Flight crew sleep during multiple layover polar flights.

This study investigated changes in sleep after multiple transmeridian flights. The subjects were 12 B747 airline pilots operating on the following polar flight: Tokyo (TYO)-Anchorage (ANC)-London (LON)-Anchorage-Tokyo. Sleep polysomnograms were recorded on two baseline nights (B1, B2), during layovers, and, after returning to Tokyo, two recovery nights were recorded (R1, R2). In ANC (outbound), total sleep time (TST) was reduced and, sleep efficiency was low (72.0%). In London, time in bed (TIB) increased slightly, but sleep efficiency was still reduced. On return to ANC (inbound), there was considerable slow wave sleep (SWS) rebound and multiple awakenings reduced sleep efficiency to 76.8%. Sleep efficiency on R2 was significantly lower than on B1 (t-test, p < 0.05) but not different from R1. To sum up, sleep of aircrews flying multiple transmeridian flights is disrupted during layovers and this effect persists during the two recovery nights. As a result, there is a marked cumulative sleep loss during multi-legs polar route trip in comparison to single leg flights. These findings suggest that following such extensive transmeridian trips, crews should have at least three nights of recovery sleep in their home time zone before returning to duty.

Subjective and objective measures of sleepiness: effect of benzodiazepine and caffeine on their relationship.

As part of a larger project on the effects of benzodiazepine and caffeine on daytime sleepiness, performance and mood, this study examined the relationship among the Multiple Sleep Latency Test, lapses during a tapping task, a Visual Analog Scale, and the Stanford Sleepiness scale. Subjects were 80 male, adult nonsmokers aged 20.3 +/- 2.7 years. The Multiple Sleep Latency Test, Stanford Sleepiness Scale, and the Visual Analog Scale were obtained at two-hour intervals beginning at 0700 h and ending at 1700 h. The tapping task (lapses) was administered each day at 0600 h, 1000 h, and 1400 h. A lapse was a 3-s or greater pause between taps. Correlations between the Multiple Sleep Latency Test and subjective (Visual Analog Scale and the Stanford Sleepiness Scale) measures were significant at 0600 h, but became nonsignificant as the day progressed. Correlations between lapses and the two subjective measures were generally nonsignificant. The two objective measures were significantly correlated in the total group but not in all treatment groups. The subjective measures were significantly correlated in the total sample and in each treatment group. This study reaffirms the importance of time of day when measuring sleepiness, and suggests that subjective and objective measures may measure different aspects of sleepiness.

Daytime sleepiness, performance, mood, nocturnal sleep: the effect of benzodiazepine and caffeine on their relationship.

The present study was part of a larger 3-day, 2-night double-blind parallel group design in which 80 young adult men were divided into eight treatment groups to examine the effects of benzodiazepines and caffeine on nocturnal sleep and daytime sleepiness, performance, and mood. The present study was done to examine further the relationship among daytime sleepiness, performance, mood, and nocturnal sleep and to determine if and how these relationships were affected by the nighttime use of benzodiazepine and the ingestion of caffeine in the morning. Subjects received 15 or 30 mg of flurazepam, 0.25 or 0.50 mg of triazolam, or placebo at bedtime and 250 mg of caffeine or placebo in the morning for two treatment days. Two objective (Multiple Sleep Latency Test and lapses) and two subjective (Stanford Sleepiness Scale and Visual Analog Scale) measures of sleepiness, five performance tests, and two mood measures (Profile of Mood Scale and Visual Analog Scale) were administered repeatedly on both days. Electroencephalogram sleep was recorded on both nights. Objective sleep measures of daytime sleepiness were not significantly related to either performance or mood, but subjects with greater daytime sleepiness had significantly longer and more efficient nocturnal sleep. Neither benzodiazepine or caffeine influenced these relationships. In contrast, higher estimates of subjective sleepiness were significantly associated with poorer mood and tended to be related to poorer performance. Caffeine significantly reduced these relationships. Nocturnal sleep measures were not related to subjective estimates of daytime sleepiness.

Benzodiazepines and caffeine: effect on daytime sleepiness, performance, and mood.

In a double-blind parallel group design, 80 young adult males were divided into eight treatment groups. Subjects received 15 or 30 mg flurazepam, 0.25 or 0.50 mg triazolam, or placebo at bedtime, and 250 mg caffeine or placebo in the morning for 2 treatment days. Two objective (Multiple Sleep Latency Test and lapses) and two subjective (Stanford Sleepiness Scale and Visual Analog Scale) measures of sleepiness, five performance tests, and two mood measures (Profile of Mood Scale and Visual Analog Mood Scale) were administered repeatedly on both days. Significant treatment effects were found for sleepiness but not for performance or mood. Early morning caffeine significantly antagonized next day hypnotic-induced drowsiness and enhanced alertness in the subjects who received bed-time placebo. Flurazepam, 30 mg, subjects were more sleepy than all other groups. Although not significantly different, the flurazepam, 30 mg, group demonstrated a trend toward poorer performance and a more negative mood than all other groups. Caffeine most improved performance of this group. In all groups, sleepiness was greatest and performance and mood poorest in early morning trials and caffeine was most effective at this time.

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.

Dose level effects of triazolam on sleep and response to a smoke detector alarm.

Thirty-six young adult, male subjects with sleep-onset insomnia were equally divided into placebo, 0.25 mg, and 0.5 mg triazolam groups to examine the effects of the hypnotic, with particular attention to dose level on efficacy, sleep stages, and awakening to a smoke detector alarm. On nights 1 and 4 of a five-consecutive-night protocol, a standard home smoke detector alarm was sounded during stage 2, 5 min after sleep onset, in slow wave sleep (SWS), and at the time of the early morning awakening. The alarm registered 78 dB SPL at the pillow. EEG arousal latency and reaction time to a button press were studied. Failure to awaken to three 1-min alarm presentations was scored as "no response." Both dose levels produced similar reductions in sleep latency, decreases in SWS, increases in stage 2, and increases in sleep efficiency. Both dose levels showed similar sedative effects to the smoke alarm. Fifty percent of triazolam subjects failed to awaken on night 1 during SWS, and EEG arousal and response latencies were significantly slowed. Some drug tolerance or sensitization to the alarm was seen by night 4. By morning, all subjects were easily awakened on both nights. The 0.25 mg dose is clearly an effective dose level for both sleep efficacy and sedative effects to outside noise, which in some instances could pose potential problems.

Evaluation of L-tryptophan for treatment of insomnia: a review.

Sleep laboratory and outpatient studies of the hypnotic efficacy of the amino acid L-tryptophan are reviewed, with particular emphasis on evaluation of therapeutic effectiveness in the treatment of insomnia. In younger situational insomniacs, whose sleep problem consists solely of longer than usual sleep latencies, L-tryptophan is effective in reducing sleep onset time on the first night of administration in doses ranging from 1 to 15 g. In more chronic, well-established sleep-onset insomnia or in more severe insomnias characterized by both sleep onset and sleep maintenance problems, repeated administration of low doses of L-tryptophan over time may be required for therapeutic improvement. In these patients, hypnotic effects appear late in the treatment period or, as shown in some studies, even after discontinuation of treatment. The improvement in sleep measures post-treatment has given rise to use of a treatment regimen known as "interval therapy", in which L-tryptophan treatment alternates with an L-tryptophan-free interval until improvement occurs. The absence of side effects and lack of development of tolerance in long-term use are important factors in the decision to embark upon a trial of L-tryptophan treatment. In addition, L-tryptophan administration is not associated with impairment of visuomotor, cognitive, or memory performance, nor does it elevate threshold for arousal from sleep.

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.

Disqualified and qualified poor sleepers: subjective and objective variables.

Sleep laboratory studies of patients complaining of insomnia have demonstrated discrepancies between subjective reports and electroencephalograph (EEG)-recorded measures. In our research studies on sleeping aids, 60% of the self-described poor sleepers who reported usual sleep latencies of at least 45 min did not meet the laboratory qualification criterion of a 30-min or longer sleep latency. To learn to predict who would qualify for our studies, we compared 30 laboratory-qualified poor sleepers (QPS) with 30 laboratory-disqualified poor sleepers (DPSs) on subjective report, mood, and all-night sleep laboratory variables. QPSs had significantly lower sleep efficiency and total sleep time in the laboratory, but these differences were due to the longer sleep latencies (50.7 +/- 27.8 min vs. 15.2 +/- 6.1 min) of the QPS group. QPSs and DPSs differed significantly in their morning estimates of their laboratory sleep latencies; as a group, QPSs gave an accurate estimate (51.6 +/- 27.8 min), but DPSs were significantly more likely to exaggerate their sleep latencies. Although we did not identify ways of predicting which poor sleepers would show sleep-onset insomnia in the sleep laboratory, we did find that, in this young, healthy population, there are poor sleepers who give an accurate report of a rather severe sleep-onset insomnia.

Laboratory note: effect on sleep latency of presleep AEP procedures.

In a 12-night study of the effects of l-tryptophan in poor sleepers, waking auditory evoked potentials (AEPs) were obtained prior to lights-out on the 3rd placebo-baseline night and the 5th treatment night. Sleep latencies were significantly shorter on both AEP nights. The components of the AEP procedure may facilitate sleep onset by promoting relaxation and lowering psychophysiological arousal level in poor sleepers.

L-tryptophan: effects on daytime sleep latency and the waking EEG.

The effects of L-tryptophan (4 g) on the waking EEG and daytime sleep were studied in a group of 20 normal adults. Subjects were assigned to a morning or afternoon group, and data were collected on two occasions, after L-tryptophan and after placebo, assigned in a counterbalanced order. L-Tryptophan significantly reduced sleep latency without altering nap sleep stages and elevated plasma total and free tryptophan levels. EEGs were digitized on-line and later analyzed for changes in 5 frequency bands: 16-40 c/sec (beta), 13.0-15.5 c/sec (sigma), 8.0-12.5 c/sec (alpha), 4.0-7.5 c/sec (theta) and 0.5-3.5 c/sec (delta). During waking EEGs, L-tryptophan significantly increased alpha time, theta time, and theta intensity and significantly decreased alpha frequency. No wave bands were altered during sleep. L-Tryptophan is an effective daytime hypnotic which can facilitate sleep onset at clock times which do not coincide with biological sleep times. The hypnotic effects may be mediated by lowering arousal level during the awake state, thus setting the stage for more rapid sleep onset.

Sleep spindle and delta changes during chronic use of a short-acting and a long-acting benzodiazepine hypnotic.

Twenty-one medically screened insomniacs were studied over 59 nights in a double-blind, parallel groups design study. The 7 patients receiving a short-acting (triazolam) and the 7 receiving a long-acting (flurazepam) benzodiazepine hypnotic showed a similar pattern and magnitude of sleep EEG changes, especially during the latter part of the 37-night treatment period. Both groups significantly increased sleep spindle rate and decreased delta count per minute. The patterns of withdrawal were also similar. Plasma levels of N-desalkylflurazepam were not significantly related to the magnitude of EEG changes.

Benzodiazepine hypnotics increase heart rate during sleep.

The cardiovascular effects of benzodiazepines administered intravenously as preoperative sedatives have received considerable study, but sleep laboratory research on benzodiazepines administered orally as hypnotics has not focused on assessment of cardiovascular changes. Analysis of heart rate (HR) data collected in sleep laboratory studies on the effects of 0.5 mg of triazolam (Halcion) and 30 mg of flurazepam (Dalmane) demonstrated that both benzodiazepine hypnotics produced a significant HR elevation that was present for up to 4 h during sleep. By the 3rd night of bedtime administration of triazolam, the HR increase was no longer statistically significant, but on the 5th night of flurazepam administration, HR was still significantly elevated over baseline levels. The HR elevation does not appear to be of clinical significance for most patients. However, this finding indicates that benzodiazepines administered at hypnotic-dose levels have peripheral as well as central effects.

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 in 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.

Effect of a short-acting benzodiazepine on brain electrical activity during sleep.

The effects of the short-acting benzodiazepine, triazolam, on EEG activity during sleep were assessed in poor sleepers. Twenty male subjects, mean age 21 +/- 2.37 years, participated. A screening night preceded 3 placebo nights, 6 treatment nights, and 2 placebo-withdrawal nights. During treatment, 10 subjects received triazolam (0.5 mg) and 10 received placebo. The treatment condition was double-blind. In addition to rate/min spindle count and number of delta half-waves/min, the auditory evoked response (AEP) was obtained on the last placebo baseline and the fifth drug night. Subjects receiving triazolam showed a significant increase in sleep spindles and a significant decrease in delta count during drug administration. Both values returned to baseline on the first withdrawal night. The AEP peak-to-trough amplitude was also significantly reduced during sleep by triazolam, but, as the time since drug ingestion increased, the amplitude of the AEP also increased. There was no difference in AEP amplitude between the two groups 5 h post-drug ingestion.

Sleep induced by L-tryptophan. Effect of dosages within the normal dietary intake.

Previous results have demonstrated sleep-inducing effects of L-tryptophan in doses of 1 to 15 g at bedtime. The present laboratory study extends the dose-response curve downward, comparing doses of 1/4 g, 1/2 g, and 1 g of L-tryptophan with placebo, in 15 mild insomniacs (subjects who reported sleep latencies of over 30 minutes). One gram of L-tryptophan significantly reduced sleep latency: the lower doses produced a trend in the same direction. Stage IV sleep was significantly increased by 1/4 g of L-tryptophan. These results at low doses have interesting implications since the normal dietary intake of L-tryptophan is 1/2 g to 2 g per day.