Double-blind,placebo-controlled comparison of zolpidem,triazolam, and temazepam in elderly patients with insomnia

Sleep disturbances and need for hypnotics are disproportionately greater in the elderly compared to younger adults. The present study provides a placebo-controlled subjective hypnotic efficacy of zolpidem, triazolam, and temazepam in elderly insomniacs. After a single-blind placebo screening week (DSM-III-R criteria), 335 elderly insomniacs (ages 60 to 85) were randomized to 28 days of double-blind treatment with zolpidem 5 mg, triazolam 0.125 mg, temazepam 15 mg, or placebo, followed by a 4-day single-blind, placebo withdrawal period. The primary efficacy parameters were self-reported sleep latency (SSL) and self-reported total sleep duration (SSD); they were measured by responses on daily Morning Questionnaires. SSL values were compared by Cox proportional hazards regression technique. SSD values were compared by ANOVA. Compared to placebo, zolpidem and temazepam produced significantly shorter SSL over the 4 treatment weeks, but triazolam did not. In the zolpidem group, SSL was significantly shorter than in the placebo group at all four treatment weeks; in the temazepam group, SSL was significantly shorter than in the placebo group at weeks 1, 3, and 4. SSD was increased above baseline levels in all groups. No tolerance to the subjective effects or rebound above baseline levels occurred in any of the treatment groups. Overall, the drugs were well tolerated. No difference was found among the placebo and treatment groups in overall adverse event incidence rates. However, compared with zolpidem and placebo, temazepam produced significantly higher incidences of drowsiness and fatigue, and triazolam produced a significantly higher incidence of nervousness than zolpidem. Drug Dev. Res. 40:230–238, 1997. © 1997 Wiley-Liss, Inc.     

Comparative efficacy of zolpidem and temazepam in transient insomnia

This study compared hypnotic effects of zolpidem 10 mg, temazepam 15 mg and placebo in healthy adults. Two factors expected to promote insomnia, the 'first night effect' and a 2-hour phase advance, were combined in a single night laboratory-based double-blinded protocol. This was a multi-center study, with data collected in 13 sleep laboratories. Subjects with normal sleep histories and without prior sleep laboratory experience were randomly assigned to treatment groups. Medications were administered 15 min before lights out, with polysomnographic monitoring for 7.5 h. Subjective questionnaires and performance tests, digit symbol substitution test (DSST) and symbol copying test (SCT), were administered at study entry and after arising. 630 subjects completed the study and provided data analyzed using repeated measures ANOVAs. Neither agent significantly reduced objective sleep latency relative to placebo. Zolpidem reduced awakenings and wake after sleep onset (WASO); temazepam did not. Both agents improved sleep efficiency and most subjective sleep measures relative to placebo, with zolpidem superior for five of six subjective outcome measures compared to temazepam. SCT, morning sleepiness and morning concentration were not altered by any treatment. Zolpidem significantly reduced morning DSST performance; temazepam did not. Zolpidem 10 mg provided greater subjective hypnotic efficacy than temazepam 15 mg in this model of transient insomnia, with reduced polysomnographic awakenings and WASO. Impairment of DSST was seen with zolpidem but not temazepam. Copyright 2001 John Wiley & Sons, Ltd.     

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.     

Rebound insomnia after abrupt discontinuation of hypnotic treatment: double-blind randomized comparison of zolpidem versus triazolam

Rebound insomnia is a transient intense worsening of sleep usually appearing within 3 days from the abrupt discontinuation of benzodiazepines (mainly short-acting), following long term use and abuse of these hypnotics. Zolpidem is an imidazopyridine, that binds selectively at ω₁-receptor subtypes within the GABA_A receptor supramolecular complex. It has a rapid onset of action and short-elimination half-life; it reduces the latency of sleep and prolongs the duration of sleep in patients with insomnia, without any major effects on sleep stages and rebound effects upon discontinuation. The present multicentre trial (three Italian centres) was aimed at assessing the symptoms/signs of rebound insomnia after discontinuation of either zolpidem or triazolam. A double-blind, randomized, parallel group trial of 20-day duration was carried out in 22 patients suffering from either transient insomnia, or short-term (situational stress) insomnia, or patients who were poor sleepers. The trial consisted of three periods: a 3-day run-in period with placebo, a 14-day active treatment period (zolpidem 10 mg od or triazolam 0.25 mg od), a 3-day withdrawal period with placebo. There were statistically significant [p = 0.0064 for Total Sleep Time (TST) and p = 0.0051 for Sleep Efficiency (SE%)] differences between triazolam- and zolpidem-treated patients during the first withdrawal night versus baseline: TST decreased to 34.5 min after triazolam but increased to 43.8 min after zolpidem, and a similar evolution was shown on SE% (a decrease of 6.3 per cent after triazolam and an increase of 9.9 per cent after zolpidem). Also the Wake-time After Sleep Onset (WASO) showed a statistically significantly (p = 0.0083) different pattern, during the first withdrawal night, remaining decreased after zolpidem (37.5 min) but suddenly increasing after triazolam (17.3 min). Also the subjective time to fall asleep changed with a statistically significant difference (p = 0.042), being increased after triazolam (8.6 min) and decreased after zolpidem (20.8 min). The results of the study demonstrate the presence of clear rebound insomnia after triazolam discontinuation, whereas such a drawback is absent with zolpidem. This allows the abrupt discontinuation of zolpidem without any need for a tapering procedure and without any risk of pharmacological dependence.     

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.     

Comparison of temazepam 7.5 mg with temazepam 15 mg for the treatment of transient insomnia

OBJECTIVE: To demonstrate the equivalent efficacy of temazepam 7.5 mg and temazepam 15 mg for the treatment of transient insomnia. RESEARCH DESIGN AND METHODS: This was a double-blind, parallel group, multicenter study. Healthy male and female subjects with previous but not current complaints of transient insomnia were enrolled. Transient insomnia was induced in the sleep laboratory by means of the 'first night' effect and by implementing a 2-h phase advance. The effects of both doses of temazepam on polysomnographic (PSG) measures of sleep were evaluated for one night. Latency to persistent sleep (LPS) and total sleep time (TST) were designated as the primary efficacy endpoints. RESULTS: One hundred and thirty-one subjects completed the study: 65 received the 7.5-mg dose, and 66 received the 15-mg dose. Treatment groups begin with the lowest effective dose, i.e., 7.5 mg. were well matched based on background demographics. No statistically significant differences between doses were detected for LPS, TST,or any other objective (PSG) measure of sleep. Furthermore, both doses were found to be clinically equivalent for LPS and TST based on predetermined criteria. Temazepam was well tolerated, and no significant differences between doses were found for adverse event (AE) incidence, mean score on the Digit Symbol Substitution Task, or mean scores on questions related to tolerability from the Leeds Sleep Evaluation Questionnaire. CONCLUSIONS: The 7.5-mg and 15-mg doses of temazepam were equally effective for the treatment of transient insomnia. In keeping with current practice guidelines, initiation of treatment with temazepam for transient insomnia should     

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.     

Zaleplon improves sleep without producing rebound effects in outpatients with insomnia. Zaleplon Clinical Study Group

The efficacy and safety of three doses of zaleplon, a novel non-benzodiazepine hypnotic, were compared with those of placebo in outpatients with insomnia in this 4-week study, using zolpidem 10 mg as active comparator. Postsleep questionnaires were used to determine treatment effects on the patient's perception of sleep, as well as any development of pharmacological tolerance during therapy or rebound insomnia or withdrawal symptoms upon discontinuation of therapy. During week 1, sleep latency was significantly shorter with zaleplon 5, 10, and 20 mg compared to placebo. The significant decrease in sleep latency persisted through week 4 with zaleplon 20 mg, and was again evident with zaleplon 10 mg at week 3. Zaleplon 20 mg also had significant effects on sleep duration, number of awakenings, and sleep quality compared to placebo. No pharmacological tolerance developed during treatment with zaleplon and there were no indications of rebound insomnia or withdrawal symptoms after treatment discontinuation. Zolpidem 10 mg had significant effects on sleep latency, sleep duration, and sleep quality compared to placebo. However, a significantly greater incidence of withdrawal symptoms and a suggestion of sleep difficulty after treatment discontinuation (rebound insomnia) for all sleep measures was seen with zolpidem compared to placebo. There was no significant difference in the frequency of adverse events with active treatment compared to placebo. These results show that zaleplon provides effective treatment of insomnia with a favourable safety profile.     

New hypnotic agents: clinical studies in general practice

The type of sleep problem should be determined so that the most appropriate hypnotic can be used, and in this respect duration of action is an important property. The benzodiazepine hypnotics are adequate for this purpose, but problems may arise due to daytime after-effects and the possibility of dependence developing. Non-benzodiazepine hypnotics may be useful alternatives and our group has undertaken double-blind comparative trials with two such compounds, namely zopiclone and zolpidem. Zopiclone was compared to temazepam in a cross-over trial on 36 patients and similar hypnotic effects were recorded. In a parallel group study, zolpidem 10 mg was compared to zolpidem 20 mg and placebo in 88 patients. Both doses of zolpidem were significantly better than placebo on a number of the parameters recorded, side-effects were negligible and there was no evidence of any rebound insomnia during the final control week.     

A translational,caffeine-induced model of onset insomnia in rats and healthy volunteers

Rationale Insomnia is a common and disabling complaint for which there is a need for improved treatments. Successful drug discovery relies on the use of appropriate animal models to assess likely outcome in the clinic. Objectives The purpose of this study was to develop a translational, caffeine-induced model of insomnia in rats and healthy volunteers. We used sleep onset latency (SOL) as a comparable sleep measure between the two species. The model was validated by two effective sleep-promoting agents with different pharmacology, zolpidem and trazodone, which have GABA-ergic and serotonergic mechanisms, respectively. Materials and methods In rats, radiotelemetry transmitters with electroencephalogram and electromyogram electrodes were implanted for sleep recording. Animals were administered with caffeine alone (10 mg/kg) or in combination with zolpidem (10 mg/kg) or trazodone (20 mg/kg), or vehicle, in crossover experiments. Home polysomnography was performed in 12 healthy male volunteers in a randomised, placebo-controlled, 4-week crossover study. Subjects received placebo, caffeine (150 mg) or caffeine in combination with zolpidem (10 mg) or trazodone (100 mg). Subjective sleep effects in volunteers were assessed using the Leeds Sleep Evaluation Questionnaire. Results Caffeine caused a significant prolongation in objective SOL in rats and humans. This effect was sensitive to zolpidem and trazodone, both of which attenuated the caffeine-induced increase in SOL. Furthermore, both hypnotics restored the disruption in subjective measures of sleep onset caused by caffeine in volunteers. Conclusions This model therefore provides a promising paradigm in which we can study novel treatments for sleep disorders and an opportunity for direct comparison of results between rodents and humans.     

Evaluation of temazepam as a hypnotic

Temazepam is a 1,4-benzodiazepine, newly marketed in the United States for the symptomatic treatment of the complaint of insomnia. The manufacturer recommends a dose of 30 mg before bedtime for most adults and 15 mg for geriatric or debilitated patients. A dose of 30 mg usually produces peak plasma concentrations within 3 hours after oral ingestion and has a mean half-life of 10 to 15 hours. Thus, temazepam is absorbed more slowly and metabolized more quickly than flurazepam, the only other benzodiazepine marketed in the United States specifically for insomnia. Eight sleep laboratory and 21 clinical studies on temazepam indicate that temazepam reduces awakening during the night and increases sleep duration. However, there was no consistent evidence that temazepam reduces sleep latency--probably because temazepam, taken at bedtime, does not reach sufficiently high blood levels in time to affect sleep onset. One sleep laboratory study on 8 insomniac patients given 35 consecutive nightly doses of 30 mg found no evidence of tolerance or rebound insomnia. Studies on tolerance, metabolism and carry-over effects have shown that temazepam has no long-acting metabolites and does not affect waking function following use at bedtime. In patients for whom hypnotic medication is appropriate, temazepam should be an effective drug for reducing most symptoms of insomnia.     

Continuous versus non-nightly use of zolpidem in chronic insomnia: results of a large-scale, double-blind, randomized, outpatient study.

New treatment strategies are encouraged in insomnia and, in particular, discontinuous treatment. The aim of this double-blind study was to compare, in a large primary care population of chronic insomniacs (> 4 weeks duration) the efficacy and safety of zolpidem 10 mg 5 nights/week and placebo 2 nights/week, to that of nightly zolpidem. Seven hundred and eighty-nine drug-free insomniacs, with a Total Sleep Time (TST) of 3-6 h/night were enrolled in seven European countries. After a placebo run-in period, treatment lasted 14 days. The primary criterion was the Clinical Global Impression improvement score (CGI-II) which showed that 65.2% of patients in the continuous and 58.6% in the discontinuous groups were rated 'much' or 'very much' improved. Even though the non-inferiority test did not show the equivalence of both regimens, the difference of 7% in responder rates does not appear to be clinically relevant. Other sleep parameters such as TST, number of nocturnal awakenings and Quality of Life scales showed marked, not significantly different, improvements in both groups. Both regimens were well tolerated and no adverse event which could be related to non-treatment nights was reported in the discontinuous group. Non-nightly zolpidem appears to be a feasible and safe additional option for the management of chronic insomnia.     

Management of Insomnia

ObjectiveTo review current issues in the pharmacologic and nonpharmacologic management of insomnia.Data SourcesControlled trials and case studies identified via MEDLINE for 1990 through April 1999 under the search terms insomnia, hypnotics, flurazepam, quazepam, estazolam, temazepam, triazolam, zolpidem, zaleplon, L-846, CL-284,846, melatonin, and valerian.Data SynthesisInsomnia is a common, undertreated disorder. Nonpharmacologic management strategies (e.g., stimulus control, relaxation therapy, sleep hygiene) are therapeutic options that, compared with medication use, provide more sustained effects. The benzo· diazepines and zolpidem are the most commonly prescribed hypnotic agents, but their use is associated with tolerance and central nervous system adverse effects. A new nonbenzodiazepine hypnotic agent, zaleplon, was very recently approved in the United States. Because of its short half-life, zaleplon will be useful in patients experiencing difficulty in falling asleep and in those who wake up at night and have trouble falling back to sleep. Antidepressants, antihistamines, and alternative medications are other treatment options. To avoid complications of therapy, hypnotic agents should be used at their lowest possible doses and for limited treatment durations.ConclusionPharmacotherapy is currently the most common treatment modality for insomnia, but long-term use of hypnotic agents can become complicated by drug tolerance, dependence, or rebound insomnia. Nonpharmacologic options–including combinations of behavioral interventions, sleep-restriction therapy, and patient education-provide longer-lasting benefits.     

Double-blind,placebo-controlled study comparing effects of zopiclone and temazepam on cognitive functioning of insomniacs

The purpose of this study was to compare the cognitive effect of two medications frequently prescribed to patients suffering from insomnia. Using a double-blind design, we evaluated three parallel groups of 20 insomniac patients treated over a period of 3 weeks with zopiclone, temazepam and placebo, respectively. Our hypothesis was that the impact of zopiclone 7.5 mg/day on cognitive functioning would be minimal 12 h after administration and that temazepam 30 mg/day would affect explicit memory, as is the case with other benzodiazepines. Patients were assessed at baseline following a 1-week, single-blind placebo-intake period, and again at the end of each of the 3 weeks of the comparative phase. Then, in order to estimate the severity and duration of potential rebound insomnia, patients were again assessed following another 1-week, single-blind placebo-washout period at the end of the 3 weeks of treatment. The overall duration of the study for each patient was thus 5 weeks. The instruments of measure used were the Hamilton scale for anxiety, daily self-rating questionnaire for assessment of sleep onset, duration and quality, and two large batteries of psychometric tests. The first of these batteries assessed memory and included span tests for short-term memory, cued recall tasks for long-term explicit memory, and a word-completion task for implicit memory; the second measured attention and concentration through the assessment of alertness, sustained attention and divided attention. The sleep and anxiety results obtained confirm the findings of previous research. Zopiclone and temazepam possess a clinically significant hypnotic activity, with no rebound insomnia or anxiety, during the week of drug withdrawal. The results indicate that the two hypnotic drugs studied have little impact on cognitive functioning. We can therefore conclude that at the doses administered over the 3 weeks, the two hypnotic drugs in question are relatively safe and efficacious in the treatment of insomnia and enable patients to enjoy a good quality of life. Copyright © 1999 John Wiley & Sons, Ltd.     

Temazepam,but not zolpidem,causes orthostatic hypotension in astronauts after spaceflight

Insomnia is a common symptom, not only in the adult population but also in many astronauts. Hypnotics, such as temazepam (a benzodiazepine) and zolpidem (an imidazopyridine), are often taken to relieve insomnia. Temazepam has been shown clinically to have hemodynamic side effects, particularly in the elderly; however, the mechanism is not clear. Zolpidem does not cause hemodynamic side effects. The purpose of this study was to determine whether the use of different hypnotics during spaceflight might contribute significantly to the high incidence of postflight orthostatic hypotension, and to compare the findings in astronauts with clinical research. Astronauts were separated into three groups: control (n = 40), temazepam (15 or 30 mg; n = 9), and zolpidem (5 or 10 mg; n = 8). In this study, temazepam and zolpidem were only taken the night before landing. The systolic and diastolic blood pressures and heart rates of the astronauts were measured during stand tests before spaceflight and on landing day. On landing day, systolic pressure decreased significantly and heart rate increased significantly in the temazepam group, but not in the control group or in the zolpidem group. Temazepam may aggravate orthostatic hypotension after spaceflight when astronauts are hemodynamically compromised. Temazepam should not be the initial choice as a sleeping aid for astronauts. These results in astronauts may help to explain the hemodynamic side effects in the elderly who are also compromised. Zolpidem may be a better choice as a sleeping aid in these populations.     

Effect of zolpidem on sleep in insomniac patients

Summary The effect of zolpidem 10 mg p.o. on sleep in patients with persistent psychophysiological insomnia was assessed by polysomnographic recordings.An improvement in sleep with no rebound insomnia was observed during treatment for two weeks. Time awake after the onset of sleep was reduced after one week and increased after two weeks, whereas sleep latency remained reduced.Zolpidem markedly increased the duration of Stage 2 sleep without affecting either slow wave sleep or REM sleep. Subjective evaluation of improvement in sleep was well correlated with sleep laboratory findings. Zolpidem did not impair the immediate memory or psychomotor performance of patients on the morning after its administration. Side-effects during the period of drug administration included drowsiness, fatigue, headache, anxiety and irritability. They were mild or moderate and wore off soon after awakening.     

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.     

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.     

Overview of the therapeutic management of insomnia with zolpidem

Benzodiazepine hypnotic agents were the mainstream pharmacotherapy for insomnia from the 1960s to the 1980s, but their safety profile proved to be not quite as perfect as originally expected with regard to daytime performance and cognition, and above all the risk of dependence. These risks are substantially diminished in the non-benzodiazepine hypnotic agents developed and marketed during the past two decades, but the fears engendered by certain benzodiazepines still greatly influence the attitude of both physicians and the general public to the treatment of insomnia. For this reason, as well as in the interests of matching the pharmacotherapy of insomnia more closely to the often fluctuating nature of this disorder, the possibility of the discontinuous or 'as needed' use of hypnotic drugs has attracted increasing attention in recent years. Current recommendations strongly favour the use of hypnotic drugs for a limited period of time. However, some insomniac patients need sleep medication for longer periods in spite of a non-pharmacological approach, whereas other patients become dependent on drugs as a result of rebound insomnia, withdrawal symptoms, or the recurrence of insomnia. The pharmacological properties of zolpidem make it feasible for non-nightly use. A double-blind, randomized, parallel-group study of continuous treatment with either zolpidem or estazolam, followed by an observation of the discontinuation of drug treatments combined with the non-pharmacological management of primary insomnia, showed a carry-over benefit for zolpidem treatment.     

Temazepam 7.5 mg: effects on sleep in elderly insomniacs

Temazepam, 7.5 mg was evaluated in the sleep laboratory in 8 elderly insomniacs, using a 14-night protocol (4 placebo-baseline nights, 7 drug nights, and 3 placebo-withdrawal nights). With short-term use temazepam was found to be effective, producing a significant improvement in total wake time from baseline (100 vs. 145 min). With continued drug administration, total wake time remained below baseline but not significantly so (125 vs. 145 min). During drug administration, there were no major CNS and behavioral adverse effects reported such as daytime sedation, memory impairment or hyperexcitability (daytime anxiety). Following drug withdrawal, there was no significant increase in wakefulness, i.e., no rebound insomnia (150 vs. 145 min).In summary, temazepam, 7.5 mg is effective in elderly subjects with short-term use and has a minimum of adverse effects. Use of hypnotic drugs is an adjunctive therapy which should be for a short-term period with subsequent short-term intermittent use as needed. Because of its low propensity for producing rebound insomnia, temazepam can be effectively used in this manner.