Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1999 Sep;48(3):367–374. doi: 10.1046/j.1365-2125.1999.00024.x

A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 h before awakening

P Danjou 1, I Paty 1, R Fruncillo 2, P Worthington 3, M Unruh 2, W Cevallos 2, P Martin 2
PMCID: PMC2014318  PMID: 10510148

Abstract

Aims

To compare the duration of the residual hypnotic and sedative effects of zaleplon with those of zolpidem and placebo following nocturnal administration at various times before morning awakening.

Methods

Zaleplon 10 mg, zolpidem 10 mg, or placebo was administered double-blind to 36 healthy subjects under standardized conditions in a six-period, incomplete-block, crossover study. Subjects were gently awakened and given medication at predetermined times 5, 4, 3, or 2 h before morning awakening, which occurred 8 h after bedtime. When the subjects awoke in the morning, a battery of subjective and objective assessments of residual effects of hypnotics was administered.

Results

No residual effects were demonstrated after zaleplon 10 mg, when administered as little as 2 h before waking, on either subjective or objective assessments, whereas zolpidem 10 mg showed significant residual effects on DSST and memory (immediate and delayed free recall) after administration up to 5 h before waking and choice reaction time, critical flicker fusion threshold and Sternberg memory scanning after administration up to 4 h before waking. Residual effects of zolpidem were apparent in all objective and subjective measurements when the drug was administered later in the night.

Conclusions

The present results demonstrate that zaleplon at the dose of 10 mg is free of residual hypnotic or sedative effects when administered nocturnally as little as 2 h before waking in normal subjects. In contrast, residual effects of zolpidem are still apparent on objective assessments up to 5 h after nocturnal administration, longer than has been reported from studies involving daytime administration.

Keywords: hypnotic, residual effects, sedative, zaleplon, zolpidem

Introduction

Insomnia is a relatively nonspecific term used to describe conditions characterized by a patient’s perception of poor or inadequate sleep [1]. It is often secondary to underlying somatic, psychiatric or social problems, but may also exist in the absence of other detectable conditions. Insomnia is reported by 10% to 45% of the adult population [2–4]. Common complaints include difficulty in falling asleep, frequent awakenings during the night or early in the morning, and sleepiness or tiredness during the day. Insomnia is more prevalent among women and the elderly and is often secondary to physical illness, psychologic disorders, pain, anxiety, or depression [5].

Many cases of secondary insomnia will resolve spontaneously with effective management of the underlying disorder or by the use of stress-relieving relaxation techniques or sleep hygiene advice to the patient. However, when pharmacotherapy is used, benzodiazepines (BZDs) are the most commonly prescribed medications. They are effective sedative/hypnotics and possess a greater margin of safety than chlormezanone, antihistaminics, barbiturates, or chloral hydrate [6, 7]. The choice of a specific BZD as a sedative/hypnotic is determined by its pharmacokinetic and pharmacodynamic profiles and the clinical characteristics of the particular patient [8, 9].

Many BZDs are not ideally suited to the management of insomnia as they are associated with significant and troublesome adverse effects. Moreover, tolerance to the sedative effects may develop after repeated use and there is a potential for dependence, abuse, and withdrawal symptoms and rebound insomnia after abrupt discontinuation [10–12]. BZDs are often associated with dose-dependent cognitive and psychomotor impairment as well as anterograde amnesia (inability to recall information occurring subsequent to drug administration) [13]. To a degree, these effects may persist into the morning after drug ingestion [14] and are collectively referred to as the ‘next day hangover’ effects of BZDs.

Zaleplon is a novel pyrazolopyrimidine hypnotic (N- [3-(3-cyanopyrazolo [1, 5-a] pyrimidin-7-yl) phenyl]-N-ethylacetamide) which binds selectivally to the BZD type 1 receptor located on the gamma-aminobutyric acid (GABAA) receptor complex and potentiates t-butylbicyclophosphorothionate binding, indicating agonist activity [15, 16]. Although structurally dissimilar to BZDs, zaleplon exhibits several similar pharmacological characteristics. Based on data derived from animal models, zaleplon shows sedative, anxiolytic, muscle relaxant, and anticonvulsive effects but seems to be devoid of next-day hangover effects. It has minimal interaction with alcohol and little risk of tolerance to its sedative effects has been shown [17]. These properties are characteristic of the optimal hypnotic.

In clinical studies, zaleplon was quickly absorbed and eliminated; the time to peak concentration (tmax) was approximately 1 h and the terminal-phase elimination half-life (t1/2) approximately 1 h [18]. Zaleplon is extensively metabolized to several metabolites, all pharmacologically inactive [19]. Zaleplon was well tolerated with no significant changes in vital signs, electrocardiograms, haematology, or clinical chemistry. With doses up to 30 mg few adverse events were reported, whilst with 60 mg all subjects reported transient impairment of concentration and co-ordination and difficulty in focusing. These events are considered to represent an exaggerated reaction of the central nervous system (CNS) to high doses of the drug [18]. Preliminary analyses of sleep laboratory data showed that administration of daily doses of zaleplon to patients suffering from primary insomnia (as described in the Diagnostic and Statistical Manual, 3rd edition, revised) significantly decreased sleep latency (P <0.001) in a dose-dependent manner for all doses from 5 to 20 mg compared with placebo [20].

Zolpidem another nonbenzodiazepine hypnotic is an imidazopyridine which also binds selectivelly to the BZD1 receptor. The currently recommended dose for short-term relief of insomnia in adults (i.e. 10 mg) was used in the present study. Zolpidem is considered to be essentially free of residual effects [21], and therefore was used as a stringent and fair comparison with zaleplon, more appropriate than a BZD with known hangover effects. The study reported here was designed to investigate the potential hangover effects of zaleplon in comparison with zolpidem.

Methods

Thirty-six healthy subjects (13 females and 23 males) were recruited to take part in this randomized placebo-controlled, double-blind, six-period, incomplete block crossover study comparing the recommended 10 mg dose of zolpidem with a 10 mg dose of zaleplon given 5, 4, 3, or 2 h before the planned awakening in the morning (i.e. 08.00 h). Each subject was involved in six treatment periods separated by washout periods of at least 48 h duration, and received placebo and each of the hypnotic drugs at 2 different times. The study protocol was reviewed and approved by the Investigational Review Board of the Methodist Hospital, Philadelphia. Subjects provided written informed consent prior to enrolment.

Subjects were hospitalized for the entire study duration (13 nights and 13 days) in the Clinical Pharmacology Unit of Wyeth-Ayerst Research, Methodist Hospital, Philadelphia, Pennsylvania, USA. They met inclusion and exclusion criteria intended to ensure that they were in good health with no present evidence or history of significant somatic or psychiatric disorders, insomnia, sleep apnoea, or drug or alcohol abuse. Urine drug screen for amphetamine, cocaine, cannabis, benzodiazepine, opiates and barbiturates as well as breath alcohol test obtained just before hospitalization were negative.

Before admission, all subjects had been trained to use the study assessments which included the Leeds Analogue Rating Scales (LARS) [22], Digit-Symbol-Substitution Test (DSST) [23] a memory test including immediate and delayed free recall of a 20 words list [24], Choice Reaction Time (CRT) [22], Critical Flicker Fusion Threshold (CFF) [25], and Sternberg Memory Scanning Test (SMST) [26]. For the first 2 nights, which were ‘acclimatization nights’, all subjects received placebo under single-blind conditions to allow them to become accustomed to the research unit and to become familiar with the study routines. Throughout the study, subjects went to bed around midnight, were awakened briefly to receive study medications (whilst in bed) at 5, 4, 3, or 2 h before morning awakening which occurred at around 08.00 h (i.e. drug administration at around 03.00, 04.00, 05.00 and 06.00 h). Immediately after each subject awoke, vital signs were taken and the Leeds sleep evaluation questionnaire (LSEQ) [27] was completed with instructions given to the subjects to take into account only the part of the night after dosing. Fifteen minutes later, the battery of study assessments was administered in the same order as above. Afterwards, a blood sample of 14 ml was taken and a breakfast was given.

A brief description of the tests used is given below:

Digit Symbol Substitution Test (DSST):

this is part of the revised Wechsler Adult Intelligence Scale [23] and assesses information processing, concentration and psychomotor performance. Subjects are requested to code for digit symbols as fast as possible. The score is the number of correct coding answers.

Critical flicker fusion (CFF) threshold:

Subjects were required to discriminate flicker from fusion while the frequency of a flickering light alternately increased or decreased. The score was the mean of three fusion/flicker threshold determinations [25].

Choice Reaction Time (CRT):

The subject has to respond as quickly as posssible to five series of 10 stimuli in a random order on 6 red LED and the derived measurements are the recognition, motor and total reaction time [23]. The Leeds apparatus was used to measure CFF and CRT.

Memory Test (Word list):

This test explores short and long-term memory, i.e. immediate and delayed free recall of words. Subjects were presented once a list of 20 words for 2 min. They were then asked to immediately recall as many words as possible within 2 min and 30 min later, they were allowed for 2 min to freely recall as many words as they could (delayed free recall). The scores correspond to the number of words correctly recalled during immediate and delayed free recall.

Sternberg Memory Scanning Task:

High-speed scanning and retrieval from short-term memory are assessed using a reaction time technique pioneered by Sternberg [26]. Subjects are required to memorize series of 2, 4, or 6 digits (the stimulus set presented sequentially for 500 ms per digit) and followed 2 s later by a probe digit. Twenty trials are performed for each series of digits comprising each 50% of correct and 50% incorrect digits (i.e. 60 presentations during the task). Series of 2–6 digits are shown randomly throughout the task. The subjects are required to respond to the probes by using a two-button Yes/No response box. Test digit (probe) has to be correctly recognized as present in the positive mode and as absent in the negative mode. The scores are the average mean reaction time for each series of digits in the positive and negative modes.

Leeds Analogue Rating Scales (LARS):

This test consisted of 11 100 mm visual analogue scales (three scales refer to sedation and eight are over feeling dummy). The subject has to assess his present feeling knowing that his usual reference corresponds to the middle of the scale [22].

Leeds Sleep Evaluation Questionnaire (LSEQ):

Subjects completed their impressions on the ease of getting to sleep, the quality of sleep, the ease of waking and the coordination of behaviour upon awakening on 10 100 mm usual analogue scales [27].

Plasma levels of zaleplon and zolpidem were determined by high performance liquid chromatography using a fluorescence detection. The limit of detection of the assay was 0.5 ng ml−1 for zaleplon and 1.0 ng ml−1 for zolpidem.

Safety and tolerability were assessed by a physical examination, routine laboratory tests, a 12-lead ECG, vital signs and by recording adverse events.

Statistical analysis

Results were subjected to an analysis of variance with subject, treatment-time, period, and treatment-time-by–period interactions as factors. If the treatment-time-by–period interaction was not significant, it was further split into treatment-by–time interaction. The primary comparisons over time were zaleplon vs placebo and zolpidem vs placebo. Secondary comparisons were made between zaleplon and zolpidem. These comparisons are presented with the 95% confidence interval based on the adjusted (least squares) means and were performed irrespective of the existence of a global effect. Correlations between plasma levels and change from baseline scores were calculated for CFF, CRT, DSST, and delayed free recall by using a Pearson coefficient. All computations were performed using SAS software 6.12. release (Statistical Analysis System, Cary, NC).

Results

Thirty-six subjects (13 women and 23 men) entered the study. Their mean age was 29.5±77 6 years. Their mean weight was 74±10.5 kg. Of these subjects, 33 completed all sessions whilst the other three withdrew before the end of the study: two for personal reasons and the other because of headache, diarrhoea and nausea, all of which were considered due to a viral infection that resolved spontaneously within a day of discharge.

The assessment of residual effects of treatments administered at 5, 4, 3, or 2 h before morning awakening generally showed significant differences between zolpidem and placebo but not between zaleplon and placebo. Zaleplon whatever the time of administration did not significantly impair psychomotor performance, arousal and cognitive function on CFF, CRT, DSST and memory function (immediate and delayed free recall and Sternberg memory scanning) compared with placebo (Figure 1–5). In addition, zaleplon significantly improved recognition, motor and total reaction times on CRT when administered 5 h before arousal. In contrast, zolpidem significantly impaired DSST (Figure 1) and memory (immediate and delayed free recall) (Figure 4) when administered up to 5 h before awakening, significantly disturbed CRT (recognition, motor and total RT), CFF and SMST reaction times in negative mode with 4 or 6 digits when administered up to 4 h before awakening (Figure 2, 3 and 5) and significantly prolonged SMST reaction times in negative mode with 2 digits when administered up to 3 h, compared with placebo. Zolpidem also significantly impaired memory (immediate and delayed free recall) (Figure 4) and CRT (recognition, motor and total) (Figure 2) at all times post-dose, SMST reaction times in negative mode with 4 or 6 digits (Figure 5) up to 4 h, and the SMST reaction times negative mode with 2 digits (Figure 5) and DSST (Figure 1) up to 3 h, when compared with zaleplon.

Figure 1.

Figure 1

Open in a new tab

Mean scores on the DSST (number of correct substitutions made in 90 s) for the pretreatment acclimitization days and for the three treatments (□ placebo, • zaleplon, ▵ zolpidem) and the four different dosing times. *P <0.05; **P <0.01; ***P <0.001 (zolpidem vs placebo).

Figure 5.

Figure 5

Open in a new tab

Mean reaction times for the positive and negative modes of the Sternberg Memory Scanning Test using a six-digit stimulus (see text). *P <0.05; **P <0.01; ***P <0.001 (zolpidem vs placebo); †P <0.05, ††P <0.01, †††, P <0.001 (zaleplon vs zolpidem). Time dose administered before awakening 5 h, 4 h, 3 h and 2 h.

Figure 4.

Figure 4

Open in a new tab

a) Mean scores for immediate recall (number of words immediately recalled from a list of 20) and b) mean scores for delayed recall (number of words correctly recalled from a list of 20 after a delay) for the pretreatment acclimitization days and for the three treatments (□ placebo, • zaleplon, ▵ zolpidem) and the four different dosing times. *P <0.05; **P <0.01; ***P <0.001 (zolpidem vs placebo).

Figure 2.

Figure 2

Open in a new tab

Choice Reaction Task; mean Total Reaction Time for each of the three treatments (□ placebo, • zaleplon, ▵ zolpidem) at each of the administration times. *P <0.05; **P <0.01; ***P <0.001 (zolpidem vs placebo).

Figure 3.

Figure 3

Open in a new tab

Mean Critical Flicker Fusion threshold for each of the three treatments (□ placebo, • zaleplon, ▵ zolpidem) at each of the administration times. *P <0.05; **P <0.01; ***P <0.001 (zolpidem vs placebo).

The change from baseline in the pharmacodynamic assessments correlated significantly with plasma levels following administration of zolpidem. Greater impairment occurred at higher plasma levels. Similar correlations were generally absent following administration of zaleplon (Table 1) and, in the case of CFF, there was a negative correlation with plasma levels, i.e. cognitive performance was improved at higher plasma levels.

Table 1.

Correlation between plasma levels of zaleplon or zolpidem and change from baseline in several pharmacodynamic variables.

graphic file with name bcp0048-0367-t1.jpg

Open in a new tab

In the subjective assessments of the LARS the visual analogue scale rating for ‘anxious’, ‘happy’, ‘relaxed’, ‘sad’, and ‘depressed’ were not significantly affected by any of the treatments. Following zolpidem given 2 h before awakening, subjects felt more ‘tired’, more ‘drowsy’, more ‘dizzy’, more ‘clumsy’, less ‘alert’, and ‘less energetic’ (P <0.01). All these feelings had disappeared at the 3 h dose interval but were present again at 4 h for more ‘drowsy’, more ‘dizzy’, and less ‘energetic’ (P <0.05). Zaleplon did not significantly alter any feeling even when it was administered 2 h before awakening. However, subjects felt less ‘tired’ and more ‘energetic’ (P <0.05) when they were administered zaleplon 5 h before awakening.

Interpretation of the LSEQ must be cautious. The sleep subjective assessment only refers to the part of the night following drug intake, i.e. 5, 4, 3 or 2 last hours of the night. Thus, the only valid variable should be behaviour following waking. Zaleplon significantly improved the ‘ease of getting to sleep’ and ‘perceived quality of sleep’ when administered 5 h before awakening compared with placebo. Zaleplon did not significantly change the ‘integrity of behaviour following wakefulness’ and ‘ease of awakening from sleep’ variables of these healthy subjects compared to placebo. As no residual effects were observed on objective tests after zaleplon it was expected that no change occurred on the ‘integrity of behaviour following waking’ of LSEQ. Zolpidem administered 4 and 3 h before awakening did not significantly change these variables compared with placebo. In contrast a significant treatment effect occurred with zolpidem administered 5 or 2 h before subjects awoke with an improvement in ‘perceived quality of sleep’ at 2 and 5 h and in the ‘ease of getting to sleep’ at 5 h, and a worsening of the ‘integrity of behaviour following wakefulness’ and ‘ease of awaking from sleep’ at 2 h before awakening. The effects of zolpidem were consistent with the impairment observed in the psychomotor tests.

There were no serious adverse experiences during the study; all adverse events were mild to moderate. Overall, the number of subjects who reported any adverse experience after administration of study drug was similar for zaleplon and placebo (11% to 33% regardless of the time of drug administration) but was significantly higher following zolpidem (56% to 72%) when zolpidem was administered 2, 3, 4 and 5 h before awakening. The total number of subjects who experienced at least an adverse event independently of the time of administration is 14, 12 and 27 over 36 after placebo, zaleplon or zolpidem, respectively. The most commonly reported adverse events for zaleplon were asthenia and somnolence. In the zolpidem group, asthenia, depersonalization, dizziness, somnolence, and abnormality in accommodation were the most frequent CNS-related adverse events.

Discussion

A sedative/hypnotic that is used in the management of insomnia should rapidly induce sleep, should not affect the architecture of sleep, should not be a respiratory depressant, and should be free of residual effects even if the patient is for some reason awakened prematurely. In addition, it should be free of adverse residual effects on memory, interactions with alcohol or other central nervous system depressants, development of tolerance, risk of dependence or abuse, or rebound insomnia.

Onset of effects and their duration (residual effects) are mainly determined by pharmacokinetic factors, particularly the rate of absorption and distribution of the active drug, its metabolic rate (including formation of active metabolites), and the terminal half-life of both the active compound and any active metabolite. Zaleplon is very rapidly absorbed and distributed, with both a tmax and t1/2 of about an hour, and it has no active metabolites. The pharmacodynamic effects are consistent with the kinetic profile, peaking at about 1 h and subsiding rapidly thereafter. After a daytime dose of 20 mg—twice that used in this study—residual effects disappeared in less than 3 h [28]. Greenblatt et al. [29] also demonstrated that zaleplon 10 mg did not produce significant changes in subjective feeling of sedation, memory assessments and EEG β waves 2 h after dosing. In contrast zolpidem produced significant changes at least up to 4 h after dosing. These effects were dose and concentration dependent. The results of this study show clearly that zaleplon 10 mg produces no residual sedation, memory impairment, or unpleasant subjective feelings when administered at night as little as 2 h before awakening. In terms of objective measures, subjective assessments, and adverse events, zaleplon was essentially indistinguishable from placebo. The only statistically significant differences between zaleplon and placebo is a decrease when the drug was administered 5 h before awakening in reaction times of the CRT indicating an improvement in performance.

The residual effects of hypnotics, such as persistent sedative effects and memory impairments, have been associated mainly with benzodiazepines that have a long half-life, e.g. flunitrazepam [30]. Compounds with a shorter half-life, such as zolpidem or triazolam, were considered to have much less such effects [31]. However, the usual conditions for testing include administration of the hypnotic at ‘usual’ bedtime followed by a battery of tests performed either the morning after or during the night, to simulate an unexpected need to awake early and function effectively. The latter sort of testing was used only with hypnotics that were free of deleterious effects in the morning. In the case of zolpidem, which has a half-life of 2–3 h, there is no measurable impairment the morning after administration of 20 mg as determined by psychometric testing [30] and the Multiple Sleep Latency Test. These results are consistent with the duration of drug activity determined using quantitative electroencephalographic (EEG) measurements, which indicated the duration of fast EEG activity to be about 4 h [32].

In the present study, the residual effects of zaleplon 10 mg and zolpidem 10 mg have been evaluated under more stringent conditions with doses given 2, 3, 4, or 5 h before waking the subjects for the morning test battery. This was done to explore the time at which zaleplon could be given without increasing the risk of psychomotor or memory impairment the next day. To avoid the confounding effects of insomnia on morning psychomotor tests, healthy subjects with no history of insomnia were recruited. The subjects had a standardized bedtime and slept until the time of drug administration, when they were gently awakened to receive the drug in bed. They then went back to sleep. In a polysomnographic study performed with midazolam under comparable conditions and in a similar population, it was shown that sleep latency following such awakening was less than 10 min [33]. In the present study, the total time allowed for sleep was 8 h.

Under these conditions, zaleplon showed no deleterious effects differing from those of placebo regardless of the time of drug administration. Zolpidem, on the other hand, produced results different from those of placebo in most of the tests. An anterograde amnesia as assessed by immediate and delayed recall of a word list and DSST impairment, was detectable for up to 5 h, whereas the effects on reaction times and CFF appeared to be of a shorter duration (i.e. 4 h). Interestingly, the subjective effects of dizziness, drowsiness, tiredness and difficulty in awakening associated with zolpidem were of shorter duration than the objective measures of impairment. This observation reinforces the recognized situation that patients may have impaired psychomotor function without being aware of it.

The present finding of residual effects up to 5 h after administration of 10 mg zolpidem suggests a longer duration of effect than was reported from daytime studies by Berlin et al. [34], who found that effects had disappeared at 4 h, or by Rush et al. [35], who reported similar results. In both of these studies, zolpidem was administered to subjects who had fasted in the morning. Allain et al. [36] showed that the administration of zolpidem 10 mg at night produced significant changes in objective tests (CFF, body sway) up to 7 h post dose. It is possible that administration to sleeping subjects delays absorption and leads to more persistent effects. Zolpidem (10 mg) pharmacokinetics was performed at night in another study [36] and showed a profile different from day time administration with a blunting plasma peak concentration and much slower elimination. However, these conditions are more appropriate than daytime dose administration and test conditions for an hypnotic.

The differences between zaleplon and zolpidem are more likely to be related to their pharmacokinetic profiles than to their pharmacology because the two compounds show a similar selectivity for the BZD type 1 receptor on the GABAA macromolecular complex [37]. The pharmacokinetic profile of zaleplon, including a rapid onset of action and short half-life, is also reflected in the efficacy of zaleplon. Clinical studies have shown that the reduction in sleep latency observed with 10 mg of zaleplon is equivalent to that observed with 10 mg of zolpidem [38] and with 0.25 mg of triazolam [39], showing that these compounds have equivalent effects in terms of sleep induction.

When an hypnotic is required to induce sleep, a swift effect and swift recovery of normal function are generally equally important. Under the conditions of this study, which are more ‘realistic’ than daytime studies, zaleplon in contrast to zolpidem produced neither objective nor subjective residual effects when administered as little as 2 h before morning awakening. These results are consistent with a pharmacokinetic profile featuring rapid absorption, distribution and clearance. Thus at the dose level used in this study (10 mg) which corresponds to the recommended dose, zaleplon would seem to provide physicians with an hypnotic free of residual effects, at least in normal volunteers.

References

  • 1.Dement WC. Rational basis for the use of sleeping pills. Int Pharmacopsychiatry. 1982;17:3–38. [PubMed] [Google Scholar]
  • 2.Bixler EO, Kales A, Soldatos CR, Kales JD, Healey S. Prevalence of sleep disorders in the Los Angeles metropolitan area. Am J Psychiatry. 1979:1257–1262. doi: 10.1176/ajp.136.10.1257. [DOI] [PubMed] [Google Scholar]
  • 3.Karacan I, Thornby JI, Anch M, et al. Prevalence of disturbances in a primary urban Florida county. Soc Sci Med. 1976:239–244. doi: 10.1016/0037-7856(76)90006-8. [DOI] [PubMed] [Google Scholar]
  • 4.Lugaresi E, Zucconi M, Bixler E. Epidemiology of sleep disorders. Psychiatr Ann. 1987;17:446–453. [Google Scholar]
  • 5.Aldrich MS. Cardinal manifestations of sleep disorders. In: Kryger MH, Roth T, Dement WC, editors. Principles and Practice of Sleep Medicine. Philadelphia: WB Saunders; 1989. pp. 313–31. [Google Scholar]
  • 6.Davis JM. Minor tranquillisers sedatives and hypnotics. In: Kaplan HI, Sadock BJ, editors. Comprehensive Textbook of Psychiatry. Baltimore: Williams and Wilkins; 1985. pp. 1537–1553. [Google Scholar]
  • 7.Harvey SC. Hypnotics and Sedatives. In: Goodman A, Gilman LD, editors. The Pharmacological Basis of Therapeutics. New York: MacMillan; 1985. pp. 339–379. [Google Scholar]
  • 8.Greenblatt DJ, Divoll M, Aberneth DR, Locniskar A, Sjhader RI. Pharmacokinetics of benzodiazepine hypnotics. Pharmacology. 1983;27:70–75. doi: 10.1159/000137913. [DOI] [PubMed] [Google Scholar]
  • 9.Nicholson AN, Marks J. Insomnia. A. Guide for Medical Practitioners. Lancaster, England: MTP Press Limited; 1983. [Google Scholar]
  • 10.Johnson C, Chernik DA. Sedative-hypnotics and human performance. Psychopharmacol. 1983;26:21–137. doi: 10.1007/BF00435262. [DOI] [PubMed] [Google Scholar]
  • 11.Kales A, Soldatos CR, Bixler E, Kales J. Rebound insomnia and rebound anxiety: a review. Pharmacology. 1983;26:21–137. doi: 10.1159/000137794. [DOI] [PubMed] [Google Scholar]
  • 12.Mendelson WB. Medications in the treatment of sleep disorders. In: Meltzer HY, Coyle JT, Kopin IJ, et al., editors. Psychopharmacology : the Third Generation of Progress. New York: Raven Press; 1987. pp. 163–172. [Google Scholar]
  • 13.Greenblatt DJ, Divoll M, Abernethy DR, Ochs HR, Shader RI. Benzodiazepine kinetics: implications for therapeutics and pharmacogeriatrics. Drug Metab Rev. 1983;14:251–292. doi: 10.3109/03602538308991391. [DOI] [PubMed] [Google Scholar]
  • 14.Allain H, Delahaye C, LeCoz F, Blin P, Decombe R, Martinet JP. Postmarketing surveillance of zopiclone insomnia: Analysis of 20.513 cases. Sleep. 1991;14:408–413. doi: 10.1093/sleep/14.5.408. [DOI] [PubMed] [Google Scholar]
  • 15.Enna SJ, Mohler H. γ-Aminobutyric acid (GABA) receptors and their association with benzodiazepine recognition sites. In: Meltzer HY, Coyle JT, Kopin IJ, et al., editors. Psychoharmacology The Third Generation of Progress. New York: Raven Press; 1987. pp. 265–272. [Google Scholar]
  • 16.Ramanjaneyulu R, Ticku MK. Binding characteristics and interaction of depressant drugs with [35S]t-butylbicyclophosphorothionate, a ligand that binds to the picrotoxin site. J Neurochem. 1984;42:221–229. doi: 10.1111/j.1471-4159.1984.tb09721.x. [DOI] [PubMed] [Google Scholar]
  • 17.Beer B, Clody DE, Mangano R, Levner M, Mayer P, Barrett JE. A review of the preclinical development of Zaleplon, a novel non-benzodiazepine hypnotic for the treatment of insomnia. CNS Drug Reviews. 1997;3:207–224. [Google Scholar]
  • 18.Beer B, Ieni A, JR, Wu WH, et al. A placebo-controlled evaluation of single, escalating doses of CL284, 846 (zaleplon), a non–benzodiazepine hypnotic. J Clin Pharmacol. 1994;34:335–344. doi: 10.1002/j.1552-4604.1994.tb02002.x. [DOI] [PubMed] [Google Scholar]
  • 19.Vanover KE, Mangano RM, Barrett JE. CL 284, 846 [Zaleplon] a novel sedative–hypnotic. evaluation of its metabolites for pharmacological activity in vitro and in vivo. Drug Dev Res. 1994;33:39–45. [Google Scholar]
  • 20.Dietrich B, Farr I. Zaleplon: dose–response evaluation in primary insomnia. In: Chase MH, Roth T, O’Connor C, editors. Sleep Research. 24A. Los Angeles: Brain Information Services/Brain Research Institute; 1995. p. 116. [Google Scholar]
  • 21.Langtry HD, Benfield P. Zolpidem a review of its pharmacodynamic and pharmacokinetics properties and therapeutic potential. Drugs. 1990;40:291–313. doi: 10.2165/00003495-199040020-00008. [DOI] [PubMed] [Google Scholar]
  • 22.Hindmarch I. Psychomotor function and psychoactive drugs. Br J Clin Pharmacol. 1980;10:189–209. doi: 10.1111/j.1365-2125.1980.tb01745.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Weschler D. The Measurement of Adult Intelligence. Baltimore: William & Wilkins Co; 1944. [Google Scholar]
  • 24.Lucki I, Rickels K, Geller AM. Chronic use of benzodiazepines and psychomotor and cognitive test performance. Psychopharmacology (Berl) 1986;88:426–433. doi: 10.1007/BF00178503. [DOI] [PubMed] [Google Scholar]
  • 25.Smith JM, Misiak H. Critical flicker frequency (CFF) and psychotropic drugs in normal human subjects—a review. Psychopharmacology. 1976;47:175–182. doi: 10.1007/BF00735818. [DOI] [PubMed] [Google Scholar]
  • 26.Sternberg S. Memory scanning: mental processes revealed by reaction time experience. Am Sci. 1969;55:421–457. [PubMed] [Google Scholar]
  • 27.Parrot AC, Hindmarch I. Factor analysis of a sleep evaluation questionnaire. Psychol med. 1978;8:325–329. doi: 10.1017/s0033291700014379. [DOI] [PubMed] [Google Scholar]
  • 28.Allen D, Curran HV, Lader M. The effects of single doses of CL 284, 846, lorazepam and placebo on psychomotor and memory function in normal male volunteers. Eur J Clin Pharmacol. 1993;45:313–320. doi: 10.1007/BF00265947. [DOI] [PubMed] [Google Scholar]
  • 29.Greenblatt DJ, Harmatz JS, von Moltke LL, et al. Comparative kinetics and dynamics of zaleplon, zolpidem and placebo. Clin Parmacol Ther. 1998;64:553–561. doi: 10.1016/S0009-9236(98)90139-4. [DOI] [PubMed] [Google Scholar]
  • 30.Bensimon G, Foret J, Warot D, Lacomblez L, Thiercelin JF, Simon P. Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 20 mg and placebo. Br J Clin Pharmacol. 1990;30:463–469. doi: 10.1111/j.1365-2125.1990.tb03798.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Schechter BR. Next day effects after night-time treatment with zolpidem. Eur J Psychiatry. 1996;11:215–305. [Google Scholar]
  • 32.Patat A, Trocherie S, Thebault JJ, et al. EEG, profile of intravenous zolpidem in healthy volunteers. Psychopharmacology (Berl) 1994;114:138–146. doi: 10.1007/BF02245455. [DOI] [PubMed] [Google Scholar]
  • 33.Tobler I, Dijk DJ, Jaggi K, Borbely AA. Effects on night-time motor activity and performance in the morning after midazolam intake during the night. Arzneimittelforschung. 1991;41:581–583. [PubMed] [Google Scholar]
  • 34.Berlin I, Warot D, Hergueta T, Molinier P, Bagot C, Puech AJ. Comparisons of the effects of zolpidem and Triazolam on previous functions, psychomotor performances, and physical sway in healthy subjects. J Clin Psychopharmacol. 1996;13:100–106. [PubMed] [Google Scholar]
  • 35.Rush CR, Griffiths RR. Zolpidem, Triazolam and Temazepam: behavioural and subject related effects in normal volunteers. J Clin Psychopharmacol. 1996;16:146–157. doi: 10.1097/00004714-199604000-00007. [DOI] [PubMed] [Google Scholar]
  • 36.Allain H, Patat A, Lieury A, et al. Comparative study of the effects of zopiclone (7.5 mg), zolpidem, flunizatrepam and a placebo on nocturnal cognitive performance in healthy subjects, in relation to pharmacokinetics. Eur Psychiatry. 1995;10(Suppl 3):129–135. doi: 10.1016/0924-9338(96)80094-0. [DOI] [PubMed] [Google Scholar]
  • 37.Sanger DJ, Morel E, Perrault G. Comparison of the pharmacological profiles of the hypnotic drugs zaleplon and zolpidem. Eur J Pharmacol. 1996;313:35–42. doi: 10.1016/0014-2999(96)00510-9. [DOI] [PubMed] [Google Scholar]
  • 38.Fry J, Scharf MB, Berkowitz DV, et al. A phase III, 28-day, multicenter, randomized, double-blind comparator- and placebo-controlled, parallel-group safety, tolerability, and efficacy study of 5, 10, and 20 mg, of zaleplon, compared with 10 mg, of zolpidem or placebo, in adult outpatients with insomnia. Sleep. 1998;21(Suppl):262. [Google Scholar]
  • 39.Walsh JK, Fry J, Erwin CW, Scharf M, Roth T, Vogel GW. Efficacy and safety of 14-day administration of zaleplon 5 mg and 10 mg for the treatment of primary insomnia. Clin Drug Invest. in press. [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES