A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects

Rebound effects after withdrawal from hypnotics are believed to trigger their chronic use and to enhance the risk of tolerance and dependence. It was the purpose of this study to investigate the acute polysomnographic withdrawal effects after a 4 week treatment with standard doses of the non-benzodiazepine hypnotics zopiclone and zolpidem compared with triazolam and placebo. Healthy male subjects between 22 and 35 years of age participated in a parallel study design. They received either zopiclone 7.5 mg (n=11), zolpidem 10 mg (n=11), triazolam 0.25 mg (n=10) or placebo (n=7) over 4 weeks in randomized and double-blind order. Sleep EEG was registered during 2 nights before treatment under placebo, on days 1, 27 and 28 of treatment and on days 29, 30, 41 and 42 under placebo. Total sleep time and sleep efficiency were lower in the 1^st night after discontinuation of triazolam (p < 0.05, t-test). After withdrawal from zopiclone or zolpidem slight but not significant rebound effects concerning sleep continuity were observed. Self-rating scales showed minimal rebound insomnia after discontinuation of all three hypnotics. In the placebo group no changes of sleep parameters were observed. Assuming that rebound insomnia is part of a withdrawal reaction, this study indicates that the risks of tolerance and dependency are low when administering zopiclone or zolpidem at the recommended doses. Received: 13 September 2000 / Accepted: 7 May 2001     

Effects of hypnotics on the sleep EEG of healthy young adults: new data and psychopharmacologic implications

Benzodiazepine hypnotics increase NREM sleep and alter its EEG by reducing delta (0.3–3 Hz) and increasing sigma (12–15 Hz) and beta (15–23 Hz) activity. We tested whether the nonbenzodiazepine hypnotic, zolpidem (10 mg), produced the same pattern of sleep and EEG changes as two “classical” benzodiazepines, triazolam (0.25 mg) and temazepam (30 mg). Sleep EEG of 16 subjects was analyzed with period amplitude analysis for 3 nights during drug administration or placebo. The effects of zolpidem were in the same direction but generally of smaller magnitude than those of the classical benzodiazepines. These differences are more likely the result of non-equivalent dosages than different pharmacologic actions. Period amplitude analysis showed that the decreased delta activity resulted mainly from a decrease in wave amplitude. In contrast, the increased sigma and beta activity were produced by increased wave incidence. Delta suppression increased with repeated drug administration but sigma and beta stimulation did not. While these findings have little relevance for the clinical choice of hypnotics they may hold important implications for the brain mechanisms involved in hypnotic tolerance and withdrawal delirium.     

Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. Zaleplon Clinical Study Group.

BACKGROUND: Zaleplon is a short-acting pyrazolopyrimidine hypnotic with a rapid onset of action. This multicenter study compared the efficacy and safety of 3 doses of zaleplon with those of placebo in outpatients with DSM-III-R insomnia. Zolpidem, 10 mg, was used as an active comparator. METHOD: After a 7-night placebo (baseline) period, 615 adult patients were randomly assigned to receive, in double-blind fashion, I of 5 treatments (zaleplon, 5, 10, or 20 mg; zolpidem, 10 mg; or placebo) for 28 nights, followed by placebo treatment for 3 nights. Sleep latency, sleep maintenance, and sleep quality were determined from sleep questionnaires that patients completed each morning. The occurrence of rebound insomnia and withdrawal effects on discontinuation of treatment was also assessed. All levels of significance were p < or = .05. RESULTS: Median sleep latency was significantly lower with zaleplon, 10 and 20 mg, than with placebo during all 4 weeks of treatment and with zaleplon, 5 mg, for the first 3 weeks. Zaleplon, 20 mg, also significantly increased sleep duration compared with placebo in all but week 3 of the study. There was no evidence of rebound insomnia or withdrawal symptoms after discontinuation of 4 weeks of zaleplon treatment. Zolpidem, 10 mg, significantly decreased sleep latency, increased sleep duration, and improved sleep quality at most timepoints compared with placebo; however, after discontinuation of zolpidem treatment, the incidence of withdrawal symptoms was significantly greater than that with placebo and there was an indication of significant rebound insomnia for some patients in the zolpidem group compared with those in the placebo group. The frequency of adverse events in the active treatment groups did not differ significantly from that in the placebo group. CONCLUSION: Zaleplon is effective in the treatment of insomnia. In addition, zaleplon appears to provide a favorable safety profile, as indicated by the absence of rebound insomnia and withdrawal symptoms once treatment was discontinued.     

Dose response effects of zolpidem in normal geriatric subjects

The dose-related hypnotic effects and effects on memory, performance, and daytime alertness of zolpidem 5, 10, 15, and 20 mg were compared with those of placebo in 30 elderly non-insomniac volunteers in a randomized, placebo-controlled, three-period crossover study. Subjects were randomized into two groups and received either placebo, zolpidem 5 mg, or zolpidem 15 mg or placebo, zolpidem 10 mg, or zolpidem 20 mg for 2 consecutive nights followed by 1 night of placebo during the same 3 nights of 3 consecutive weeks. Polysomnographic results showed statistically significant decreases in sleep latency and increases in sleep efficiency at all doses. Subjective reports also showed improved sleep latency, total sleep time, and sleep quality. REM percent was slightly decreased at doses of 10 and 20 mg. No consistent effects on memory or performance were observed, and the Multiple Sleep Latency Test showed no effects on daytime sleepines. There was no objective evidence of rebound insomnia upon drug discontinuation.     

The effects of clomethiazole on polysomnographically recorded sleep in healthy subjects

Clomethiazole is widely used in European countries to treat alcohol withdrawal symptoms including delirium tremens. The current study aimed to explore the effects of clomethiazole on the sleep of healthy volunteers. We postulated both a hypnotic and a REM suppressive effect as well as the occurrence of a rebound phenomenon following three days of treatment with clomethiazole. The study group was composed of five men and five women. The probands were examined in the sleep laboratory throughout a course of seven nights. The first night was considered as the adaptation night and the second as the baseline night. Prior to nights 3 to 5, probands took 384 mg clomethiazole at 22 hours. The 6^th and 7^th nights served to record potential effects of medication discontinuation.The current study confirms the indication in the scientific literature with regard to hypnotic and REM–suppressive effects of clomethiazole, as well as a rebound phenomenon following discontinuation of the medication. The effect of clomethiazole on the sleep EEG was most obvious in the first half of the night. The analysis of the polysomnogram in terms of each half of the night gave no indication of a rebound phenomenon during the second half.The REM sleep–suppressing component of clomethiazole is of great interest in connection with its use in treating delirium tremens. The rebound phenomenon in healthy controls after only three days of medication at a relatively low dosage of clomethiazole underscores the need to administer it in doses individually tailored to the extent of the alcohol withdrawal syndrome in the individual patient.     

Sleep EEG changes after zolpidem in mice

Zolpidem is a widely used hypnotic that binds preferentially to alpha1GABAA receptors. We determined the role of these receptors in the effects of zolpidem on sleep in mutant mice carrying zolpidem-insensitive alpha1GABAA receptors and wild-type controls. Sleep was promoted by zolpidem in both genotypes. In wild-type mice non-REM sleep EEG power was markedly reduced in a broad frequency band >5 or 9 Hz after 5 and 10 mg/kg zolpidem, respectively. In mutants a power reduction appeared at the highest dose only, and was restricted to some low frequencies and the 9-10 Hz bin. We conclude that the effects of zolpidem on the sleep EEG in mice are distinct from the changes typically induced by benzodiazepines, and are primarily mediated by alpha1GABAA receptors.     

Long-term, non-nightly administration of zolpidem in the treatment of patients with primary insomnia

INTRODUCTION: While it is common practice that hypnotics are used on a non-nightly basis, few investigations have been undertaken to evaluate the efficacy of the intermittent dosing strategy. The present study was designed to further evaluate this issue within a large scale, double-blind, placebo-controlled, long-term trial. METHOD: Patients who met DSM-IV criteria for primary insomnia participated in the study from January 2000 through October 2001. Patients were randomly assigned to 1 of 2 treatment groups (zolpidem 10 mg or placebo) for a period of 12 weeks. Ten pills were provided in foil packs on an every-other-week basis, and patients were instructed to take no fewer than 3 and no more than 5 pills per week. Sleep was evaluated daily with sleep diaries. Pill use was recorded in the sleep diaries. RESULTS: 199 patients (mean +/- SD age = 41.0 +/- 12.8 years; 71% female) were randomly assigned to treatment. On mean, patients receiving zolpidem exhibited (vs. baseline) a 42% decrease in sleep latency, a 52% reduction in number of awakenings, a 55% decrease in wake time after sleep onset, and a 27% increase in total sleep time. These positive clinical gains did not diminish with time and were not associated with dose escalation. There was also no evidence of rebound insomnia. CONCLUSIONS: Over a period of 12 weeks of intermittent treatment with zolpidem, sleep continuity was significantly improved, the clinical gains were sustained, and there was no evidence of subjective rebound insomnia between doses or increases in the amount of medication used during the study interval.     

Non-benzodiazepines for the treatment of insomnia

Benzodiazepine hypnotics, the mainstay of pharmacological treatment for insomnia, have been associated with altered sleep architecture, psychomotor and memory impairment, rebound insomnia, withdrawal effects, tolerance, dependence, abuse potential and respiratory depression. Non-benzodiazepines, such as zolpidem, zopiclone and zaleplon, demonstrate hypnotic efficacy similar to that of benzodiazepines along with excellent safety profiles. Non-benzodiazepines generally cause less disruption of normal sleep architecture than benzodiazepines. Psychomotor and memory impairment may be less problematic with non-benzodiazepines, especially when compared to longer-acting benzodiazepines. Rebound insomnia and withdrawal symptoms occur infrequently upon discontinuation of non-benzodiazepines and may be less common and milder than those seen upon discontinuation of some benzodiazepines. For the long-term treatment of insomnia, which is generally not recommended, zolpidem and zopiclone are particularly good options because they do not develop tolerance rapidly and have a low abuse potential. Limited data indicate that zaleplon has low tolerance and abuse potential, although further experience is needed to determine its long-term efficacy and safety profile. Since non-benzodiazepines produce minimal respiratory depression, they may be safer than benzodiazepines in patients with respiratory disorders. The choice of which hypnotic to use should be based on the patient's primary sleep complaint, health history, adverse effects and cost.     

Independence of sleep EEG responses to GABAergic hypnotics: biological implications

GABAergic hypnotics are known to depress non-rapid eye movement delta and rapid eye movements and to stimulate non-rapid eye movement sigma (spindles) and beta EEG. This study addressed the question of whether the magnitudes of these effects are significantly correlated. Data were from a study in 16 normal subjects whose sleep was recorded for five nights under placebo and for three nights each under zolpidem (10 mg), triazolam (0.25 mg) and temazepam (30 mg). EEG was analyzed with both period-amplitude and power spectral (FFT) analysis. The magnitudes of the EEG and eye movement density responses were not significantly correlated for any of the three drugs. It is therefore unlikely that sleep responses to GABAergic drugs can be explained by the common cellular action (increased chloride conductance) of these drugs. We suggest that the sleep EEG responses are manifestations of complex (but consistent) interactions of excitation and inhibition in large brain systems although certain aspects of these responses (e.g. the different time courses of delta vs sigma and eye movement responses) may reflect molecular adaptations. A separate observation in this study was the strong traitlike characteristics of the sleep variables studied. These variables were highly correlated across nights of baseline sleep; in addition, individual differences in baseline sleep were significantly retained on the third night of temazepam administration.     

Efficacy and side effects of flurazepam, fosazepam, and nitrazepam as sleeping aids in psychogeriatric patients.

Efficacy and side effects of flurazepam 15 mg, fosazepam 60 mg, and nitrazepam 5 mg were studied in 17 psychogeriatric patients. The drugs were equipotent in maintaining sleep but nitrazepam had more side effects than the other hypnotics, and it induced a rebound insomnia after withdrawal. All hypnotics lost some of their efficacy towards the end of 7 days' administration. Patients with evident cerebrovascular disease were vulnerable to the side effects of the benzodiazepine hypnotics. The side effects did not correlate with the age of a patient. In addition, no correlations were found between the serum levels of fosazepam or its main metabolite and the side effects.     

Contribution of zolpidem in the management of sleep disorders]

Zolpidem is a nonbenzodiazepine hypnotic agent belonging to a new class of psychotropic drugs the imidazopyridines which enhance the GABAA receptor function by interacting with a specific receptor population. Zolpidem binds selectively to the Omega-1 receptor subtype and from a pharmacological point of view differs from benzodiazepines (BZD) by producing a strong sedative and hypnotic profile which predominates over the anticonvulsivant and anxiolytic activity and moreover appears practically devoid of myorelaxant properties. From a pharmacodynamic point of view, these results suggest that zolpidem facilitates more selectively than BZD, GABAA function and produces a selective hypnotic effect. Though if the role played by receptors in tolerance and dependence has not been yet fully elucidated, it could be described as an adaptative process to sustained stimulation of GABA function. Animal data obtained with zolpidem differs substantially from that of the BZD and indicates that repeated zolpidem administration may not lead to phenomena of tolerance and withdrawal syndrome after abrupt drug discontinuation. In human following oral intake, zolpidem is very rapidly (Tmax: 30-40 min) absorbed. The clearance is essentially metabolic and less than 1% is recovered in urine. The apparent plasma half-life is of 2.0-2.5 hours in most adult subjects and metabolites are totally inactive. The hypnotic activity of zolpidem and its effects on sleep architecture have been assessed in polysomnographic studies: 11 studies in 579 healthy volunteers and 12 studies in 202 insomniac patients. From all the patient studies, it emerges clearly that zolpidem at the dose of 10 mg significantly decreases sleep onset latency, the number and the duration of nocturnal awakenings, and concomitantly increases total sleep time. Furthermore, at variance with what observed with reference benzodiazepine hypnotics, zolpidem does not alter patient sleep architecture: it increases only moderately stage 2, it increases, when reduced, stages 3 and 4 (slow wave sleep) and it does not decrease REM sleep. Clinical studies conducted on more than 4,000 insomniac patients have clearly shown that at the dose of 10-20 mg, zolpidem induces from the first night a definite hypnotic effect in all types of insomnia. In elderly subjects an initial dose of 5 mg should be considered. The possible presence of residual effects during the day following administration of zolpidem has been assessed in 535 healthy volunteers and in 133 insomniac patients according to a double blind (versus placebo and/or benzodiazepine) controlled design.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of zolpidem on cyclic alternating pattern, an objective marker of sleep instability, in Japanese patients with psychophysiological insomnia: a randomized crossover comparative study with placebo

OBJECTIVE: A placebo-controlled randomized crossover study to investigate the effects of zolpidem on sleep stability in Japanese insomniac patients was performed using the cyclic alternating pattern (CAP) rate, a polysomnographic marker that reflects sleep instability. METHODS: Seventeen patients (5 M and 12 F, mean age: 40.4+/-13.6 years) who met the International Classification of Sleep Disorders (ICSD) criteria for psychophysiological insomnia were evaluated. During the first period, patients were administered the placebo on the first night, followed by either zolpidem or the placebo on the second night (treatment night). The second crossover period was conducted after a minimum 3-day observation. Improvement in the overnight CAP rate was the primary endpoint. Secondary endpoints included the CAP variables, conventional sleep variables, EEG arousals, subjective evaluation of sleep quality (measured by means of a visual analogue scale and the St. Mary's Hospital Sleep Questionnaire), and drug safety. RESULTS: Zolpidem significantly decreased the overnight CAP rate values (57.6 vs. 39.0%, p=0.009) and improved "sleep depth" (p=0.044) and "sleep quality" (p=0.023) subjective questionnaire scores. Zolpidem also significantly improved VAS (p=0.036). The amount of time spent in sleep stages 3+4 was significantly increased by zolpidem without affecting the amounts of stage 2 and rapid eye movement (REM) sleep. Significant negative correlations were found when the sleep quality score was matched to the CAP rate (p=0.022). No serious adverse events occurred during the study. DISCUSSION: In Japanese patients with psychophysiological insomnia, zolpidem increased sleep stability by significantly improving the overnight CAP rate. Zolpidem also improved sleep depth and sleep quality, both subjectively and objectively.     

Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study

BACKGROUND: Over recent years, the use of antidepressants for the symptomatic treatment of insomnia has grown substantially, but controlled studies are still lacking. Our study is the first investigation to prove objective efficacy and tolerability of low doses of a sedating antidepressant in a randomized, double-blind, and placebo-controlled manner in patients with primary insomnia. METHOD: Forty-seven drug-free patients meeting DSM-IV criteria for primary insomnia (mean +/- SD duration of complaints = 11.2+/-9.7 years) received either 25-50 mg of the tricyclic antidepressant doxepin or placebo for 4 weeks followed by 2 weeks of placebo withdrawal. Sleep was measured by polysomnography at baseline and the first night of application, at 4 weeks of treatment and the first to third night of withdrawal, and after 2 weeks of withdrawal. RESULTS: In the doxepin-treated patients who completed the study (N = 20, 47.6+/-11.3), medication significantly increased sleep efficiency after acute (night 1, p < or = .001) and subchronic (night 28, p < or = .05) intake compared with the patients who received placebo (N = 20, 47.4+/-16.8 years of age). Latency to sleep onset was not affected since the patients had normal baseline sleep latencies. Investigators found doxepin to cause significantly (p < or = .05) better global improvement at the first day of treatment. Patients rated sleep quality (p < or = .001) and working ability (p < or = .005) to be significantly improved by doxepin during the whole treatment period. Overall rebound in sleep parameters was not observed, but patients with severe rebound insomnia were significantly more frequent in the doxepin group (night 29, p < .01, night 30, p < or = .01; night 31, p < or = .05). No significant group differences in side effects were found, but 2 doxepin-treated patients dropped out of the study due to specific side effects (increased liver enzymes, leukopenia, and thrombopenia). CONCLUSION: The results support the effectiveness of low doses of doxepin to improve sleep and working ability in chronic primary insomniacs, although subjective effects were light to moderate, and in some patients, rebound insomnia and specific side effects have to be considered.     

The sleep EEG's microstructure in depression: alterations of the phase relations between EEG rhythms during REM and NREM sleep

OBJECTIVE: We investigated the microstructure of sleep electroencephalograms (EEGs) of 13 unmedicated depressive inpatients and 13 healthy controls matched in sex and age, hypothesizing that depressives depict an alteration of certain EEG oscillations across the night. METHODS: We digitized the sleep EEGs with a sampling rate of 100 Hz (bipolar derivation C(z)-P(z), 1440 single sweeps; 2048 data points each), calculated the time course of delta (1-3.5 Hz), theta (3.5-7.5 Hz), alpha (7.5-15 Hz), and beta (15-35 Hz) activity over the night, and determined the correlation coefficients of these different EEG rhythms separately for rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. RESULTS: For both groups we detected a clear difference between REM and NREM sleep cycles at certain frequency bands. The most impressive changes occurred for the delta/beta and theta/beta correlations, which change their signs between NREM (negatively correlated) and REM (positively correlated) sleep cycles. Following an analysis of variance model with repeated measurement design, a statistically significant group effect (P=0.024) between depressives and controls was observable during NREM sleep for the delta/beta (P=0.010) and theta/beta (P=0.018) interactions. CONCLUSION: We detected alterations of certain sleep EEG oscillations during the NREM sleep cycle, where the delta/beta as well as the theta/beta activities were higher (negatively) compared to healthy controls. Together with previous investigations on the influence of antidepressants on the microstructure of sleep EEGs, this is another hint that the NREM sleep cycle plays a major role in depression.     

Zaleplon, A Novel Nonbenzodiazepine Hypnotic, Effectively Treats Insomnia in Elderly Patients Without Causing Rebound Effects

BACKGROUND: Insomnia is a very common symptom, particularly in the elderly. Thus, all hypnotic medications should be carefully evaluated in the elderly population. Zaleplon, a new nonbenzodiazepine hypnotic with a short elimination half-life (approximately 1 hour), was evaluated in the current study. METHOD: This multicenter, randomized, placebo-controlled outpatient study evaluated the efficacy and safety of zaleplon, 5 and 10 mg, in elderly patients with insomnia (as defined by DSM-IV); zolpidem, 5 mg, was the active comparator. Sleep was assessed in 549 elderly patients (>/= 65 years old) by using morning questionnaires completed after each of 7 baseline nights during which placebo was given, 14 nights of double-blind treatment, and 7 nights of placebo after discontinuation of active treatment. RESULTS: Zaleplon, 10 mg, and zolpidem, 5 mg, significantly reduced sleep latency during both weeks of the study. Zaleplon, 5 mg, reduced sleep latency only during week 2. Sleep duration was increased with zolpidem, 5 mg, during weeks 1 and 2 and with zaleplon, 10 mg, during week 1. No clinically significant rebound insomnia was observed after discontinuation of treatment with zaleplon, whereas evidence of rebound effects was seen with zolpidem. There was no significant difference between either zaleplon dose and placebo in the frequency of any central nervous system adverse events. CONCLUSION: Zaleplon is effective in reducing latency to sleep without evidence of undesired effects in elderly patients with insomnia.     

The Importance of Residual Effects When Choosing a Hypnotic: The Unique Profile of Zaleplon

BACKGROUND: Insomnia is a prevalent medical disorder that has significant effects on occupational performance, health, and quality of life. Insomnia places an enormous burden on society through increased visits to physicians, loss of productivity in the workplace, and an increased rate of accidents. An estimated sum of $100 million is spent each year on direct treatment of unresolved insomnia. Physicians need to initiate early effective treatment to prevent development of chronic insomnia and its associated morbidity. Institution of good sleep hygiene practices may be useful in some patients but may not be adequate for resolution of all sleep problems. Behavioral treatments, while effective and durable, are time consuming and not widely utilized in clinical practice. Pharmacotherapy includes benzodiazepine hypnotics, but concerns regarding adverse effects (e.g., residual sedation) prompted the search for safer options. DATA SOURCES: Published and presented studies containing clinical data on zaleplon, a new nonbenzodiazepine sleep medication, were identified via MEDLINE, Current Contents (ISI database), bibliographic reviews, and consultation with sleep specialists. RESULTS: Zaleplon effectively shortens sleep onset time and improves the quality of sleep in patients with insomnia. Whether administered at bedtime or later at night, zaleplon is devoid of residual sedative effects that impair next-day functioning. Follow-up studies evaluating the long-term efficacy and safety of zaleplon showed that decreased time to sleep onset was maintained during therapy lasting up to 52 weeks, without a withdrawal syndrome after discontinuation. CONCLUSION: Insomnia is recurrent and unpredictable in nature. Despite the long-term morbidity of this sleep disorder, research evidence and practice guidelines have not explored long-term use of hypnotics. Many patients could benefit from long-term drug therapy with a sleep medication that is devoid of residual effects and can be taken at bedtime or later as symptoms occur, rather than nightly in anticipation of a sleep problem.     

Effect of slow-wave sleep deprivation on topographical distribution of spindles

Spindle activity, visually scored in the 12-15 Hz range over antero-posterior midline derivations, has been assessed in ten normal subjects during a baseline and a recovery sleep after 2 nights of selective slow-wave sleep (SWS) deprivation. The recovery sleep, characterized by a significant increase of stage 4 and SWS as compared to the baseline, revealed that sleep spindles are reduced in the first NREM sleep cycle. The size of this reduction in spindle density progressively decreased in the course of the night, paralleling the depletion of SWS rebound. Topographical distribution of spindle activity showed a global linear increase over consecutive NREM-REM sleep cycles, regarding to the whole antero-posterior midline EEG derivations except the occipital one. It is concluded that the SWS rebound after 2 nights of selective SWS deprivation is associated with a reduction of spindles during stage 2.     

Efficacy and safety of zolpidem extended release in elderly primary insomnia patients.

OBJECTIVES: To evaluate the clinical efficacy and safety of zolpidem extended release for the treatment of primary insomnia in elderly patients. METHODS: A randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 205 (117 women, 88 men; mean age 70.2 +/- 4.5 years) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined primary insomnia patients were randomized to 3 weeks of nightly treatment with either zolpidem extended release 6.25 mg or placebo; 198 patients completed the study. RESULTS: Relative to placebo, zolpidem extended release 6.25 mg significantly decreased wake time after sleep onset during the first six hours of the night, as measured by polysomnogram (PSG). PSG latency to persistent sleep was reduced and PSG total sleep time was increased, both at nights 1/2 and 15/16. Patient self-report measures were significantly better with zolpidem extended-release 6.25 mg than with placebo throughout treatment. Some PSG measures indicated a worsening of sleep for a single night after abrupt discontinuation of zolpidem extended release. No next-morning residual effects were observed. The overall incidence and nature of adverse events was comparable between the two groups. CONCLUSIONS: Zolpidem extended release 6.25 mg improved both sleep maintenance and sleep induction in elderly primary insomnia patients during three weeks of administration.