Cheryl L. Spinweber

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.

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.

BRIEF COMMUNICATION: 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 ¼ g, ½ 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 Ltryptophan significantly reduced sleep latency: the lower doses produced a trend in the same direction. Stage IV sleep was significantly increased by ¼ g of L-tryptophan. These results at low doses have interesting implications since the normal dietary intake of L-tryptophan is ½ g to 2 g per day.

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.

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.

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.

Chronic insomnia: Effects of tryptophan, flurazepam, secobarbital, and placebo

This study compared the effects of l-tryptophan (1 g), secobarbital (100 mg), flurazepam (30 mg), and placebo on sleep in 96 serious insomniacs. Each treatment was given nightly for 7 nights in a separate-group design. Outcome measures were subjective estimates by subjects of a number of sleep parameters during the week of treatment and for 1 week after, and an overall evaluation made by subjects and investigators at the end of the 2 weeks. During the treatment week, flurazepam produced significant improvement on several sleep measures compared to placebo, while tryptophan and secobarbital did not. Flurazepam and secobarbital produced withdrawal symptoms during the post-treatment week, while tryptophan and placebo did not. Sleep latency was not significantly improved by tryptophan during the treatment week, but continued to improve during the post-treatment week, resulting in a significant difference between tryptophan and baseline in week 2.

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 potantial problems.

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.