The sleep–wake cycle and sleeping pills

Physiology & Behavior 90 (2007) 285 – 293

The sleep–wake cycle and sleeping pills Björn Lemmer Institute of Experimental and Clinical Pharmacology and Toxicology, Ruprecht-Karls-University of Heidelberg, Maybachstr, 14, 68169 Mannheim, Germany Received 22 August 2006; received in revised form 4 September 2006; accepted 4 September 2006

Abstract Sleeping pills are drugs which are used world-wide to combat sleep disturbances, and to prevent symptoms due to maladjustment to shiftwork or jet-lag. Today, benzodiazepines and the so-called “non-benzodiazepines”, such as zolpidem, which both act on benzodiazepine receptors, are drugs of first choice and they are substitutes for barbiturates. Their use as sleeping pills in insomniacs is established after appropriate medical diagnosis. Symptoms from shiftwork or jet-lag are due to an internal desynchronisation of biological rhythms, and there is ample evidence that benzodiazepines are not effective in preventing these symptoms. Cabin crews in particular should never take sleeping pills, in order not to impair cognitive functions or to reduce the reactivity needed to fly an aircraft safely. The biological clock(s) cannot be reset instantaneously by any drug. © 2006 Elsevier Inc. All rights reserved. Keywords: Benzodiazepines, Circadian rhythms, Hypnotics, Jet-lag, Shiftwork

1. Introduction Rhythmicity is the most ubiquitous feature of nature. Rhythms are found in life from unicellular to complex multicellular organisms in plants, animals and humans. The frequencies of rhythms in nature cover nearly every division of time. There are rhythms which oscillate once per second (e.g. in the electroencephalogram) and once per several seconds (respiratory rhythm, heart rate, blood pressure), up to rhythms which oscillate once per year (circannual rhythms). The most evident environmental change is that between day and night, which results from the regular spin of the earth around its central axis and seems to have induced the predominant oscillation, the circadian rhythm (the about-24hour rhythm; circa = about, dies = day). There is clear evidence demonstrating that living systems including humans are not only organized in space but that they are also highly organized in time, a fact which had already been noted in the 18th and beginning of the 19th centuries[1–9]. Circadian rhythms have been documented throughout the plant and animal kingdom at every level of eukaryotic organization. Circadian rhythms, by definition, are endogenous in nature, driven by oscillators or clocks, and persist under freeE-mail address: [email protected]. 0031-9384/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2006.09.006

running conditions. In various species (Drosophila melanogaster, Neurospora, Mouse, Golden hamster, Man) even the genes controlling circadian rhythms have been identified (genes: per, frq, clock, tau, hclock, hBmal, hper1, etc.). In general, the endogenous clock in humans does not run exactly at a frequency of 24 h but somewhat slower. The rhythm in human body temperature which is timed by the biological clock has a period of about 24.2–24.5 h under freerunning conditions i.e. without environmental time-cues or Zeitgebers (e.g. light, temperature). Zeitgebers entrain the circadian rhythm to a precise 24-hour period. Zeitgebers are, therefore, necessary to entrain a living subject to a “normal” period of 24 h. Importantly, endogenous biological rhythms are anticipatory in nature Thus, rhythmicity, inherent to all living systems, allows them to adapt more easily and to survive better under changing environmental conditions during the 24 h of a day as well as during varying conditions of the changing seasons. Circadian rhythms are present in virtually all physiological and behavioral functions. In humans and rodents, light is the most effective Zeitgeber for the biological clock. There is a direct pathway of photic information for the circadian clock via the retinohypothalamic tract, and an indirect pathway through the intergeniculate leaflet. The primary circadian photoreceptors seem to be the melanopsin-containing ganglia in the retina.

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Fig. 1. Sleep–wake patterns in sleep disorders (left) and circadian phenotypes from mutant animals (right) under L:D (left part) or under free-run conditions (right part). ASPS = advanced sleep phase syndrome, DSPS = delayed sleep phase syndrome [69].

The regulation of the sleep–wake cycle is generated by complex interactions of the endogenous clock and the homeostatic sleep drive [10,11]. The circadian clock is responsible for promoting wakefulness during the day and facilitating sleep during the night. Sleep disorders are the result of misalignment between the biological clock and the physical and social 24hour environment. Sleep–wake patterns in sleep disorders are shown in Fig. 1 and compared with circadian phenotypes from mutant animals. This figure shows the similarity of delayed sleep phase syndrome (DSPS) in humans to the circadian phenotype of ‘long period’ mutant animals, and the advanced sleep phase syndrome (ASPS) to the circadian phenotype of short period mutant animals. In addition, shiftwork and jet-lag cause circadian sleep disorders. Details will be discussed in other contributions in this special issue. Several groups of drugs are used to treat sleep disorders. Melatonin and bright light will be discussed elsewhere in this volume. This review will focus on those classes of sedatives/ hypnotics for which information on their effects on the sleep– wake cycle is available and which are widely prescribed (see Table 2). Only limited data have been published concerning the chronopharmacology of these compounds, i.e. referring to circadian time-dependent effects and pharmacokinetics [8,9].

ride channel receptor complex. Whereas classical benzodiazepines such as diazepam or flunitrazepam are bound to all subtypes of specific benzodiazepine receptor sites (BZ1–BZ3) at this complex, the so-called “non-benzodiazepines”, such as the imidazopyridine derivative zolpidem, have predominant affinity to the benzodiazepine receptor subtype BZ1, which mainly mediates sedation (Table 1). Thus, the term “nonbenzodiazepines” are not correct but have been introduced in recent years. Barbiturates, which are no longer used as hypnotics nowadays, bind to a different binding site at the GABAA–benzodiazepine–chloride channel receptor complex; whether this binding site is a physiological receptor is still under debate. In recent years the prescription of non-benzodiazepines has increased world-wide. The number of prescriptions of benzodiazepines and “non-benzodiazepines” in Germany in the years 2000–2004 is given in Table 2. It clearly shows that the prescriptions of benzodiazepines decreased continuously, whereas the “non-benzodiazepines” increased slightly. This trend reflects the advantage of the “non-benzodiazepines” in more selectively binding to BZ1 receptors and having less sideeffects, as well as interfering less with the homeostatic process in the sleep–wake cycle, as hypnotics, as will be discussed below.

2. Sedatives/hypnotics 3. Rhythm in benzodiazepine receptor binding Gamma-aminobutyric acid (GABA) and exogenous benzodiazepines are thought to play a role in the neuronal regulation of circadian rhythms, including the sleep–wake cycle. Different sedatives/hypnotics act on the GABAA/benzodiazepine/chloTable 1 Benzodiazepine receptor subtypes in rats and inhibitor constants (Ki, nmol/l) of the benzodiazepine flunitrazepam and the non-benzodiazepine zolpidem [12]

Localisation Flunitrazepam Zolpidem Functions

Omega-1 (BZ1) Omega-2 (BZ2)

Omega-3 (BZ3)

Brain 2.5 26.0 Sedation

Peripheral organs, brain 2.3 1036 Anxiolytic activity

Brain, spinal cord 1.4 180.0 Muscle relaxation

Benzodiazepine receptors are functionally coupled to GABAA receptors as part of the GABAA–benzodiazepine– chloride channel receptor complex and mediate the behavioral Table 2 Prescription of sedative/hypnotics as DDD (divided daily dose) in Germany from 1996–2005 [19] Sedatives/hypnotics

Benzodiazepines “Non-benzodiazepines” zolpidem, zopiclone, zalepone

Million DDD 1996

2002

2005

206 67

92 69

66 77

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Table 3 Effects of benzodiazepines or non-benzodiazepines (imidazopyridines) on sleep and hormonal functions in man Subjects

Parameter

Drugs/dose/duration

[DT] Dosing time

Reference

[E] Effects Sleep disturbance, EEG, wrist motor activity case report, hypernychthermeral Healthy, n = 12 EEG, EOG, PSG, multiple sleep latency test

Healthy, n = 48, 12 h shift of sleep–wake cycle

PSG, EEG, EOG, EMG

Flurazepam 15 mg Vitamin B12 for weeks Placebo, double-blind Triazolam 0.5 mg Flurazepam 30 mg

Placebo, double-blind Triazolam 0.25, 0.5 mg Flurazepam 15, 30 mg

DT: not given E: under flurazepam and vitamin B12 advanced sleep period and normal sleep–wake cycle DT: before bedtime 00:00–08:00 h, before phase shifted bedtime 12:00–20:00 h E: sign. sleep loss under placebo after shift, active medication reversed sleep loss, flurazepam most and triazolam least impaired waking function DT: 30 min before bedtime under control and after 12 h sleep–wake shift

PSG, cortisol, melatonin, growth hormone, prolactin

Baseline data, triazolam 0.5 mg for 3 days

Healthy, men, n = 12

Performance assessment battery

Placebo Triazolam 0.25 mg

Healthy, young, n=8

PSG

Healthy, n = 15, simulated night shift

Multiple latency test, wrist actography

Healthy, female, n = 28

Psychomotor performance, sleep

Placebo Flunitrazepam 2 mg Triazolam 0.5 mg Flurazepam 30 mg Double-blind cross- DT: night shift start 22:30 h, drug 5 min prior over bedtime (07:00–09:00 h) Placebo Triazolam 0.25 mg E: triazolam lengthened daytime sleep and improved nighttime alertness, but subjects did not perceive improved alertness at night Double-blind, DT: 1.5 h before bedtime placebo-controlled cross-over Placebo Alprazolam 1 / 3 mg Bromazepam 3 / 6 mg Clobazepam 10 / 20 mg Oxazepam 30 / 50 mg Lorazepam 1 / 2 mg E: all were effective hypnotics; hang-over (impairing psychological functions) at day after drug ingestion of alprazolam, oxazepam, lorazepam, but no sign. similar side-effects of clobazepam and bromazepam Triazolam, DT: 4–5 h before sleep onset previous night 0.25–0.50 mg Vitamin B12, 3 mg E: under triazolam sleep phase advance 2–3 h/day; vitamin B12 had no effect Placebo DT: after 3 h advance triazolam dosing time at bedtime Triazolam 0.5 mg/3 E: no marked changes in sleep pattern by triazolam, nights sleep onset advanced by 3 h; body temperature sign. advanced by triazolam Placebo, doubleDT: 23–24:00 h blind, cross-over Zolpidem 10 mg/1 w E: zolpidem caused no psychometric dysfunction, sleep flunitrazepam architecture remained unaffected, flunitrazem caused 2 mg/1 w sign. memory impairment

Healthy, n = 12, sleep advance

PSG, rectal temperature

Chronic sleep disturbance, n = 17 women

PSG, verbal learning, sleep quality, daytime sleepiness and activation

[21]

[22]

E: placebo sign. sleep loss and daytime sleepiness, 0.25 mg triazolam not better than placebo, flurazepam mitigated insomnia, carry-over effect: more sleepy than placebo DT: sleep from 23:00–07:00 h, bedtime dosing 22.30 h E: triazolam induced a transient hyperprolactinemia, did not abolish hormone secretion nor timing of endocrine events by circadian clock DT: 20:30 and 08:30 h, diurnally active (07:00–23:00 h) E: triazolam had a more severe detrimental effect on cognitive performance when timed at 20:30 h (p b 0.05) DT: single bedtime dose E: benzos depress slow EEG waves without disrupting homeostatic and ultradian processes of sleep regulation.

Healthy, men, n=6

Patients, delayed sleep PSG phase syndrome (DSPS), n = 5

[20]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

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Table 3 (continued) Subjects

Parameter

Drugs/dose/duration

Healthy, female, n=8

PSG, growth hormone (GH), Placebo thyreotropin (TSH), prolactin, Zolpidem 10 mg melatonin

Healthy, n = 33 westward flight with 5 h delay

Rectal temperature, jet-lag score

Placebo, double-blind Zopiclone 7.5 mg

Healthy, n = 6 simulated 8 h westward travel

PSG, sleep recordings, plasma cortisol, growth hormone

Triazolam 0.5 mg

Healthy, n = 9

PSG, polysomnography, sleep latency

Healthy, young, n = 10

PSG

Placebo Zolpidem 10 mg/3 n Zopiclone 7.5 mg/3 n Placebo, cross-over design Zolpidem 10 mg Triazolam 0.25 mg

[DT] Dosing time

Reference

[E] Effects

Healthy, n = 40

Healthy, n = 8

Primary insomnic patients, placebo, n = 111, drug n = 360 Healthy, n = 33

Insomniac women, n = 18 Healthy, male/ female, n = 7 Simulated shiftwork

Psychomotor, cognitive functions, critical flicker fusion, choice reaction time, memory tests

Strenuous exercise, growth hormone, cortisol, prolactin

Interactive voice responses system: sleep latency, total sleep time, number of awakenings, sleep quality, daytime alertness Actigraphy

Driving performance, psychomotor skill, PSG, in real life conditions Psychomotor tasks, visual analog questionnaire, drug effect questionnaire, food consumption

Randomized, placebo-controlled, double-blind, cross-over Zaleplon 10/20 mg s.d. Zolpidem 10 mg s.d. Placebo, cross-over design Zolpidem 10 mg Nightly for 6 months: placebo Eszoplicone 3 mg (S-enantiomer of zopiclone) Placebo Zolpidem 10 mg Zopiclone 7.5 mg Flunitrazepam 1 mg Placebo Temazepam 20 mg Zolpidem 10 mg Placebo Zolpidem 5 or 10 mg

DT: 22.45 h E: increase in stage III and IV sleep, moderate hyperprolactinemia, no change in endocrine markers cortisol, melatonin, TSH, GH DT: 30 min before bedtime on day 1 and 2 before and days 1, 2, 5, 6 (Dx) after westward flight E: sleep less fragmented on D1, sleep curtailment D2, D3 under placebo prevented. Jet-lag scores did not differ between groups DT: 04:00 h (3 h before bedtime) 1st day, 07:00 h (at bedtime) 2–5 days post-shift E: triazolam sign. facilitated adaptation of circadian rhythmicity and sleep–wake cycle homeostasis DT: bedtime, 23:00 h E: %S1 sleep sign, decreased and %S2 increased by zopiclone, no effect with zolpidem SWS increased by both

[31]

[32]

[33]

[34]

DT: ad bedtime 23:00 h

[35]

E: 1st night slow wave sleep increased by zolpidem not triazolam, during withdrawal triazolam, not zolpidem, increased worsening of mood in morning, zolpidem did not affect sleep latency DT: middle of night

[36]

E: sign. detrimental residual effects by zolpidem but not zaleplon

DT: ad bedtime 23:00 h

[37]

E: 1st night slow wave sleep increased by zolpidem not triazolam, No effect on hormonal secretion during exercise DT: nightly

[38]

E: eszoplicone improved all components of insomnia as defined by DSM-IV, including patient ratings of daytime function DT: 22:30–23:30 h E: drugs sign. reduced motor activity, 1st and 2nd post-drug night zolpidem and zopiclone increased activity compared to placebo

[39]

DT: 02:00 h [40] E: 5.5 h after drug dosing absence of sign. residual effects both after temazepam and zolpidem. Certain patients more susceptible. DT: 1 h before bedtime on day shift and on night shift for 3 [41] consecutive days under 2 shift conditions. E: shift changes produced performance impairment, mood alterations, decrease in food intake. Zolpidem attenuates some shift-change disruptions.

DT = dosing time, E = effects, PSG = polysomnography, s.d. = single dose.

effects of exogenous benzodiazepines. Benzodiazepine receptor binding was also shown to be circadian phase-dependent: Kafka et al. [13] showed that 3H-diazepam binding to rat brain homogenates peaked at the transition between the activity and the rest phases. Evaluating the binding of 3H-flunitrazepam to membranes from various regions of rat brain showed prominent

daily rhythms in receptor number in the frontal lobe and the cerebellum, but not in temporo-parietal regions, the hypothalamus or medulla/pons. Binding was highest during late periods of sleep [14]. In rat cerebral cortex the peak in the number of binding sites as labeled by 3H-flunitrazepam was found at midnight in rats under a light:dark cycle of 12:12 h with lights

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Table 4 Effects of benzodiazepines or non-benzodiazepines (imidazopyridines) on sleep in rodents Subjects

Parameter

Drugs/dose/application

[S] Synchronisation

Reference

[DT] Dosing time [E] Effects Sprague–Dawley Sleeping time, hexobarbital oxidase rats, male, n = 6–10/group Wistar rats, female

Wistar rats, male, n = 72 n = 180

Sleeping time, hexibarbital oxidase by liver preparations Sleeping time, mortality Sleeping time, oxidation in liver in vitro

Rats

Mortality

Golden hamster, male

Wheel-running activity

Syrian hamster, male

Wheel-running behavior

Syrian hamster, male

Wheel-running activity

Syrian hamster, male

Wheel-running activity

Syrian hamster, male

Wheel-running activity

Syrian hamster, female

Luteinizing hormone (LH),wheel-running activity

Syrian hamster, male

Wheel-running activity

Wistar rats, male n = 18

EEG, EMG

Wistar rats, male, intact and SCN lesions Wistar rats, male, n = 10

Body temperature, EEG, EMG

Field mouse, male Mus booduga, n = 15

Running wheel

EEG, EMG after SCN lesion

Hexobarbital, 150 mg/kg S: D:L = 12:12 h, lights on 06:00 h i.p. DT: every 4 h E: peak in sleeping time at 02:00 h, peak in hexobarbital oxidase activity at 10:00 h Hexobarbital, 40 mg/kg S: L:D = 12:12, lights on 07:00 h i.p. DT: 02:00, 08:00, 14:00, 20:00 h E: no rhythm in sedation, peak in hexobarbital oxidation at early morning (08:00 h) Phenobarbital, 190 mg/kg S: L:D = 07:00–19:00, 19:00–07:00 i.p. DT: every 3 h Hexobarbital, 150 mg/kg E: phenobarbital: highest mortality and longest sleeping time at 14:00 h, lowest at mid-activity; hexobarbital: peak oxidation at end of dark phase ith sleeping time at its minimum Phenobarbital 190 mg/kg S: L:D = 12:12 h, lights on 06:18:00 h i.p. DT: every 3 h E: mortality highest at late rest phase Diazepam 2.5–12.5 mg/ S: DD, light pulse (LP) at CT13.5 or CT18 kg DT: 30 min prior LP E: diazepam blocked phase advance by LP, phase delays were unaffected Vehicle triazolam 2.5 mg S: L:D = 14:10 h DT: 0, 3, 6, 9, 12, 15, 18, 21 h after activity onset E: phase shift in circadian rhythm in locomotor activity Vehicle triazolam S: DD 0.05–5.0 mg i.p. DT: 6 h before onset of activity E: dose-dependent phase advance in rhythm Vehicle triazolam 2.5 mg S: L:D = 14:10 abrupt shift of LD cycle by 8 h DT: 6–7 h before expected onset of activity after shift E: 50% reduction in time of resynchronisation by triazolam Vehicle S: L:D = 14:10 h, then LL triazolam 0.5 mg DT: in LL flumazenil 15 min before triazolam CT6, 12, 21 RO 15–1788 (flumazenil) E: flumazenil blocked phase advancing and phase delaying benzodiazepine receptor effects of triazolam antagonist 0.1–5.0 mg Triazolam 2.5 mg S: DD (activity) or LL (LH) DT: 3–6 h before and 6–9 h after onset of activity E: triazolam facilitates reentrainment of activity of 8 h advance; phase advance rhythm in LH of females by 2–3 h in LL Vehicle S: LD, 8 h advanced, access to wheel and nest boxes or confined to nest Triazolam 1.5, 2.5 mg i.p. DT: 1 h after advanced to advanced dark onset E: triazolam failed to enhance rate of reentrainment, phase-shifting effect mediated through increase in activity, hamsters became atactic Vehicle S: L:D = 12:12 h, DD for 10 days Triazolam 0.4 mg/kg DT: CT18 (6 h after lights off E: rats in LD had a stronger hypnotic response than rats in DD Triazolam 0.2–1.6 mg/kg S: DD DT: CT18 E: in SCNx no increased sleep after triazolam, in intact rats triazolam in middle of activity increased sleep Vehicle, cross-over S: constant dim red light, sleep deprivation 09:00–15.00 h Triazolam, 0.4 mg/kg DT: 14:55–15:00 h injection of vehicle/triazolam After SCNx and 6 h E: major sleep regulation present in SCNx rats, triazolam induced sleep, deprivation triazolam induced sleep dependent upon accumulated sleep debt Diazepam (1 mg/ml) as S: DD 2 h pulses DT: at 12 CT points E: diazepam advanced activity at CT2, phase delays at all other time points.

[47]

[50]

[48]

[49]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

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Table 4 (continued) Subjects

Parameter

Drugs/dose/application

[S] Synchronisation

Reference

[DT] Dosing time [E] Effects Wistar rats, male, n = 6

PSG

Diazepam 3/6 mg/kg Zolpidem 1–10 mg/kg

S: LD: 08:20:00 h, [62] DT: 09:30 h and 22:00 h E: Diazepam and zolpidem induced hypothermia, only diazepam disrupted sleep architecture Midazolam, 2 mg/kg plus S: L:D = 12:12, lights on 07:00 h [63] Sprague–Dawley Duration of latency, rats, female, loss of righting reflex ketamine, 40 mg/kg DT: 11:00, 15:00, 19:00, 23:00, 03:00, h n = 7/group (LRR), post-LLR ataxia E: LRR, post-LRR and total pharmacological response with maximum in the rest phase at 11:00 h Wistar rats, Radiotelemetry: motor Diazepam 3 mg/kg/day S: L:D = 12:12 h [64] male, n = 5 activity, body temperature for 3 weeks DT: 1 h subcutaneously before lights off E: increase in motility by diazepam from first day until end of treatment, no effect on period and phase, amplitude increased in 3rd week; rhythm in body temperature not affected

PSG = polysomnography, S = synchronising schedule, DT = dosing time, E = effects.

on from 07:00–19:00 h [15]. Pinealectomy blunted the nocturnal peak and caused a significant depression of binding sites at noon [15]. Also, in human platelets of 7 healthy subjects (diurnal activity from 07:30–23:00 h) a circadian rhythm in benzodiazepine binding sites was described with peak values at the middle of the night and a peak-trough difference of about 20% of the 24-h mean; affinity (kd-value) was unaffected [16]. Thus, both in humans and rats peak values in benzodiazepine binding sites were found predominantly during the activity period. Semiquantitative analysis of autoradiograms for 3H-diazepam and 3H-flunitrazepam revealed a moderate level of binding to the nucleus suprachiasmaticus (SCN), a low level of binding in the intergeniculate leaflet (IGL), and the highest level in the dorsal raphe nucleus, nuclei involved in the circadian timing systems [17]. Unfortunately, no circadian time-dependency in binding was examined in this study. Thus, in this review the effects of these drugs on circadian rhythms, the sleep–wake cycle and shifts of the light–dark cycle, e.g. in simulated and real transmeridian flights, are discussed. 4. Effects of sedatives/hypnotics on the sleep–wake cycle in man Ideally, a hypnotic drug should reduce the latency to sleep onset, enhance those aspects of sleep which are related to recuperative processes and leave unaffected other sleep functions which are already optimal even in insomniac patients [18]. Though the benzodiazepines are superior in this respect to barbiturates, further progress has been achieved some years ago with the so-called non-benzodiazepines, which are also antagonists at BZ receptors. Data on the effects of various benzodiazepine and nonbenzodiazepine derivatives on the sleep–wake cycle in humans are compiled in Table 3. The findings in healthy subjects as well as in patients suffering from sleep disorders demonstrate that though benzodiazepines and non-benzodiazepines promote sleep, benzodiazepines have a more pronounced effect in dis-

rupting homeostatic and sleep-promoting regulatory mechanisms (Table 3). This difference is of clinical relevance since benzodiazepines are known to have hang-over effects the next morning (daytime sleepiness and impaired cognitive functions), can lead to a low-dose dependency and can induce withdrawal effects on chronic application [42]. These data clearly demonstrate that benzodiazepine receptor antagonists should not be used to combat any problems in nocturnal shiftwork. Diazepam was studied in humans in their circadian timedependency in the pharmacokinetics [43] as well in their circadian effects [44]. These studies showed that morning dosing (5 mg) resulted in higher peak drug concentrations than evening dosing under postprandial conditions [43]. Sedative effects were also more pronounced after morning dosing than dosing in the evening [44], demonstrating implications for daytime psychological functions. In contrast, Gillooly et al. [24] reported evidence for a more severe detrimental effect of 0.25 mg triazolam on cognitive performance when dosed at 20:30 than at 08:30 h. Side-effects and toxicity of benzodiazepines – though differences are observed within this group of drugs (see Table 3) – are much less than those of barbiturates, and, therefore, benzodiazepines replaced the barbiturates as sleeping pills some years ago. Further progress to a better tolerability was achieved by the non-benzodiazepines such as zopiclone which predominantly act on BZ1 receptors (see above). The results of studies on sleep–wake cycle and sleep architecture compiled in Table 3 give further evidence that non-benzodiazepines have minimal impact upon sleep architecture and the homeostatic processes of sleep regulation. They sometimes even increased activity on days after drug dosing. Zolpidem also seems not to change the circadian rhythm in hormones such as cortisol, melatonin, growth hormone, thyreotropine and prolactin (Table 3) even though the plasma concentration of these hormones has been obtained before, during and after strenuous physical exercise [37]. In simulated westward travel, triazolam facilitated adaptation of circadian rhythmicity and of the sleep–wake cycle [33]. After a westward flight across 5 time zones the non-benzodiazepine

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zopiclone caused less fragmented sleep on the first day after flight and the sleep curtailment observed under placebo was prevented [32]. However, zopiclone caused lowered jet-lag scores. The beneficial effects of benzodiazepines are not universally reported when traveling across 5 time zones. For example, temazepam had no effect on jet-lag, time to adjustment, or range of performance measures compared to placebo in a group of British athletes [45]. 5. Effects of sedatives/hypnotics on the sleep–wake cycle in rodents Whereas barbiturates are no longer used as sedative/hypnotic drugs in humans, these compounds were studied in rodents for their circadian-dependent effects on sleep duration, mortality and metabolism by the liver. It is interesting to note that as early as 1836, Kreutzer mentioned in his book Handbuch der allgemeinen thierärztlichen Arzneiverordnungs-Lehre that the time of day can have an influence on the dosage and the effect of drugs (Selbst die Tageszeit scheint nicht ohne Einfluβ auf die Wirkung und Gabe von Arzneien zu seyn) [46]. Nair and Casper [47] had shown in rats that the duration of sleep by injection of hexobarbital at different times of day (lights on from 06:00 to 18:00 h) displayed a circadian phasedependency with peak duration during the rest span. At the same time hexobarbital oxidation in liver homogenates was at its lowest value, nicely explaining the rhythm in effectiveness by circadian variations in drug metabolism [47]. Further support was presented by Müller [48], who confirmed that, in rats, the duration of sleep induced by the barbiturate phenobarbitone (190 mg/kg i.p.) was dependent on the time of drug application. The longest sleeping time on injection of a high dose of phenobarbitone (of rats which survived) was found at 14:00 h coinciding with the highest phenobarbitone-induced mortality [48]. Maximum hepatic drug oxidation of phenobarbital in vitro occurred at the end of the dark phase [48], indicating the importance of metabolism for drug mortality. These findings on phenobarbitone mortality in rats were again confirmed by von Mayersbach [49]. He showed that all rats died when phenobarbitone (190 mg/kg) was injected in the middle of the resting phase, whereas none of the rats died after injection around midnight. Also, the half-maximum lethal dose (LD50) of diazepam in mice was circadian phase-dependent, with the highest toxicity (lowest LD50) in the early rest phase [65]. Furthermore, the dose-dependent sedation by chlorpromazine in rats was most pronounced when the drug was injected at the onset of the rest phase [66]. These animal experiments clearly demonstrate that central sedative drugs have a more pronounced effect when given in the rest period, at a time where physical activity is also at its lowest (see [8]). Arousal in the activity phase is obviously able to counteract the sedative effects of these drugs. The effects of the benzodiazepines, diazepam and triazolam were mainly studied on wheel-running activity in Syrian hamsters kept under a light–dark cycle (LD), during free-run in total darkness (DD), and after a phase shift of the light–dark cycle. The research group of Turek (see Table 4) first

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demonstrated a phase-shifting effect of triazolam which was prevented by application of the benzodiazepine receptor antagonist flumazenil. Based on their findings they postulated that benzodiazepines may be helpful in reducing jet-lag symptoms. Similarly, Subramanian and Subbaraj [61] showed a phase advance by application of diazepam at CT2 in the field mouse. However, Mrosovsky and Salmon [57] showed that triazolam induced ataxia in hamsters, which led to an apparent increase in activity; thus activity as a non-photic Zeitgeber was responsible for the phase-shifting effect. Recently, there is further proof that benzodiazepines can also increase activity in rats as determined by radio telemetry: Chronic administration of diazepam (3 mg/kg) to Wistar rats for 3 weeks 1 h before the onset of darkness (L:D = 12:12 h) increased motor activity from the first day until the end of the treatment, but exerted no effects on length of period nor on phase of locomotor activity [64]. The rhythm in body temperature was not affected by diazepam. A drug combination to achieve anaesthesia in rats, the benzodiazepine midazolam and ketamine, revealed significant treatment–time differences when injected at five different times of day [63]. The loss of righting reflex (LRR), post-LRR ataxia and total pharmacological response occurred when the drugs were injected in the rest phase. In rats, triazolam was studied by investigating the EEG, EMG and body temperature (Table 4). In DD, rats showed a more pronounced hypnotic effect than in LD, and increased sleep after triazolam was prevented by SCN lesions (SCNx) [59,60] However, sleep regulation was still observed in SCNx rats [60]. In comparison to diazepam, the non-benzodiazepine zolpidem disrupted the sleep architecture of rats less [62]. This is an interesting experimental observation, since in humans there is sound evidence that so-called non-benzodiazepines, in general, induce less disturbances in the sleep architecture than do the benzodiazepines (see above, Table 3). Thus, with regard to the sleep–wake circadian rhythm in humans, animal experiments confirm that non-benzodiazepines are preferable to benzodiazepines as sleeping pills. 6. Conclusion Sleep disorders can be regarded as a misalignment between the regulatory mechanisms of the circadian clock and external environmental, social and/behavioral factors. Sleeping pills can be used to reduce insomnia or excessive daytime sleepiness after a bad night. They can help to coordinate the demands of the circadian clock on sleep architecture and sleeping deficiencies. At present, there is no drug which can mimic or induce a more “physiological” sleep. Drugs discussed in this review induce a “pharmacological” sleep. Whereas the barbiturates are no longer used due to their small therapeutic range, their toxicity and side-effects, benzodiazepines and, moreover, the so-called non-benzodiazepines, are the drugs of choice. Since both the latter drugs act via benzodiazepine receptors they can have acute side-effects (dose-dependant anterograde amnesia), can induce low-dose dependency and withdrawal symptoms after chronic misuse [67,68]. The non-benzodiazepines when

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