Effects of a new butyrophenone derivate (Buronil®) on nocturnal sleep in normal man

Nocturnal sleep was studied in eight young normal volunteers (3 female and 5 male students) with polygraphic technique during 2 periods of 10 nights each. After 2 adaptation and 2 baseline nights with placebo, they were given methylperone (Buronil®) 10 or 50 mg per night during three nights and then again placebo for three withdrawal nights. The study was made double blind. The scoring of the records was done according to the manual by Rechtschaffen and Kales (1968). No changes of sleep stages were seen during the drug periods. The lower dose gave an increase of sleep latency but a decrease of number of awakenings during the night. An increase of REM-periods was shown after 50 mg and also a decrease of REM-latency and REM-density. The only significant change during withdrawal periods was a decrease of REM-sleep after methylperone 50 mg, so there was no barbiturate type of withdrawal. The change was also different from that of chlorpromazine, which has no clear rebound effect.     

Can an inert sleeping pill affect sleep? Effects on polysomnographic,behavioral and subjective measures

RATIONALE: Since two recent meta-analyses on sleep changes associated with placebo in clinical trials suggested a beneficial effect of placebo treatments, pointing to a dissociation between subjective and objective measures of sleep, the current experiment was directly aimed to assess the effects of an inert compound, administered with the suggestion that it was a hypnotic substance in subjects with mild sleep complaints. OBJECTIVES: The aim of this study was to compare subjective, behavioral, polysomnographic (PSG), and quantitative electroencephalographic (EEG) changes during a night preceded or not by the intake of two 50-mg lactose capsules. METHODS: Ten female students, selected by the Pittsburgh Sleep Quality Index, slept for three consecutive nights in a sleep laboratory, with the experimental (EXP) night defined by the administration of two 50-mg lactose pills. Self-ratings of sleep quality and performance were assessed upon morning awakening of baseline (BSL) and EXP nights. RESULTS: The EXP nights were self-rated as more restful and characterized by a decreased number of nocturnal awakenings than the BSL nights. PSG measures showed that wakefulness after sleep onset significantly decreased during the EXP night as compared to the BSL night. The EXP nights also showed an increase of 0.5-4.0 Hz power during nonrapid eye movement sleep and a decrease of EEG activity in the beta frequency range during rapid eye movement sleep only at central brain sites. A specific improvement of behavioral measures was also found upon morning awakening after the EXP night compared to the BSL night. CONCLUSIONS: The administration of an inert pill improves both the subjective and objective quality of sleep. The reduced sleep fragmentation and the effects on some quantitative EEG markers of sleep homeostasis suggest that the experimental manipulation induced coherent changes in the subsequent sleep, resembling an enhancement of sleep pressure. The regional differences of EEG activity suggest the involvement of a specific physiological mechanism distinct from that of effective treatments.     

Differential effects of the new central adrenergic agonist modafinil and d-amphetamine on sleep and early morning behaviour in elderlies

Modafinil (CRL 40476) is a new central alpha-adrenergic agonist with vigilance-promoting properties. In a double-blind, placebo-controlled sleep laboratory study its single-dose effects on sleep and early morning behaviour were investigated and compared with d-amphetamine. Ten elderly healthy volunteers (mean age: 68 years) spent 12 nights in the sleep laboratory: one adaptation night, one baseline night, five drug nights (100 mg and 200 mg modafinil; 10 mg and 20 mg d-amphetamine; placebo) and five subsequent washout nights. The drugs were administered orally in one week intervals at 10:00 p.m., and all-night somnopolygraphic investigations were performed between 10:30 p.m. and 6:00 a.m. A self-rating scale for sleep and awakening quality as well as psychometric tests were completed in the morning. d-amphetamine caused a dose-dependent impairment of sleep maintenance and sleep architecture, while modafinil did not. Thus, a significant reduction of total sleep time, REM-sleep and sleep stage 2 was seen after d-amphetamine when compared to placebo and 100 mg modafinil. Corresponding with these objective results, subjective sleep quality deteriorated significantly only after 20 mg d-amphetamine as compared to placebo. Morning investigations revealed an increase of CFF after 20 mg d-amphetamine. Pulse rate, evening and morning blood pressure remained unchanged. These findings suggest a different mode of action of the two compounds.     

The effect of chronically administered delta-9-tetrahydrocannabinol upon the polygraphically monitored sleep of normal volunteers

This study describes the effect of two weeks of delta-9-tetrahydrocannabinol (THC) administration upon normal sleep. The two subjects, two brothers in their 20s, slept in the laboratory for 27 consecutive nights and then, after four nights at home, for four additional nights. One subject, after an adaption night, received placebo for four baseline nights, 30 mg of THC for the next 14 nights, and placebo during four withdrawal nights. The other subject received placebo during this entire period. One year later the subjects alternated these conditions.

The subjects had difficulty falling and staying asleep during the first two nights of placebo after 14 consecutive drug nights. This mild drug withdrawal insomnia was not accompanied by the increase of REM sleep which frequently accompanies withdrawal of other drugs.

Starting after about a week of THC administration, and continuing for a week after drug discontinuance, there was a marked decrease in the type of sleep associated with slow waves in the electroencephalogram, nonREM sleep stages 3 and 4. The fact that prolonged, but not acute use, suppresses slow wave sleep indicates that this commonly used drug produces a poorly understood change in brain physiology.     

A psychophysiological investigation of the long-term effects of clozapine upon sleep patterns of normal young adults

A 25-night single-blind cross over design was employed to determine the long-term effects of clozapine on the sleep patterns of six normal young adults. Subjects received 12.50 mg placebo on the first and last five nights, whereas on the intermediate 15 nights 12.5 mg clozapine was administered. The subjects slept in the laboratory on the third and fourth nights to obtain baseline recordings, and on the eight, twelfth, sixteenth, and twentieth nights to determine the effects of clozapine on sleep variables. Recordings on nights 21 and 25 were used to assess withdrawal effects. Percentage stage 1 sleep and indices of body movements during sleep were significantly reduced, suggesting that clozapine may have sleep-inducing properties. There was no significant rebound of stage REM sleep during drug withdrawal despite a small but significant reduction in stage REM during drug administration. Numerous side effects, indicative of sleepiness, were reported on the mornings following drug administration, and there was evidence of a rapid tolerance to clozapine. These findings may limit the efficacy of clozapine as an hypnotic agent over an extended period of time. Further research on insomniac subjects is therefore indicated.     

L-Tryptophan administered to chronic sleep-onset insomniacs: Late-appearing reduction of sleep latency

The effects of 3 g l-tryptophan on sleep, performance, arousal threshold, and brain electrical activity during sleep were assessed in 20 male, chronic sleep-onset insomniacs (mean age 20.3±2.4 years). Following a sleep laboratory screening night, all subjects received placebo for 3 consecutive nights (single-blind), ten subjects received l-tryptophan, and ten received placebo for 6 nights (double-blind). All subjects received placebo on 2 withdrawal nights (single-blind). There was no effect of l-tryptophan on sleep latency during the first 3 nights of administration. On nights 4–6 of administration, sleep latency was significantly reduced. Unlike benzodiazepine hypnotics, l-tryptophan did not alter sleep stages, impair performance, elevate arousal threshold, or alter brain electrical activity during sleep.     

Rebound insomnia in normals and patients with insomnia after abrupt and tapered discontinuation

Rebound insomnia was studied in subjects, aged 25–50 years, with insomnia complaints and normal sleep, insomnia complaints and disturbed sleep, and normal sleep with no complaints (N=21,n=7 per group). Standard sleep recordings were collected on a baseline night and after abrupt discontinuation of 6 nights of 0.50 mg triazolam, tapered discontinuation (3 nights of 0.50 mg, 2 nights of 0.25 mg, and 1 night of 0.125 mg triazolam) and 6 nights of placebo. Significantly disturbed sleep on the discontinuation night compared to the baseline night was found. The relative degree of rebound insomnia was greater in the abrupt condition than in either the tapered or placebo conditions. The tapered condition reduced sleep time by half that of the abrupt condition which was twice the reduction found in the placebo condition. An overall (regardless of group or condition) difference in baseline versus discontinuation sleep was found, suggesting that pill discontinuation itself leads to sleep disturbance. Subjects did not differ in rebound insomnia as a function of pre-existing sleep disturbance.     

Dose determinants of rebound insomnia.

A polysomnographic assessment in healthy normal sleepers of possible dose relations for rebound insomnia was conducted. As an additional measure of rebound the study included a direct test of sleep/wake tendency during the night of drug discontinuation. Twelve, healthy men (21-30 years) each received placebo, 0.25 mg and 0.50 mg triazolam for 6 consecutive nights followed by a discontinuation night and 14 nights of recovery at home. The three conditions were presented, double-blind, in a latin square design. On night 6 of drug administration both doses increased total sleep time compared to placebo, but 0.50 mg did not improve sleep beyond 0.25 mg. On drug discontinuation (night 7) wake time over the 8 h recording and sleep latency after an experimental awakening (02.30 h) were increased with 0.50 mg compared to placebo and 0.25 mg. On these measures of rebound 0.25 mg did not differ from placebo. Thus rebound insomnia occurred only at a dose (0.50 mg) which produced no additional hypnotic efficacy in these normal sleepers. Whether tests of sleep/wake tendency make a useful measure of rebound insomnia needs further clarification.     

Effects of single and multiple doses of dexnafenodone,imipramine and placebo on sleep of young healthy volunteers

The effects on polygraphically recorded sleep of single and repeated doses of dexnafenodone (20 mg daily) were determined in 12 young, healthy subjects, and compared to those of imipramine (75 mg daily: six subjects) and placebo (six subjects). After two adaptation nights, sleep was recorded at baseline (night 0), and after the first (night 1) and last (night 5) evening administration of the study drugs. REM sleep was substantially inhibited in both nights under the two active treatments, whereby the effect appeared immediately. With the exception of slow wave sleep (SWS), which was more reduced in night 1 under imipramine than under dexnafenodone, the other sleep stages were essentially unchanged. Time awake during bed rest increased under both active treatments, with a more rapid increase under dexnafenodone. Dexnafenodone, a potent inhibitor of noradrenaline, and to a lesser degree of serotonin reuptake, induced changes in the pattern of sleep which are comparable to those of non-sedating tricyclic antidepressants. The mode of action as well as the pharmacodynamic profile of dexnafenodone led to the expectation that this new substance will show antidepressive activity on a clinical level.     

Human sleep during chronic morphine intoxication

The sleep of 6 opiate addicts was studied for 11 nights during 3 phases of a chronic morphine cycle. The control phase consisted of 5 consecutive nights before morphine administration. The induction phase consisted of 1 night at 21–36 days after the onset of morphine administration, when the daily dose was 140–220 mg. The stable dose phase consisted of 5 consecutive nights after the subjects had received 240 mg of morphine daily for 8–19 weeks. No sleep could be studied during the withdrawal phase. Sleep was continuously monitored with EEG, EMG and EOG.Chronic morphine produces signs of a small but persistent sleep disturbance: delta sleep (early night) becomes less stable and shifts toward later in the night, waking state increases during the middle of the night, REM sleep (especially its activated EEG without eye movements) decreases, the REMS cycle increases, and bursts of delta activity (with mean duration of 5–6 sec) increase. Although this disturbance persists throughout the night, it is much less than that seen after single doses of morphine in a previous study. With chronic morphine, therefore, partial tolerance develops to the sleep disturbance produced by morphine. The small but persistent nocturnal arousal during chronic morphine contrasts with the sedation seen during chronic methadone. Both opioids produce an increase in delta bursts during chronic administration, which might be an EEG phenomenon specific to chronic opioid intake.A summary of these data was presented at the 54th annual meeting of the Federation of American Societies of Experimental Biology, Atlantic City, New Jersey, April 12–17, 1970. An abstract is included in Fed. Proc. 21, 384 (1970). These data were also summarized at the 10th annual meeting of the Association for the Psychophysiological Study of Sleep, Santa Fe, New Mexico, March 25–28, 1970. An abstract is included in Psychophysiology 7, 346 (1971).     

Biperiden administration in normal sleep and after rapid eye movement sleep deprivation in healthy volunteers

Twenty-six healthy volunteers were randomly assigned to one of four groups. Groups Bip-4 and Bip-6, each with six subjects, received 4 and 6 mg of biperiden, respectively, and were studied on acclimatization, baseline, biperiden, and follow-up nights. Group REM-P (n = 7) and Group REM-Bip (n = 7) were studied on acclimatization, baseline, six nights of REM sleep deprivation, and one recovery (treatment) night with either placebo (group REM-P) or biperiden (group REM-Bip), and one follow-up night. Biperiden 4 and 6 mg increased REM sleep latency and biperiden 6 mg reduced REM sleep time. On the recovery night following REM sleep deprivation Group REM-P and REM-Bip showed an increase in sleep continuity. REM sleep time in the REM-P group was increased during the recovery (treatment) night (REM sleep recovery), while the REM-Bip group did not show a significant REM sleep increase during recovery (treatment) night. It was not until the follow-up night that REM sleep increased in the REM-Bip group.     

Flunitrazepam (Ro 5-4200) and sleep cycle in normal subjects

The action of flunitrazepam (Ro 5-4200) a benzodiazepine derivative was assessed on the sleep cycle of normal volunteers by means of all-night recordings. Baseline placebo nights were compared with the drug (2 mg p.o.) and with the placebo postdrug nights.Flunitrazepam induced a shift to faster frequencies of the EEG and increased non-rapid eye movement sleep. REM sleep was decreased at the expense of a smaller number of REM periods and shifted to the last two thirds of the night. During drug administration an adaptation was seen to the depressive action on REM sleep. Following withdrawal, an REM rebound was observed only during the first thirds of the night.This study was supported by a grant from Hoffmann-La Roche.     

Effects of triazolam (0.5 mg) on sleep,performance, memory,and arousal threshold

The effects of a short-acting benzodiazepine hypnotic, triazolam (0.5 mg), on sleep, performance, and arousal threshold were assessed in 20 male poor sleepers (age 21±2.37 years). Following a laboratory screening night, all subjects received placebo for 3 nights (single-blind), ten received triazolam and ten placebo for 6 nights (double-blind), and all received placebo on 2 withdrawal nights (single-blind). All effects described below were statistically significant. Triazolam reduced sleep latency and increased total sleep time and sleep efficiency. Percent Stage 2 was increased and percent Stage 4 was reduced during treatment. Morning performance, measured 8.25 h post-drug, showed no decrements. Acute effects were assessed on treatment night 6 during arousals from sleep at 1.5, 3, and 5 h post-administration: performance was impaired in triazolam subjects on the Wilkinson 4-Choice Reaction Time Test, Digit Symbol Substitution Test, Williams Word Memory Test, and Card Sorting Task. In the morning following treatment night 6, long-term memory was tested using a recognition task requiring subjects to identify words presented during night-time test batteries: triazolam subjects correctly identified fewer target words. Triazolam administration produced anterograde amnesic effects. However, in a Paired Associates Test learned prior to drug ingestion on the previous evening, triazolam did not impair morning recall of word pairs. Threshold for arousal from slow wave sleep was elevated during treatment, and triazolam subjects did not show increased sensitivity to the arousing tone over nights as did placebo subjects.     

Flunitrazepam (Ro 5-4200) and sleep cycle in insomniac patients

The action of flunitrazepam (Ro 5-4200), a benzodiazepine derivative, was assessed on the sleep cycle of insomniac patients by means of all-night reeordings. Baseline placebo nights were compared with the drug (2–8 mg p.o.) and with the placebo post-drug nights.Flunitrazepam induced a shift to faster frequencies of the EEG and a disappearance of sleep stages 3 and 4 while stage 2 was increased. In 10 out of 12 studied insomniacs the compound was effective in inducing and maintaining sleep (decrease in NREM sleep latency, wake time and number of wakes) throughout the drug administration period. Both NREM and REM sleep were increased, the latter most likely in relation to a blockade of processes precluding NREM emergence.The hypnotic action of flunitrazepam was still present during the first withdrawal night, pointing out to a carry over effect.Supported by a grant from Hoffman-La Roche.     

Midazolam: dose-response studies of effectiveness and rebound insomnia

Midazolam, an investigational hypnotic, was evaluated for effectiveness, side effects, and withdrawal phenomena in doses of 10, 20, and 30 mg in three separate sleep laboratory studies, each including 4 placebo-baseline nights, 7 drug nights, and 3 placebo-withdrawal nights. Only a slight to moderate degree of effectiveness was shown across the three doses; this effectiveness was much more pronounced during the first third of the night. There was no dose-response effect for effectiveness with either initial or continued drug administration. In general, there was less effectiveness on the last 3 drug nights, indicating a potential for the development of tolerance over a relatively short period of time. Following withdrawal there was a marked dose-related worsening of sleep above baseline levels (rebound insomnia).     

Serum concentrations of methaqualone after repeated oral doses of a combination formulation to human subjects

Summary Concentrations of methaqualone have been measured in the serum of five male human subjects receiving five consecutive evening doses of a combination formulation containing methaqualone (250 mg), carbromal (300 mg) and benactyzine (0.33 mg) in each tablet. After administration of the first dose, mean peak serum concentrations of methaqualone (1.2 µg/ml) occurred at 3 h. After obtaining peak levels, mean concentrations of methaqualone declined rapidly during the next 6 h and there-after more slowly during the next 18 h. After administration of the last (fifth) dose, mean peak serum concentrations of methaqualone (1.9 µg/ml; 1.5 µg/ml above the predose level) occurred at 2 h. After attaining peak levels, mean concentrations of methaqualone declined rapidly during the next 6 h, and thereafter more slowly, with a half-life of approximately 10 h. Mean concentrations of methaqualone in serum samples 24 h after the second, third, fourth or fifth doses were not significantly different (0.3 µg/ml – 0.6 µg/ml) during this period of dosing. This suggests that significant accumulation of methaqualone in the serum did not occur during a period of five consecutive evening doses of the combination formulation.     

Effects of Neurotropin on polysomnographic patterns in normal humans

The effects of Neurotropin, an analgesic drug, on polysomnographic patterns were investigated in 6 male healthy volunteers aged from 18 to 23 years (mean age 21.1 years). Polysomnographic recordings were made for 6 consecutive nights from each subject. An inert placebo, identical to the Neurotropin tablets, was given on the first 3 nights and on the sixth night. Forty-eight mg of Neurotropin (4 tablets containing 12 mg of Neurotropin each) was administered on the fourth and fifth nights. The drug and placebo were administered orally 30 min before starting the record of polysomnograms, i.e. around 22.00 h and continued until the natural awakening of the subjects the next morning. The polysomnographic record of the first night was discarded from the data, because of the first night effect. Neurotropin, given on the fourth night, significantly reduced total sleep time, stage 3 and percent of stage 3 as compared to those of the baseline placebo nights. Neurotropin given on the fifth night significantly decreased only total awakening time. These effects were not observed on the sixth placebo night (recovery night). As for the subjective assessments, no obvious changes were observed after administration of the drug. These results suggest that Neurotropin decreases total sleep time as well as stage 3 sleep. However, these effects are transient and unaccompanied by rebound phenomena. It is further suggested that Neurotropin seems to elevate slightly and transiently the arousal level.     

Rapid eye movement (REM) sleep increases by auditory stimulation reverted with biperiden administration in normal volunteers.

Auditory stimulation during REM sleep increases REM sleep time. The purpose of the present work was to determine if the selective muscarinic M-1 antagonist biperiden could modify the effect of the auditory stimulation on REM sleep. Twelve healthy volunteers were divided into placebo and biperiden groups. All the volunteers were studied under sleep laboratory conditions as follows: one acclimatization night, one baseline night, four nights with auditory stimulation either with placebo or biperiden, and two follow-up nights. Biperiden (4 mg) or placebo in identical capsules was administered 1 hour before beginning the sleep recordings. REM sleep time and REM density in the placebo group were increased relative to baseline by auditory stimulation. Biperiden blocked the REM time increase over the three treatment nights and suppressed the REM density increase over all four treatment nights. Biperiden also increased the latency compared to the placebo group. The present findings suggest that M-1 mechanisms are related to REM sleep regulation.     

Polygraphic sleep recordings in patients with endogenous depression before and after treatment with amitriptyline-N-oxide (author's transl)]

15 endogenous-depressive patients were treated with 3 X 20 mg amitriptyline-N-oxide for 20 days. Polygraphic sleep recordings were taken during the first seven and last six nights. In a single-blind study the patients were given placebo for the first four days, amitriptyline-N-oxide was applied during the following 13 days and on the last three days placebo was given again. The statistical evaluation showed the following results: a) Latency times up to the first deep sleep and to the first REM-phase decreased under the effect of the substance. b) Relative sleep duration (without wakefulness) increased. c) Actual sleep duration (without wakefulness and stage A) was similar. d) The frequency of awakenings during the night diminished under amitriptyline-N-oxide and increased somewhat when placebo was given again. The original values were not reached. The frequency of awakenings from REM-phases increased during the first three nights of medication and decreased in the last three nights the substance was administered. When placebo was given again, the original values were exceeded. e) Duration of wakefulness after waking up during the night decreased under amitriptyline-N-oxide and increased when the medication was discontinued. Here again the original values were not reached. After waking up during the night most waking time was spent in stage C. A placebo effect can be excluded. The effects of amitriptyline-N-oxide are compared to those of hypnotics, other antidepressants, antipsychotics and tranquilizers in the discussion.     

Treatment of benign essential hypertension

Summary Furosemide (Impugan^®) 12.5, 25 or 40 mg twice daily, has been compared as an antihypertensive with hydrochlorothiazide 12.5 mg twice daily and a placebo. A double blind, cross-over design was used with a run-in period of 4 weeks, preceding five 4-week periods of treatment with these compounds alone. There were 34 patients in the trial, 17 men and 17 women. Paired comparison showed that furosemide 25 or 40 mg twice daily and hydrochlorothiazide 12.5 mg twice daily had a similar hypotensive effect, irrespective of the initial blood pressure. Furosemide 40 mg twice daily and hydrochlorothiazide 12.5 mg twice daily caused a slight fall of blood pressure as compared with placebo (0.10>p>0.05, p<0.05). There was a distinct correlation between blood pressure and age. Serum K⁺ fell significantly during treatment, particularly with hydrochlorothiazide 12.5 mg twice daily, as well as with furosemide 25 or 40 mg twice daily. As compared with placebo, urinary output increased significantly after furosemide 12.5, 25 or 40 mg twice daily, but it rose only to a non-significant extent after hydrochlorothiazide. The fall of blood pressure and decrease in serum K⁺ were linearly related. There were only a few, mild side effects which did not necessitate discontinuation of the trial.