Repeated dose effects of lormetazepam and flurazepam upon driving performance

Summary The residual effects of lormetazepam 1 mg and 2 mg in soft gelatine capsules on driving performance were assessed and compared to those of flurazepam 30 mg, which is also a powerful hypnotic, but possesses a far less favourable pharmacokinetic profile with a longacting sedative metabolite. Driving performance was tested 10 to 11 h and 16 to 17 h post administration, after 2 days on placebo (baseline), and 2,4 and 7 days of drug treatment (active), and after 1 and 3 days following the resumption of placebo (washout). The driving test consisted of operating an instrumented motor-vehicle over a 72 km highway circuit in light traffic. Flurazepam 30 mg significantly impaired the ability to control the lateral position of the vehicle compared to placebo baseline measurements. The degree of impairment was substantial in the female subjects and was greater in the morning than in the afternoon. Lormetazepam 1 mg showed no residual effect on driving performance. Lormetazepam 2 mg impaired driving performance to some extent on the following morning, 10 to 11 h post administration, but no residual effect was found in the afternoon. All drugs improved sleep quality and prolonged sleep duration to more or less the same extent.     

Effects of lormetazepam and of flurazepam on sleep.

Nine poor sleepers of mean age 61 years took part in a double-blind, balanced order study in which, during three periods of 3 weeks, each took lormetazepam 1 mg, lormetazepam 2.5 mg, and flurazepam 30 mg. Using electrophysiological measures, sleep was found to increase by 0.75 h with each treatment condition, mainly through more of stage 2 sleep. The treatments reduced the delay to sleep and led to fewer and shorter awakenings, with little difference among the three treatments. Slow-wave sleep was reduced by flurazepam and by lormetazepam 2.5 mg. After flurazepam intake ceased, there was evidence of persisting drug effects for as long as 7 nights. In contrast, when lormetazepam 2.5 mg ceased, there was significant rebound reduction of sleep duration below baseline for up to 3 withdrawal nights, and there was a similar though non-significant trend after lormetazepam 1 mg had ceased. Wakefulness in the final 2 h of nocturnal recording during the third week of drug intake was significantly reduced below baseline by flurazepam, but was little affected by lormetazepam. The differences among the treatment conditions could be attributed to the long-persistence of flurazepam vs the more rapid elimination of lormetazepam.     

The effects of flurazepam,lorazepam, and triazolam on sleep and memory

This study evaluated the effects of flurazepam 30 mg, lorazepam 4 mg, triazolam 0.5 mg, and placebo upon sleep and memory in eleven normal male subjects continuously monitored for nighttime EEG, EOG, and EMG recording. Subjects received each drug or placebo for two consecutive nights per week for 4 weeks in a repeated measures, double-blind, Latin Square design. Three hours post-administration, subjects were awakened and presented with a series of tasks. Recall was assessed immediately following task presentation and after the final morning awakening. The results showed that every drug significantly decreased stage 1, increased stage 2, and produced no change in stage 3–4 sleep in comparison to placebo. Only lorazepam significantly decreased REM percent. Post-drug recall was significantly decreased in comparison to placebo at night and was further decreased in the morning. Morning recall was significantly poorer when the return to sleep was 2.5 min or less than when the return to sleep was greater than 5 min following the nighttime awakening in all drug conditions. These results indicate that 1. failure of memory consolidation rather than failure of retrieval is the most likely explanation for the morning memory loss and 2. hypnotic drug properties, measured by latency to fall back asleep, affect memory consolidation.     

The effects of lormetazepam on aspects of memory,sleep and human performance

The effects of lormetazepam 1 mg, 1·5 mg, 2 mg, a verum—triazolam 0·5 mg and placebo were examined in ten normal female volunteers, on tests of psychomotor function, performance and analogue rating scales for subjective sedation, sleep and early morning behaviour. Results showed all doses of lormetazepam to be effective hypnotics and free from residual effects 10 h after drug ingestion when tested on critical flicker fusion threshold (CFF), choice reaction time (CRT), simultated car tracking task and Maddox wing. Acquisition and immediate recall of word lists was poorer following administration of lormetazepam 1·5 mg and triazolam 0·5 mg. On memory scanning, lormetazepam 1 mg was the only dose completely free from residual impairment 10 h following administration.     

Intranasal absorption of flurazepam, midazolam, and triazolam in dogs.

Intranasal delivery of flurazepam, midazolam, and triazolam was studied in a dog model as a possible alternate route of drug administration for treatment of insomnia. Four beagles received each hypnotic by both intranasal and oral routes on two separate occasions. Plasma concentrations for each hypnotic after dosing were measured by electron-capture gas-liquid chromatography. The mean intranasal absorption rates (tmax) of flurazepam, midazolam, and triazolam were 1.7, 2.0, and 2.6 times faster, respectively, compared with oral dosing. The mean dose-normalized peak concentrations (Cmax) after intranasal delivery were 16.4, 2.9, and 3.4 times higher, respectively, versus oral administration. The mean dose-normalized AUCs estimated for these compounds after nasal administration were 2.4-, 2.5-, and at least 2-fold larger than after oral administration for midazolam, triazolam, and flurazepam, respectively. If these observations can be extrapolated to humans, the faster absorption achieved by the intranasal route would appear to benefit insomniacs characterized by difficulty in falling asleep because of an anticipated faster sedative effect onset. The higher peak concentrations and larger amounts absorbed in the case of intranasal midazolam and triazolam delivery may lead to dose reduction.     

Residual and acute effects of flurazepam and triazolam in normal subjects

Residual and acute effects of flurazepam and triazolam were studied in two double-blind, crossover, placebo controlled, single-dose experiments. Psychological and physiological effects were determined 10 h after night administration (flurazepam 30 mg and triazolam 0.5 mg), and for 6 h after morning ingestion (flurazepam 15 mg and triazolam 0.25 mg). Both drugs produced similar "hangover" effects, impairing motor performance and increasing sleepiness on the following morning. After morning administration pronounced sedative effects were found with triazolam, while flurazepam effects were mild and hard to distinguish from placebo. The clinical relevance of these findings is discussed, suggesting that these drugs may be conceived as belonging to two different types of hypnotic agents.     

Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study

We studied sleep and daytime function in insomniac patients who took either flurazepam, 30 mg, triazolam, 0.5 mg, or placebo 30 minutes before bedtime. Subjects were 21 patients with either a primary or a secondary diagnosis of chronic psychophysiological insomnia or insomnia associated with personality disorder. Seven subjects were randomly assigned to each condition. The study used a three group by 9 week, double-blind design with three nocturnal sleep recordings each week. During week 1, subjects took no capsules; week 2, subjects took placebo; weeks 3 to 7, flurazepam, triazolam, or placebo; weeks 8 and 9, placebo. Daytime tests for alertness and performance were administered during weeks 1, 3, 5, 7, and 8. Flurazepam showed hypnotic efficacy for weeks 3 to 5. Triazolam showed hypnotic activity for weeks 3 to 7. Although not significant overall, discontinuation of flurazepam produced rebound insomnia in six of seven subjects sometime during the two withdrawal weeks. The relationship between plasma concentration of desalkylflurazepam, the principal active metabolite of flurazepam, and sleep disturbance suggested that the onset of the rebound insomnia depended on the rate of drug washout. Discontinuation of triazolam produced a significant rebound insomnia on the first and second nights of drug withdrawal. Placebo subjects showed improved sleep throughout weeks 2 to 9 of the study. Daytime testing revealed significantly decreased daytime alertness and decreased performance for flurazepam subjects during weeks 3 to 7, although these effects reverted toward baseline despite continued drug administration.     

Hypnotic activity and effects on performance of lormetazepam and camazepam--analogues of temazepam.

1 The effects of lormetazepam and camazepam on sleep electroencephalography, visuo-motor coordination, digit symbol substitution and subjective assessments of mood and sleep quality were compared with placebo in six young adult males (18-27 years). The study was double blind. 2 Over the dose range 0.5, 1.0 and 2.0 mg, lormetazepam increased total sleep time (P less than 0.05), reduced wakefulness (P less than 0.05) and drowsy sleep (linear effect P less than 0.05). With 2.0 mg there were increases in stage 3 (P less than 0.05) and reduction in rapid eye movement sleep (P less than 0.01). Overnight ingestion of 2.0 mg, was followed by impaired visuo-motor coordination and fewer substitutions with the digit symbol test. 3 The hypnotic effect of 10-20 mg camazepam was limited to reduced awake activity (P less than 0.05), and with 20 mg there were increased substitutions on the digit symbol test. After 40 mg overnight stage 4 sleep was reduced (P less than 0.001) and performance at the digit symbol test was impaired (P less than 0.05 at 9.75 h). Morning ingestion of 20 mg camazepam did not alter performance, and the subjects assessed themselves to be more relaxed. 4 Lormetazepam is not specially indicated for those involved in skilled activity, but may prove useful for patients with insomnia resistant to other drugs. Camazepam would appear to be a promising anxiolytic with minimal effects on performance.     

Aminorex produces stimulus effects similar to amphetamine and unlike those of fenfluramine.

A 4-methyl derivative of aminorex has recently appeared on the clandestine market as a designer drug. In the present study, the stimulus effects of aminorex itself were evaluated in rats trained to discriminate either 0.75 mg/kg S(+)-amphetamine or 1.5 mg/kg fenfluramine from saline. The amphetamine stimulus (ED50 = 0.14 mg/kg) generalized to aminorex (ED50 = 0.23 mg/kg), which was found to be slightly less potent than (+)-amphetamine. Fenfluramine stimulus generalization did not occur to aminorex. Thus, the stimulus effects of aminorex are qualitatively similar to those of amphetamine and unlike those of fenfluramine.     

Dose-related effects of flurazepam on human sleep-waking patterns

Two consecutive nights of flurazepam at each of 15, 26, and 45 mg were compared to placebo in a Latin-square double-blind crossover design using 24 healthy young-adult males. Flurazepam had significant hypnotic effects on objective and subjective measures of efficacy: shorter sleep latency, longer sleep time, and fewer awakenings. It also induced morning sedation along with decrements in cognitive performance. Flurazepam had dose-related impacts on both human and computer-scored EEG-EOG parameters: less stages 3+4 and decreased EEG , less stage 1 REM and decreased REM density, more stage 2 and increased EEG spindling. Also, EEG and movement artifact were decreased and EEG was increased. Only a few of the EEG-EOG variables and none of the subjective indices had cumulative changes on the two drug nights. Stage shifting was unaffected at the two lower doses on the first night but decreased at all three dose levels on the second night; percent stages 3+4 was unaffected on the first night but decreased at all dose levels on the second night. The rate of waveform activity was also diminished by a greater amount on the second night. This study conclusively established that flurazepam affects the EEG-EOG architecture of sleep on each of the first two nights of administration.     

Residual effects of lormetazepam on mood and performance in healthy elderly volunteers

Summary 45 subjects aged over 65 years were randomly assigned to treatment with lormetazepam 0.5 mg or 1 mg or placebo. Mood and performance were measured with a battery of computerized tests. Subjects were tested before and after 1 and 8 nights of treatment. Pre- and post-treatment scores were analysed by a multivariate covariance technique, the pre-treatment score serving as covariate.The single and repeated doses of lormetazepam resulted in impairment of performance in a memory task, and the repeated dose administration impaired performance of a perceptual task. The single administration of a low dose gave an improvement in fine motor control. No change was found in the mood states of the subjects.This study was supported by a grant from Wyeth Laboratoria B. V.     

A comparison of the effects of flurazepam 30 mg and triazolam 0.5 mg on the sleep of insomniacs

The effects of oral, bedtime triazolam 0.5 mg and flurazepam 30 mg, on the laboratory sleep of 12 insomniacs were compared in a double blind, crossover study. A 22 consecutive night schedule was used: Nts. 1–2 placebo; 3–6 first drug; 7–8 placebo; 9–14 no drugs; 15–16 placebo; 17–20 second drug; 21–22 placebo. In 6 Ss first drug was triazolam and second drug was flurazepam. In the other 6 Ss the drug order was reversed. Effects on sleep were assessed objectively by conventional EEG/EOG/EMG sleep recordings and subjectively by questionnaires administered each morning. Side or toxic effects were assessed by physical exams, clinical lab tests, and twice daily questionnaires. During their administration the two drugs were practically indistinguishable in their effects. Both significantly reduced objective and subjective measures of insomnia, such as total wake time and sleep latency. On discontinuation the drugs differentially affected sleep, e.g., on the first post flurazepam night total sleep time was significantly more than baseline whereas on first post triazolam night, total sleep time was significantly less than baseline. There were no remarkable side or toxic effects with either drug.     

Alcohol and triazolam: differential effects on memory,psychomotor performance and subjective ratings of effects

The effects of alcohol (0.80 g/kg) and the benzodiazepine hypnotic triazolam (0.25 mg/70 kg) were compared directly in a double-dummy, double-blind, placebo-controlled, repeated-measures design in 18 healthy volunteers. While alcohol (0.80 g/kg) and triazolam (0.25 mg/70 kg) produced comparable levels of psychomotor performance impairment, a dissociation was observed, such that the magnitude of memory impairment (measured by d', participants' sensitivity in discriminating between old and new words in the recognition memory paradigm) was greater with triazolam than with alcohol, whereas subjective ratings of the overall strength of drug effect were higher with alcohol than with triazolam. Participants also adopted a more conservative response bias in the recognition memory paradigm in the alcohol (0.80 g/kg) condition relative to both placebo and triazolam (0.25 mg/70 kg). In addition to characterizing the adverse effects of two widely used psychoactive substances, the present results may also contribute to the understanding of underlying neurochemical mechanisms.     

Administration of triazolam prior to recovery sleep: effects on sleep architecture,subsequent alertness and performance

The effects of triazolam (0.125, 0.25, and 0.5 mg) versus placebo on recovery sleep staging, subsequent alertness and psychomotor performance were evaluated in humans. Forty-five healthy male subjects were deprived of sleep for 24 h, then administered a single dose of triazolam or placebo using a double-blind procedure. Subjects then attempted to obtain recovery sleep under non-sleep-conducive conditions (sitting upright in a well-lit, crowded chamber) for the next 6 h, followed by 18 more hours of sleep deprivation. During all sleep deprivation periods subjects were tested bihourly on a performance assessment battery which included symbol digit modalities tests (SDMT), four-letter search (FLS), logical reasoning (LR), time estimation (TE), visual vigliance (VV), and short term memory (STM) tasks. Sleepiness levels were measured objectively with multiple sleep latency tests (MSLT) and subjectively with the Stanford Sleepiness Scale (SSS). Compared to placebo, all doses of triazolam resulted in increased amounts of stage 3–4 sleep, and the 0.5 mg dose significantly reduced awakenings (Ps<0.05). Although subjects receiving triazolam averaged 21–42 min more total sleep time (TST) than subjects receiving placebo, differences in TST were not statistically significant. Apparent triazolam-mediated benefits to sleep quality resulted in no obvious improvements in performance or alertness levels during subsequent sleep deprivation. It was concluded that the increases in stage 3–4 sleep amouts were most likely due to triozolam-mediated increases arousal thresholds, and the triazolam mediated changes in sleep parameters obtained in the present study were not indicative of substantial changes in the recuperative value of sleep.This material has been reviewed by the Walter Reed Army Institute of Research, and there is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the position of the Department of the Army or the Department of Defense     

Comparison of the residual effects of two benzodiazepines (nitrazepam and flurazepam hydrochloride) and pentobarbitone sodium on human performance.

1 The residual effects of two benzodiazepines, nitrazepam (10 mg) and flurazepam hydrochloride (30 mg), and pentobarbitone sodium (200 mg) were studied by adaptive tracking and by reaction time. Performance was measured at 10 h, 13 h, 16 h, 19 h and 34 h after ingestion of each drug. Impaired performance on adaptive tracking was observed at 10 h, 13 h, 16 h and 19 h after nitrazepam and pentobarbitone sodium and at 10 h, 13 h and 16 h after flurazepam hydrochloride. Enhanced performance was observed at 34 h after nitrazepam and pentobarbitone sodium. 2 Increased reaction time persisted to 16 h after nitrazepam, flurazepam hydrochloride and pentobarbitone sodium and reaction time was also increased at 34 h after nitrazepam and pentobarbitone sodium. 3 During the morning immediately after ingestion, the subjects as a group were able to differentiate correctly between placebo and drugs, but they were not able to assess accurately the persistence of the residual effects of nitrazepam and pentobarbitone sodium. 4 Flurazepam hydrochloride would appear to be a more promising benzodiazepine than nitrazepam for use as a hypnotic by persons involved in skilled activity. There was a rapid recovery of performance during the afternoon and, unlike pentobarbitone sodium and nitrazepam, subjects retained the ability to recognize impaired skill.     

Comparison of the effects of quazepam and triazolam on cognitive-neuromotor performance

The pharmacological activity of quazepam, a BZ₁ specific benzodiazepine, was compared to the effects of triazolam, a BZ₁, BZ₂ nonspecific benzodiazepine. Using a double-blind procedure, single oral doses of quazepam (15 or 30 mg), triazolam (0.5 or 1.0 mg) and placebo were administered to 21 healthy young men according to a random Latin square design balanced for order of drug administration. The drug effects on the performance of motor coordination and cognitive tasks were monitored for 7 h following drug ingestion. The results did not indicate any differential effects on cognitive-neuromotor performance for the BZ₁ specific quazepam and 2-oxoquazepam compared with the BZ₁, BZ₂ nonspecific N-desalkylflurazepam metabolite. The impairment magnitude for 30 mg quazepam was closer to that of 0.5 mg triazolam. The onset of the initial drug effect was considerably slower for quazepam than for triazolam. The time course of the impairment profiles for the tasks was compared to pharmacokinetic data from previous studies and suggested that published pharmacokinetic rate constants explain only a limited portion of the impairment time course. In particular, the performance scores were already showing recovery from peak impairment 2 h post-drug ingestion, although quazepam's potent N-desalkylflurazepam metabolite has been found to maintain a maximum plateau level from 2 to 24 h.     

Progesterone effects on the discriminative stimulus, subjective and performance effects of triazolam in healthy, premenopausal women

There is accumulating evidence that sex plays a critical role in drug abuse. Female sex hormones have been shown to affect central nervous system function and modulate the effects of drugs of abuse. For example, γ-aminobutyric acid type A (GABA(A)) receptor function is positively modulated by progesterone metabolites. There is evidence from preclinical in-vitro and in-vivo studies as well as some clinical research suggesting that progesterone and its metabolites may enhance the behavioral effects of benzodiazepines, which also serve as positive modulators of GABA(A) receptors. The purpose of this experiment was to determine the independent and combined discriminative stimulus, subjective and psychomotor effects of progesterone and triazolam in healthy adult premenopausal women. Oral micronized progesterone (100 mg), triazolam (0.06, 0.12 and 0.25 mg/70 kg) and placebo were administered to healthy, premenopausal women (n=9) under conditions of low circulating sex hormones. Triazolam alone functioned as a discriminative stimulus and produced prototypical sedative-like effects (e.g., performance impairment, enhanced reports of sedative effects). Progesterone alone produced sedative-like effects on several subjective and performance measures, and the dose combination effects of progesterone and triazolam on several subjective measures of drug effect were similar to the summation of the two drug effects in isolation. Progesterone did not substitute for or modify the discriminative stimulus effects of triazolam. These results suggest that the parent hormone, progesterone, and triazolam have discordant neuropharmacological mechanisms of action. Additional research is necessary to determine the degree to which neurosteroids influence sex differences in benzodiazepine use and abuse.     

Multiclinic double-blind comparison of triazolam and flurazepam for seven nights in outpatients with insomnia.

In this two-clinic seven-day double-blind study, 0.5 mg triazolam (Halcion) was compared to flurazepam (Dalmane) in the treatment of insomnia. Two clinical investigators completed 118 outpatients, 61 on triazolam and 57 on flurazepam. Five patients, four on triazolam and one on flurazepam, discontinued because of side effects; and three patients, one on triazolam and two on flurazepam, discontinued because of ineffectiveness of the medication. Analysis of pooled data for the 110 evaluable patients showed that 0.5 mg triazolam was significantly better than 30 mg flurazepam on the following parameters: (1) how much the medication helped the patients sleep, (2) onset of sleep, (3) duration of sleep, (4) evaluation of duration of sleep, and (5) feeling of restfulness in the morning. The trend for all other parameters favored triazolam treatment, but the values did not reach statistical significance. Side effects were similar in both groups, with drowsiness being reported most frequently. No change in efficacy indicating tolerance development during the seven days of drug administration was observed in either group.     

The effects of triazolam and nitrazepam on sleep quality, morning vigilance and psychomotor performance

1. Repeated doses of triazolam 0.5 mg and mitrazepam 10 mg were given to two groups of consenting volunteers. 2. Measures of choice reaction time, critical flicker fusion threshold, and mental arithmetic ability were made the morning following nocturnal medication with either the active drug or placebo. 3. The subjects' assessment of sleep and early morning behaviour were obtained on 10 cm-line visual analogue scales. 4. Both drugs were rated as effective hypnotics while, at the same time, ratings of the ease of awakening from sleep and the errors produced in a mental arithmetic task were impaired. 5. Objective measures of performance and subjective reports of "hangover" differentiated nitrazepam from triazolam. A significant impairment of early morning performance found with nitrazepam was not found following treatment with triazolam.