use. Chronic nightly hypnotic use at therapeutic doses by primary insomniacs does not lead to rebound insomnia or withdrawal symptoms.     

Benefit-risk assessment of zaleplon in the treatment of insomnia.

Insomnia is a heterogeneous, highly prevalent condition that is associated with a high level of psychiatric, physical, social and economic morbidity. The treatment of insomnia involves pharmacological and non-pharmacological interventions. The mainstay of pharmacological treatment of insomnia has been the benzodiazepines, the introduction of which represented a significant improvement over the barbiturates and chloral hydrate. Although benzodiazepines have been shown to be efficacious in treating insomnia, they have also been associated with a number of adverse effects including tolerance, dependence, withdrawal and abuse potential, impairment in daytime cognitive and psychomotor performance (including an increased risk of accidents and falls), adverse effects on respiration and the disruption of normal sleep architecture with reduction in both slow wave sleep and rapid eye movement. In the last decade, the treatment of insomnia has been supplemented by the introduction of a number of non-benzodiazepine hypnotics including zolpidem, zopiclone and, most recently, zaleplon. Zaleplon possesses a unique pharmacological profile, with an ultra-short half-life of about 1 hour, and selective binding to the BZ1(omega1) receptor subtypes of the GABA(A) receptor. This unique pharmacological profile predicts a number of pharmacodynamic properties that account for a unique benefit-risk profile. Consistent with these predictions, zaleplon has been shown in a number of studies to be efficacious in promoting sleep initiation, but less so in promoting sleep maintenance. The adverse effects associated with zaleplon have been shown to be more rapidly resolved and/or lesser in magnitude than those associated with benzodiazepines (including triazolam) and the longer acting non-benzodiazepine hypnotics (zolpidem and zopiclone). This improved risk profile includes: the effects of zaleplon on psychomotor and cognitive performance; tolerance, withdrawal and rebound; respiratory depression; sleep architecture; and other treatment-emergent adverse effects. The unique benefit-risk profile of this agent may be particularly suitable for certain patients with insomnia and provides yet another option in the management of this impairing condition.     

扎来普隆与唑吡坦治疗失眠症的多中心随机双盲对照比较

目的 :评价国产Ⅱ类新药扎来普隆治疗失眠症的有效性和安全性。方法 :采用多中心随机双盲双模拟、阳性药平行对照研究。唑吡坦组 12 0例 ,扎来普隆组 118例分别口服扎来普隆片 10mg·d- 1或唑吡坦片 10mg·d- 1。 14d为一个疗程。结果 :意向性 (ITT)分析样本病人有 2 38例。疗效评价的睡眠障碍量表 (SDRS)评分在治疗结束时较基线显著减少 (F检验 ,P <0 .0 1)。唑吡坦组的有效率77.5 % ,扎来普隆组的有效率 73.7% ,差异无显著意义 (P >0 .0 5 )。不良反应分析显示 2组较常见的不良反应为思睡、口干、便秘、头晕和头痛。结论 :国产扎来普隆与唑吡坦具有类似的疗效 ,不良反应相当。为治疗睡眠障碍的安全而有效的新药。     

Zolpidem is not superior to temazepam with respect to rebound insomnia: a controlled study.

This randomised controlled trial was conducted to compare zolpidem to an equivalent dose of temazepam with respect to subjective rebound insomnia after cessation of 4 weeks of treatment in chronic insomnia (zolpidem 10 mg, n=79; temazepam 20 mg, n=84). Both agents improved total sleep time (TST) as well as sleep onset latency (SOL) significantly during the 4 treatment weeks. Prevalence rates for rebound insomnia, defined as a worsening of TST or SOL of more than 40% compared to baseline, were 27% for TST and 53% for SOL in the Zolpidem condition and 26% and 58%, respectively, in the temazepam condition. No significant differences were found between both agents with respect to rebound insomnia, nor with respect to their efficacy or safety. We conclude that in clinical practice zolpidem has no advantages over temazepam with respect to rebound insomnia.     

Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis

OBJECTIVES: To compare the clinical effectiveness of zaleplon, zolpidem or zopiclone (Z-drugs) with either benzodiazepines licensed and approved for use in the UK for the short-term management of insomnia (diazepam, loprazolam, lorazepam, lormetazepam, nitrazepam, temazepam) or with each other. METHODS: MEDLINE, EMBASE, PsycINFO, Science Citation Index/Web of Science were searched from 1966 to March 2003 and The Cochrane Library, reference lists of included studies and a number of psychopharmacology journals. Randomized controlled trials comparing either benzodiazepines with the Z-drugs or any two of the Z-drugs in patients with insomnia were included. Outcome measures included: sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness. RESULTS AND CONCLUSIONS: Twenty four eligible studies were identified with a total study population of 3,909 (17 studies comparing a Z-drug with a benzodiazepine and 7 comparing a Z-drug). Insufficient or inappropriately reported data meant that meta-analysis was possible only for a small number of outcomes. There are few clear, consistent differences between the drugs. Some evidence suggests that zaleplon gives shorter sleep latency but shorter duration of sleep than zolpidem, reflecting the pharmacological profiles of the drugs.     

Dose-response effects of zaleplon as compared with triazolam (0.25 mg) and placebo in chronic primary insomnia

The effects of two nights of treatment with the short-acting benzodiazepine receptor agonist zaleplon, triazolam, or placebo was assessed in chronic primary insomniacs using two concurrent, multi-center, randomized, double-blind, Latin Square crossover studies. Study 1 (n = 47) compared zaleplon (10 and 40 mg) to triazolam (0.25 mg) and placebo. Study 2 (n = 36) compared zaleplon (20 and 60 mg) to triazolam (0.25 mg) and placebo. For each study, polysomnographically recorded sleep parameters and patient reports of sleep quality were collected during baseline and two consecutive nights during the four treatment phases in each study. All doses of zaleplon produced significant decreases in latency to persistent sleep. Although no minimally effective dose could be determined, dose-response effects were apparent. Triazolam 0.25 mg produced a decrease in latency to persistent sleep that was comparable to that of zaleplon 10 mg. Only the triazolam dose and the 60 mg dose of zaleplon produced significant increases in total sleep time over placebo. Zaleplon 40 and 60 mg and triazolam produced decreases in the percentage of REM sleep compared to placebo. Patient reports of efficacy were consistent with objective findings. In addition, all doses of zaleplon tended to increase while triazolam decreased the percentage of stage 3/4 sleep. There was no evidence of residual daytime impairment for any of the zaleplon doses, however, triazolam administration produced significant impairment in performance on a digit copying test. A higher number of adverse events were seen with the 40 and 60 mg doses of zaleplon compared to triazolam (0.25) and placebo. At higher doses, zaleplon is more effective than triazolam at reducing latency to persistent sleep in chronic insomnia and is not associated with the decrease in slow-wave sleep or residual impairment observed with triazolam. However, increases in total sleep time were apparent only at doses which produced concomitant increases in the number of adverse events. In contrast, triazolam (0.25 mg) produced increases in total sleep time (;25 min) and decreases in latency to persistent sleep at a dose of 0.25 mg. Copyright 2000 John Wiley & Sons, Ltd.     

Chronic morphine administration in cats: effects on sleep and EEG

Sleep-wakefulness and EEG responses to a chronic morphine treatment (2 mg/kg/day, IP, during 15 days) were studied in 8 cats provided with electrodes for EEG, EMG and EOG records. Results indicated that, in contrast to a resistance of the cats to exhibit overt signs of tolerance in the immediate behavioral and EEG responses to morphine, tolerance developed in sleep since: 1) there was a reduction in its onset latency after the initial insomnia period; 2) despite that the initial insomnia period was present throughout the treatment, compared to the effects of the first MS day, the total amount of both NREM sleep and REM sleep significantly increased in subsequent drug days, the total amount of REM sleep reached similar placebo values from day 5; 3) the restoration in the total amount of both sleep states was due to significant increases that occurred from day 5 after the first 6 hours of the MS injection. During the 19-24 hours after MS injections, increases of NREM and REM also resulted statistically significant compared to placebo values. A biphasic depressed and aroused response occurred during early withdrawal. REM sleep rebound was present after MS discontinuation and in the following week. Similarities with effects of opiate chronic administration in other species are discussed. These results support the potential use of the cat for the study of neural mechanisms involved in sleep chronic effects of opiates.     

Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia

Zolpidem is an imidazopyridine agent that is indicated for the short term (< or = 4 weeks) treatment of insomnia (recommended dosage 10 mg/day in adults and 5 or 10 mg/day in the elderly or patients with hepatic impairment). Data have shown that the hypnotic efficacy of zolpidem is generally comparable to that of the benzodiazepines flunitrazepam, flurazepam, nitrazepam, temazepam and triazolam as well as nonbenzodiazepine hypnotic agents such as zopiclone and trazodone in the treatment of elderly and adult patients with insomnia. The comparative efficacy of a recently available nonbenzodiazepine hypnotic zaleplon and zolpidem has yet to be established. There was no evidence of tolerance developing to the hypnotic effects of zolpidem in a number of studies of up to 6 months' duration. However, tolerance has been described in a few patients taking the drug at high dosages for periods of up to several years. Zolpidem is well tolerated in patients with insomnia and the most common adverse events are generally nausea, dizziness and drowsiness. Although zolpidem produced some psychomotor and memory impairment over the first few hours after administration, it had few next-day effects (including effects on daytime well-being and morning coordination). In this respect, it was comparable or superior to flunitrazepam and flurazepam and comparable to other benzodiazepines in patients with insomnia. Zolpidem appears to have a low potential for abuse. Conclusions: Zolpidem is effective and well tolerated in patients with insomnia, including the elderly. Studies have shown that zolpidem generally has similar efficacy to other hypnotics including benzodiazepines and zopiclone. Zolpidem appears to have minimal next-day effects on cognition and psychomotor performance when administered at bedtime. In addition, there is little evidence of tolerance to the hypnotic effects of zolpidem, or rebound insomnia or withdrawal symptoms after discontinuation of the drug when it is given as recommended (10 mg/day for < 1 month) or over longer periods.     

Ramelteon: a review of its use in insomnia

Ramelteon (Rozeremtrade mark) is the first melatonin receptor agonist to be approved for the treatment of insomnia; it is not classified as a controlled substance. In patients with chronic insomnia, objectively assessed latency to persistent sleep (LPS) at week 1 was improved with oral ramelteon 8 mg administered 30 minutes before bedtime, compared with placebo, and this effect was maintained throughout the duration of 5-week and 6-month clinical studies. Subjectively assessed sleep latency (sSL) improved in some, but not all, studies. When a statistically significant improvement in sSL occurred at week 1, the effect was maintained throughout the duration of the 5-week studies, but not at all timepoints throughout a 6-month study. Improvements in objectively assessed total sleep time (TST) and sleep efficiency (SE) were only reported during the first week of treatment. Improvements in other objective or subjective measures of sleep were not consistent. Ramelteon was generally well tolerated, did not impair next-day cognitive or motor performance and was not associated with withdrawal symptoms, rebound insomnia or abuse potential. Thus, ramelteon provides a well tolerated option for the treatment of patients with insomnia characterized by difficulty in sleep onset.     

Pharmacodynamic profile of Zaleplon,a new non-benzodiazepine hypnotic agent

The challenge in developing hypnotic agents for the treatment of insomnia is to balance the sedative effect needed at bedtime with the residual sedation on awakening. Zaleplon is a novel pyrazolopyrimidine hypnotic agent that acts as a selective agonist to the brain omega(1) receptor situated on the alpha(1) subunit of the GABA(A) receptor complex. Zaleplon was proven to be an effective hypnotic drug as it consistently and significantly reduced latency to persistent sleep in insomniac patients for doses of 10 mg and above in polysomnography studies. The pharmacodynamic profile of zaleplon on psychomotor performance, actual driving and cognitive function, including memory, was assessed in several randomized, double-blind, placebo-controlled studies in healthy young subjects as well as insomniac patients by using various positive controls (zolpidem, zopiclone, triazolam and flurazepam). The recommended hypnotic dose of zaleplon in young adults (10 mg) produced minimal or no impairment of psychomotor and memory performance even when administered during the night as little as 1 h before waking. No impairment of actual driving was observed when zaleplon 10 mg was administered either at bedtime or in the middle of the night as little as 4 h before waking. Zaleplon 20 mg, twice the recommended dose, generally produced significant impairment of performance and cognitive functions when these functions were measured at the time of peak plasma concentration, i.e. 1 h after dose administration, and no impairment of driving abilities was observed 4 h after a middle-of-the-night administration. In contrast, consistent detrimental residual effects on various aspects of psychomotor and cognitive functions were observed with the therapeutic doses of the various commonly prescribed hypnotic agents used as comparators, e.g. zolpidem 10 mg up to 5 h after dose administration, zopiclone 7.5 mg up to 10 h after, flurazepam 30 mg up to 14 h after and triazolam 0.25 mg up to 6 h after. Also, zolpidem 10 mg and zopiclone 7.5 mg were also shown to significantly impair driving ability the next morning when this was measured 4 h and up to 10 h after dose administration, respectively. The present review shows that zaleplon 10 mg has little or no residual effect when administered in the middle of the night, as late as 1 h before waking, and is devoid of impairment of driving abilities as assessed by actual driving 4 h after dose administration. The lack of clinically significant or minimally statistically significant residual effects of zaleplon even at its peak concentration may be explained by its unique pharmacokinetic (rapid elimination half-life) and pharmacodynamic (low affinity, and specific binding profile to various subunits of the GABA(A)receptor) profiles. These properties allow zaleplon to be used for treatment of symptoms only when they occur, either at bedtime or later in the night, without incurring significant risk of developing next-day impairment of psychomotor and cognitive functioning. Copyright 2001 John Wiley & Sons, Ltd.     

Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study

We studied sleep and daytime function in insomniac patients who took either flurazepam, 30 mg, triazolam, 0.5 mg, or placebo 30 minutes before bedtime. Subjects were 21 patients with either a primary or a secondary diagnosis of chronic psychophysiological insomnia or insomnia associated with personality disorder. Seven subjects were randomly assigned to each condition. The study used a three group by 9 week, double-blind design with three nocturnal sleep recordings each week. During week 1, subjects took no capsules; week 2, subjects took placebo; weeks 3 to 7, flurazepam, triazolam, or placebo; weeks 8 and 9, placebo. Daytime tests for alertness and performance were administered during weeks 1, 3, 5, 7, and 8. Flurazepam showed hypnotic efficacy for weeks 3 to 5. Triazolam showed hypnotic activity for weeks 3 to 7. Although not significant overall, discontinuation of flurazepam produced rebound insomnia in six of seven subjects sometime during the two withdrawal weeks. The relationship between plasma concentration of desalkylflurazepam, the principal active metabolite of flurazepam, and sleep disturbance suggested that the onset of the rebound insomnia depended on the rate of drug washout. Discontinuation of triazolam produced a significant rebound insomnia on the first and second nights of drug withdrawal. Placebo subjects showed improved sleep throughout weeks 2 to 9 of the study. Daytime testing revealed significantly decreased daytime alertness and decreased performance for flurazepam subjects during weeks 3 to 7, although these effects reverted toward baseline despite continued drug administration.     

Dose determinants of rebound insomnia.

A polysomnographic assessment in healthy normal sleepers of possible dose relations for rebound insomnia was conducted. As an additional measure of rebound the study included a direct test of sleep/wake tendency during the night of drug discontinuation. Twelve, healthy men (21-30 years) each received placebo, 0.25 mg and 0.50 mg triazolam for 6 consecutive nights followed by a discontinuation night and 14 nights of recovery at home. The three conditions were presented, double-blind, in a latin square design. On night 6 of drug administration both doses increased total sleep time compared to placebo, but 0.50 mg did not improve sleep beyond 0.25 mg. On drug discontinuation (night 7) wake time over the 8 h recording and sleep latency after an experimental awakening (02.30 h) were increased with 0.50 mg compared to placebo and 0.25 mg. On these measures of rebound 0.25 mg did not differ from placebo. Thus rebound insomnia occurred only at a dose (0.50 mg) which produced no additional hypnotic efficacy in these normal sleepers. Whether tests of sleep/wake tendency make a useful measure of rebound insomnia needs further clarification.     

Rebound insomnia: duration of use and individual differences.

This study assessed consistency, duration of use, and individual difference in rebound insomnia. Eleven healthy men, 20-30 years old, with normal sleep by both subjective and polysomnographic criteria, received each of four treatments in a double-blind Latin Square design (triazolam 0.50 mg for 1, 6, and 12 nights and placebo for 12 nights), followed by two placebo discontinuation nights. Triazolam increased sleep compared with placebo without differences in effects between the first and last nights of treatment. On discontinuation following active drug, sleep efficiency was reduced compared with placebo, but duration of administration did not alter the likelihood or intensity of rebound insomnia. Those subjects (5) showing poorer sleep on discontinuation from the 12-night treatment also had poorer sleep in the 1- and 6-night treatment. Subjects with rebound insomnia had poorer baseline sleep and a greater drug effect than did subjects without.     

Zolpidem for insomnia

INTRODUCTION: The imidazopyridine derivative zolpidem , which acts as a benzodiazepine (BZ) receptor agonist, is the most widely prescribed hypnotic drug in the US. AREAS COVERED: This review addresses the neuroreceptor properties of zolpidem; clinical pharmacokinetics, pharmacodynamics and drug interactions; efficacy as a hypnotic; adverse effects; tolerance, dependence and withdrawal; relation to motor vehicle accidents and complex sleep behaviors; and new dosage forms. EXPERT OPINION: Approved doses of zolpidem (10 mg for adults, 5 mg for the elderly) are consistently effective in reducing sleep latency and consequently increasing sleep duration in patients with insomnia. However, favorable effects on sleep maintenance are observed less consistently. Residual daytime effects are unlikely with recommended doses, and provided that at least 8 h elapse prior to arising. Hypnotic efficacy is maintained with repeated nightly use, and the risk of rebound insomnia is low. Dependence and abuse of zolpidem are no more likely to occur than with typical benzodiazepines. Newly available novel dosage forms of zolpidem have increased therapeutic options for patients with insomnia variants such as sleep maintenance insomnia and middle-of-the-night awakening.     

Zolpidem: a review of its use in the management of insomnia

Zolpidem (Ambien, Stilnox, Myslee, an imidazopyridine, is a nonbenzodiazepine hypnotic indicated for the short-term treatment of insomnia. Zolpidem improves sleep in patients with insomnia. Its overall tolerability is favourable when administered according to the manufacturer's prescribing information, with a low propensity to cause clinical residual effects, withdrawal, dependence or tolerance. In addition, most evidence suggests that the drug is associated with minimal rebound insomnia. In the only clinical trials that investigated the use of a hypnosedative drug in an 'as-needed' regimen, zolpidem produced a global improvement in sleep. Thus, zolpidem continues to be a useful therapeutic option in the pharmacological treatment of patients with insomnia.     

The dose effects of zolpidem on the sleep of healthy normals

This study determined the dose effects of zolpidem in 12 healthy males with normal sleep patterns. Subjects spent 7 weeks, 3 consecutive nights per week, in the laboratory and had a 4-night washout between treatments. The first week was a screening and adaptation week. Then subjects received zolpidem (2.5, 5.0, 7.5, 10.0, or 20.0 mg) or placebo on the first two nights for each of the next 6 consecutive weeks. Treatments were organized in a Latin square design and administered in a double-blind fashion. On the third night of each treatment, subjects always received placebo. The 5.0 mg and larger doses of zolpidem significantly decreased latency to persistent sleep and wake before sleep. Sleep maintenance measures were not affected by zolpidem. The 7.5 mg and higher doses of zolpidem significantly increased total sleep time. The only significant sleep stage effect was a decrease in percent of rapid eye movement sleep at only the 20 mg dose. No consistent discontinuation effects were found. Zolpidem was hypnotically active at doses as low as 5.0 and 7.5 mg, and sleep stage effects occurred only at the 20 mg dose, thus separating the dose range of hypnotic and sleep stage effects.     

Zaleplon - a review of a novel sedative hypnotic used in the treatment of insomnia

Zaleplon (N-[3-(3-cyanopyrazolo[1,5-a] pyrimidin-7-yl) phenyl]-N-ethyl acetamide) is a non-benzodiazepine recently introduced for clinical use. This agent is indicated for the short-term treatment of insomnia. Preclinical studies have shown that the benzodiazepines triazolam and Ro17-1812 can substitute for zaleplon in animals trained to distinguish zaleplon from saline. The benzodiazepine antagonist flumazenil can antagonise the discriminative stimulus effect of zaleplon. These findings suggest that zaleplon is recognised by animals as a benzodiazepine agent. Zaleplon is active after ip. and oral administration in a variety of motor performance tests, including locomotor activity, rotarod and the loaded grid. Zaleplon has been shown to be active in a number of different anticonvulsant models, including the pentylenetetrazole, isoniazid and electroshock models. The compound is also reported to be active against convulsions induced by bicuculline, picrotoxin and strychnine. Studies in anxiolytic models suggest that zaleplon may have weak anxiolytic activity. From preclinical studies, it appears zaleplon possesses a reduced risk of tolerance compared to triazolam, is less likely to potentiate the effects of ethanol and is unlikely to produce amnestic effects. In man, zaleplon is rapidly absorbed and undergoes extensive presystemic metabolism. The compound has a plasma half-life of approximately one hour and is metabolised primarily via the aldehyde oxidase system to form 5-oxo-zaleplon. This metabolite, along with other minor metabolites formed in vivo, do not appear to contribute to the activity of zaleplon. Metabolites of zaleplon are excreted primarily via the urine. Phase I studies suggest that single daytime doses of zaleplon up to 15 mg are well-tolerated. Short-term impairment of performance occurs when zaleplon is administered during the day at doses epsilon 20 mg. However, given the short half-life of the compound, significant impairment of daytime performance is unlikely if zaleplon is administered at bedtime or shortly after retiring for the evening. Results from Phase II/III studies suggest that zaleplon (5 - 20 mg) produces a dose-dependent reduction in sleep latency in patients suffering from primary insomnia. The clinical efficacy of zaleplon persists for at least four weeks at doses of 10 mg and 20 mg. Studies in patients with a history of drug abuse suggest that the abuse potential of zaleplon (at doses above the therapeutic dose range) is similar to that seen with the benzodiazepine triazolam.     

Rebound insomnia: a critical review

Rebound insomnia, a worsening of sleep compared with pretreatment levels, has been reported upon discontinuation of short half-life benzodiazepine hypnotics. This paper reviews the existing sleep laboratory studies for the presence or absence of rebound insomnia following treatment with triazolam, temazepam, and flurazepam in insomniac patients or poor sleepers and, when possible, in normals. The results indicate that rebound insomnia is a distinct possibility after discontinuation of triazolam in both insomniacs and normal controls. Compared with baseline, disturbed sleep was reported in insomniacs or poor sleepers for the first 1 or 2 nights of withdrawal in seven of nine polygraphically recorded sleep studies following triazolam 0.5 mg and in one of two studies following triazolam 0.25 mg. In one study conducted in normal volunteers, rebound insomnia was observed following triazolam 0.5 mg but not triazolam 0.25 mg. In another study, which used subjective reports of sleep rather than polygraphic recordings, rebound insomnia was significantly attenuated after triazolam 0.5 mg by tapering the dose over 4 nights. The risk of rebound insomnia after temazepam 15 or 30 mg was low. In keeping with its long elimination half-life, flurazepam (30 mg) continued to exert beneficial effects for the first 2-3 withdrawal nights, but the possibility of a mild rebound insomnia cannot be dismissed during the intermediate withdrawal period (nights 4-10) following prolonged, consecutive, nightly administration (more than 30 nights). The benzodiazepine hypnotics are generally preferred over other types (barbiturates or nonbenzodiazepine, nonbarbiturate), but there are advantages and disadvantages related to half-life of the benzodiazepines. The risk of rebound insomnia is greater with the short half-life as compared with the long half-life benzodiazepines.     

Clinically important drug interactions with zopiclone,zolpidem and zaleplon

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted. Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs. Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The fact that these drugs are newer to the market and have not been as extensively studied as the conventional benzodiazepines may be the reason for this. Another explanation may be a difference in CYP metabolism. While triazolam and midazolam are biotransformed almost entirely via CYP3A4, the newer hypnosedatives are biotransformed by several CYP isozymes in addition to CYP3A4, resulting in CYP3A4 inhibitors and inducers having a lesser effect on their biotransformation.