A comparative assessment of the risks and benefits of zopiclone: a review of 15 years' clinical experience.

Zopiclone is a cyclopyrrolone hypnosedative that is chemically unrelated to the benzodiazepines but nevertheless potentiates gamma-aminobutyric acid-mediated neuronal inhibition, and has demonstrated proven efficacy and good tolerability in the treatment of insomnia over 15 years of use. Zopiclone is indicated for short term use, and should not be prescribed for more than 4 weeks. This review compares the efficacy of zopiclone with that of a number of commonly used short-, medium- and long-acting benzodiazepines. Zopiclone at dosages of 7.5 mg/day has demonstrated efficacy equivalent and in some cases greater to that of flurazepam 30 mg/day, nitrazepam 5 mg/day, flunitrazepam 1 to 2 mg/day, temazepam 20 mg/day, triazolam 0.125 to 0.5 mg/day and midazolam 15 mg/day. Zopiclone-treated patients reported themselves to be less impaired by daytime sedation than patients treated with the medium- and long-acting hypnosedatives flurazepam, nitrazepam and flunitrazepam. Zopiclone and temazepam showed similar effects on daytime behaviour while zopiclone appeared to have somewhat better effects on daytime well-being than the short-acting triazolam and midazolam. There has been no clinical comparison with the frequently used medium-acting benzodiazepines lormetazepam and brotizolam and the imidazopyridine hypnosedative zolpidem. Data from clinical trials, pooled analyses and postmarketing surveillance including over 30,000 patients showed that with the exception of bitter taste (reported by <10% of zopiclone recipients), the tolerability profile of zopiclone is similar to that of placebo. Clinical trials found no evidence for significant rebound insomnia and indicated that the risk of withdrawal reactions with therapeutic doses of zopiclone is very low. In addition, to date, dependency appears very low, although abuse potential should be considered following a history of addiction or psychiatric illness. Evaluation of the accumulated evidence from over 2.5 billion units dispensed in more than 30 countries indicates that zopiclone is effective, well tolerated and an excellent alternative to benzodiazepines in the short term treatment of insomnia.     

Loprazolam. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in insomnia

Loprazolam is a 1,4-benzodiazepine with hypnotic properties, advocated for use in acute or chronic insomnia. As loprazolam has a half-life of 7 to 8 hours in healthy adults it may have advantages over longer-acting hypnotics, particularly when residual sedative effects on the day after ingestion are undesirable, although at doses greater than 1 mg residual sedation may occur. In addition, it may reduce daytime anxiety, following a hypnotic dose the night before, more effectively than the short-acting drug, triazolam. In short term comparative studies loprazolam was clearly superior to placebo, and was at least as effective as triazolam, flurazepam, nitrazepam, flunitrazepam or temazepam in hastening sleep onset, reducing nocturnal awakenings and increasing total sleep duration and quality. In the small number of patients with chronic insomnia who have received extended treatment with loprazolam, no evidence of tolerance has occurred, although rebound insomnia was evident 3 days after drug withdrawal in several studies. Thus, with its 'intermediate' elimination half-life, loprazolam would appear to have some potential advantages over both long- and short-acting hypnotics in selected patients, although further studies are needed to fully elucidate its place in therapy.     

Triazolam: a review of its pharmacological properties and therapeutic efficacy in patients with insomnia

Triazolam is a triazolobenzodiazepine with hypnotic properties, advocated for use in acute or chronic insomnia, situational insomnia in hospitalised patients, and insomnia associated with other disease states. As triazolam has a relatively short half-life of about 2 to 3 hours in healthy subjects and has only 1 short acting active metabolite, alpha-hydroxytriazolam, it would seem more suitable as an hypnotic than longer acting drugs such as flurazepam, nitrazepam or flunitrazepam, particularly when residual sedative effects on the day after ingestion are undesirable. Thus, with usual hypnotic doses of triazolam (0.25 or 0.5 mg) impairment of psychomotor and cognitive function is generally not carried over into the day after ingestion, although at doses of 1 mg or greater, residual effects may appear. In short term comparative studies triazolam was clearly superior to a placebo, and was at lest as effective as flurazepam, or other benzodiazepines such as nitrazepam or diazepam, in hastening sleep onset, reducing nocturnal awakenings, and increasing sleep duration. In other studies it was often superior to chloral hydrate, methyprylone or quinalbarbitone (secobarbital). In a small number of patients with chronic insomnia receiving extended treatment with triazolam in a clinical setting or in some sleep laboratory studies, no evidence of tolerance occurred; however, some evidence of reduced effect with repeated administration has been reported in one sleep laboratory study. Thus, a definitive statement about the likelihood of tolerance occurring on repeated administration is difficult to make at this time.     

Treatment of insomnia with two benzodiazepines: a double-blind crossover study

Summary Twenty-eight patients (12M, 16F) with insomnia were treated with nitrazepam 5 mg/d and oxazepam 25 mg/d, each for 11 days, in a double-blind crossover comparison with placebo. Half the patients received nitrazepam in the first drug period, and oxazepam in the second and the other half followed the contrary sequence.Both nitrazepam and oxazepam were found to be effective in inducing sleep and increasing sleep quality. No effects on dreaming or adverse effects were found. Nitrazepam did influence the frequency of awakening, but only in the second drug period. In the first period it reduced self-waking.It is concluded that both nitrazepam and oxazepam were effective in inducing sleep and in improving sleep quality.This study was in part supported by NATO (project no. RG. 0029/88)     

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.     

Sleep laboratory studies in periodic limb movement disorder (PLMD) patients as compared with normals and acute effects of ropinirole

Periodic limb movement disorder (PLMD) occurs in a variety of sleep disorders and can cause insomnia as well as hypersomnia with daytime somnolence. The aim of this study was to investigate 12 untreated PLMD patients as compared with 12 normal controls and to measure the acute effects of 0.5 mg ropinirole (Requip((R))) - a non-ergoline dopamine agonist - as compared with placebo. In three nights (adaptation, placebo, ropinirole night) objective and subjective sleep and awakening quality were evaluated. In the target variable 'periodic leg movements per hour of sleep' (PLM/(hTST)) PLMD patients showed an increased value of 42/h (normal 0-5/h) with a greater number of arousals due to periodic leg movements (PLM) in sleep. They further demonstrated an increased number of awakenings, sleep stage S1, S4, stage shifts and decreased S2, but there were no significant differences concerning total sleep time, sleep efficiency (SE), subjective sleep quality and morning measures of mood, drive and drowsiness. However, measures of attention variability, numerical memory, fine motor activity and reaction time performance were impaired. Ropinirole 0.5 mg was shown to significantly improve the index PLM/(hTST) by 64% and arousals due to PLM, increase spontaneous arousals, REM-latency, stage 2 and stage shifts and decrease SREM. In the morning attention variability was attenuated and numerical memory augmented. Thus, ropinirole improved some sleep architecture and early morning measures of performance but specifically all PLM variables, which suggests a dopaminergic pathogenesis in PLMD. 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.     

Residual effects of zopiclone on subsequent daytime functions in normal humans

The influence of zopiclone and nitrazepam on arousal level, muscle strength, psychomotor performance and memory function using the photopalpebral reflex (PPR), critical flicker frequency (CFF), tapping test, pursuit rotor test (PRT), choice reaction test (CRT) and memory drum test (MDT) were investigated on the day following drug administration. After the control tests were completed at 1800 h, nine healthy male university students were given zopiclone 10 mg, nitrazepam 10 mg and placebo in a double-blind, crossover design at 2300 h. The performance on the tests, as well as the recording of subjective assessments, were repeated at 0800, 1100 and 1400 h the next day. Both nitrazepam and zopiclone produced a prolongation of PPR latency and a decrease of CFF. The effects of zopiclone were weaker and shorter in duration than those of nitrazepam. Tapping rate, PRT and CRT improved or did not change, and there were no significant differences between the drugs. The MDT was impaired by both drugs in the morning, with nitrazepam continuing to produce memory impairment, while zopiclone did not produce further deterioration. No significant changes were observed in the subjective assessment of the subjects. These results suggest that a medium dose of zopiclone lowers arousal level and impairs memory, especially during the morning following drug administration, but produces no change in muscle strength, psychomotor performance or self-assessment. Finally, the residual effects of zopiclone appear to be weaker than those of nitrazepam.     

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.     

右旋与消旋佐匹克隆治疗睡眠障碍的随机双盲双模拟临床试验

目的以消旋佐匹克隆为阳性对照药评价右旋佐匹克隆治疗睡眠障碍的疗效及安全性。方法用双盲双模拟随机对照临床试验方法，每晚睡前，分别口服（试验与对照药）右旋和消旋佐匹克隆口服3，7．5mg，疗程为14天。结果右旋佐匹克隆（试验组）为68例，痊愈率为20．59％；消旋佐匹克隆（对照组）为57例，痊愈率为14．04％。药物不良反应发生率分别为36．76％，49．12％。2组临床疗效及药物不良反应发生率比较具有统计学差异。结论右旋佐匹克隆治疗睡眠障碍，安全、有效。     

Evaluation of the efficacy of metaclazepam and its effects on sleep,psychomotor performance and cognitive function in anxious patients

The effects of single and multiple doses of metaclazepam were investigated in 60 anxious patients. A 15 mg nocturnal dose of metaclazepam was compared to two daily doses (5 mg in the morning and 10 mg at bedtime) in terms of efficacy and effects on various aspects of sleep, cognitive function and psychomotor performance. Anxiolytic efficacy was assessed by means of questionnaires, including the Self Rating Anxiety Scale of Zung, State Trait Anxiety Inventory of Spielberger, and a modified version of the Hamilton Anxiety Rating Scale. Hypnotic activity was evaluated using a clinical rating of insomnia questionnaire. The psychometric battery consisted of tests of Critical Flicker Fusion, Choice Reaction Time and Digit Span. In terms of clinical efficacy, metaclazepam administered in either dosage regimen demonstrated a good anxiolytic activity profile. Both dosage regimens were effective in improving the quality and quantity of sleep, however the number of intermittent awakenings were significantly higher with the daily divided dose. In addition, the nocturnal administration of metaclazepam did not appear to be associated with any undesirable side effects or decrements in psychomotor performance the following morning. In conclusion, it appears that a 15 mg bedtime dose of metaclazepam is efficacious in relieving anxiety without impairing psychomotor performance the following morning. © 1998 John Wiley & Sons, Ltd.     

西药疗效不佳的患者配合中药治疗心脾两虚型失眠临床观察

目的 观察心脾两虚型失眠服用佐匹克隆片疗效不佳的患者加服归脾汤加减的临床效果.方法 选取2012年1月至2014年12月来自本院门诊的心脾两虚型失眠患者,睡前患者口服西药佐匹克隆片3.75 mg,每晚1次;将服用3d后疗效不佳的80例患者随机分为对照组和治疗组.对照组睡前口服佐匹克隆片7.50 mg,每晚1次;治疗组睡前口服佐匹克隆片3.75 mg,每晚1次,同时加用归脾汤加减治疗.2周后观察中西医临床疗效以及不良反应发生率.结果 治疗组痊愈12例,显效17例,有效10例,总有效率为97.5％;对照组痊愈8例,显效12例,有效12例,总有效率为80.0％;两组比较差异有统计学意义(P＜0.05).两组睡眠质量比较,治疗前后组内比较及治疗后组间比较,差异有统计学意义(P＜0.05).对照组、治疗组不良反应发生率分别为22.5％、5.0％,差异具有统计学意义(P＜0.05).结论 心脾两虚型失眠患者口服佐匹克隆片疗效不佳时采用中西医结合治疗临床效果明显,能够有效改善患者睡眠质量,同时不良反应发生率低,值得临床推广应用.     

Benzodiazepine associated reversal of the effects of experimental sleep fragmentation

Thirty-six healthy young men and women (age 21–35) received 0.00, 0.25, or 0.50 mg triazolam (n = 12 per group) while undergoing experimental sleep fragmentation in which sleep was disrupted by presenting tones to produce brief EEG arousals (without shortening sleep time). The following day subjects' daytime function was assessed using the Multiple Sleep Latency Test and a divided attention performance task. The fragmentation of sleep produced significant disruption of nocturnal sleep and it reduced daytime alertness. Both active drug doses, relative to placebo, reversed the experimentally produced sleep disturbance and they restored daytime alertness.     

Zopiclone versus flurazepam in insomnia: prolonged administration and withdrawal

Zopiclone (7.5 mg), a cyclopyrrolone derivative with a 6.5 h half-life, and flurazepam (30 mg) were compared to placebo in a randomized double-blind study involving 36 adult patients suffering from insomnia. All previous psychotropic drugs were discontinued 1 week prior to the study. During 4 weeks, 12 patients received zopiclone, 12 flurazepam and the others placebo. Thereafter, all patients received single-blind placebo for 3 nights. Rapidity of sleep onset, sleep duration, frequency of nocturnal awakenings, psychomotor coordination and side-effects were assessed daily with a questionnaire and a symptom checklist. The results of the study suggest that zopiclone 7.5 mg was at least as potent as flurazepam 30 mg in inducing and maintaining sleep. Both drugs maintained their efficacy during the 4 weeks of treatment. However, the two drugs differed in that flurazepam impaired psychomotor coordination whereas zopiclone did not demonstrate daytime protracted effects on psychomotor performance. Upon discontinuation of drug treatment, score values of the different sleep parameters under study returned to the baseline values. Side-effects were mild and consistent with earlier studies.     

Double-blind evaluation of the efficacy and safety of temazepam in outpatients with insomnia.

1 The efficacy and safety of temazepam 30 mg, compared with glutethimide 500 mg and placebo, were evaluated in double-blind conditions in a 4-day study in 75 outpatients with a history of insomnia. 2 Temazepam and glutethimide were rated by the patients as effective and significantly superior to placebo for general quality of sleep, time required to fall asleep, frequency of nocturnal and early morning awakenings, and duration of sleep. 3 Residual effects reported for temazepam and glutethimide immediately after awakening and during the day were similar to or less than those reported for placebo.     

Effect of zopiclone on the arousal level of healthy volunteers assessed by the averaged photopalpebral reflex

The averaged photopalpebral reflex (PPR) represents the mean of summed reflex contractions of the orbicularis oculi muscle in response to periodic photic stimuli. The latency of PPR can be used to assess a drug effect on human arousal level, since it is prolonged if there is a reduction in the arousal level of the subject. In the present study of the clinical effects of zopiclone, healthy male volunteers aged 18-22 years were given zopiclone 5 mg and 10 mg, nitrazepam 5 mg and 10 mg, or placebo, in a double-blind, cross-over design. Changes in the latencies of PPR were examined from 0.5 to 4 h after medication. Both zopiclone and nitrazepam prolonged the latency in a dose-dependent manner, but the prolongation induced by zopiclone appeared more rapidly, was slightly more marked and lasted for a shorter period than that induced by nitrazepam. Zopiclone produced slightly fewer subjective changes, such as vagueness of thought and weakness, than did nitrazepam. From these results, it is suggested that zopiclone possesses a potent hypnotic action which appears more rapidly and is slightly more potent and shorter lasting than that of nitrazepam. In addition, zopiclone may also exhibit fewer side effects, such as vagueness of thought and weakness than nitrazepam, and it may cause less "hang over".     

Zopiclone and triazolam in insomnia associated with generalized anxiety disorder: a placebo-controlled evaluation of efficacy and daytime anxiety

In a double-blind placebo-controlled study, following a 1 week washout, 75 outpatients suffering from generalized anxiety disorder with severe insomnia as the target symptom were randomly assigned to 4 weeks of treatment with zopiclone 7.5 mg, triazolam 0.5 mg or placebo at bedtime. Zopiclone was significantly better than placebo on most sleep parameters. Triazolam tended to be superior to placebo, but its superiority was significant only on the sleep induction factor. Triazolam-treated patients presented significantly more day-time-interdose anxiety than zopiclone as assessed by the weekly HARS and Clinical Global Assessment of Anxiety. Although daytime-interdose anxiety was observed with both drugs, this treatment emergent symptom was more frequent and severe with triazolam. Side-effects were of a mild to moderate intensity for both zopiclone and triazolam; however, taste perversion frequently appeared with zopiclone. Although both drugs share similar pharmacological properties and bind to benzodiazepine receptors, they differ significantly with respect to side-effects and daytime anxiety.     

A double-blind placebo-controlled trial of zopiclone 7.5 mg and temazepam 20 mg in insomnia

Zopiclone, a cyclopyrrolone with hypnotic properties was compared with temazepam and placebo in the treatment of insomnia. After a week's washout period, suitable subjects were allocated at random to zopiclone 7.5 mg or temazepam 20 mg or placebo for 2 weeks. Measurements of psychomotor function using the Leed's psychomotor tester and letter cancellation were carried out on day 0, 7 and 14. Sleep latency, duration of sleep and number of times waking during the night were recorded on a sleep diary filled by the subjects nightly. Forty-four subjects completed the trial, 15 taking zopiclone, 16 taking temazepam and 10 taking placebo. Both zopiclone and temazepam had significant hypnotic properties when compared to placebo. Zopiclone increased total sleep time in both weeks of the trial while temazepam increased sleep time in the first week only. There was no significant deterioration in psychomotor performance at the end of both weeks for zopiclone. Critical flicker fusion was significantly increased in subjects on temazepam. There were no abnormalities for both zopiclone and temazepam subjects in the blood picture, renal profile, liver function, urine and ECG before and after the study. Zopiclone is an effective hypnotic comparable to temazepam.     

The dose effects of zopiclone

The dose effects of zopiclone on sleep were studied in 12 subjects. Subjects who complained of insomnia and had their complaint verified by nocturnal polysomnography were included in the study. Four consecutive nights of adaptation and screening, while on placebo, were followed by six 3-night drug administration periods separated by a 4-day placebo washout period spent at home. Each of the subjects received placebo, 2·5, 5·0, 7·5, 10·0 or 15·0 mg of zopiclone administered in a double-blind, randomized, six-way Latin square design. Zopiclone at all doses significantly increased total sleep time and decreased latencies to sleep compared to placebo dose. Dose differences were found for total sleep time and wake during sleep with 5·0 mg and larger doses differing from 2·5 mg. No further improvement was produced by doses greater than 5·0 mg. Sleep staging effects changed in a dose-dependent fashion with the 7·5 mg and higher doses significantly different from both placebo and the 2·5 mg dose. In general, hypnotic effects leveled off at the 5 mg dose while sleep stage effects increased with higher doses.     

Influence of some dopaminoceptor agents on nitrazepam-induced sleep in the domestic fowl (Gallus domesticus) and rats

The influence of apomorphine, levodopa and haloperidol was studied on nitrazepam sleep using young chicks and rats. In addition, the influence of dopamine and ADTN was studied in young chicks. Nitrazepam dose-dependently (0.4-51.2 mg/kg, i.p.) induced behavioural sleep in chicks. However, higher doses of nitrazepam (12.8-51.2 mg/kg, i.p.) were required to induce behavioural sleep in rats. Dopamine (12.5-100 mg/kg, i.p.) and ADTN (2.5-80 mg/kg, i.p.) delayed the onset but prolonged nitrazepam sleep in chicks: these effects were statistically significant. Levodopa (12.5-100 mg/kg, s.c.) and apomorphine (0.2-0.8 mg/kg, s.c.) profoundly delayed the onset and shortened the duration of nitrazepam sleep in both chicks and rats. Noradrenaline (20-80 mg/kg, i.p.) shortened the onset and prolonged nitrazepam sleep in chicks. Pimozide (1-8 mg/kg, i.p.) potentiated nitrazepam sleep and antagonized the effects of dopamine, levodopa and ADTN on nitrazepam sleep in chicks. Similarly, haloperidol (0.5-1.0 mg/kg, i.p.) potentiated nitrazepam sleep and antagonized the effects of levodopa and apomorphine on nitrazepam sleep in rats. The EEG synchronization and decreased EMG induced by nitrazepam (1.6 mg/kg, i.p., and 12.8 mg/kg, i.p., for chicks and rats, respectively) were antagonized by levodopa (12.5 mg/kg, s.c.). The behavioural and electroencephalographical results suggest that enhancement of dopaminergic neurotransmission may be involved in the mechanisms of wakefulness in both chicks and rats.