Effects of 2-week treatment with temazepam and diphenhydramine in elderly insomniacs: a randomized, placebo-controlled trial

A randomized, controlled, crossover clinical study compared 14-night treatment with 15 mg temazepam, 50 mg diphenhydramine, and placebo in elderly individuals with insomnia (mean age, 73.9 years; range, 70-89 years). Primary outcome measures were subjective assessments of sleep recorded on sleep diaries. Secondary measures were the morning-after psychomotor impairment, using the digit symbol substitution task and the manual tracking task, and the morning-after memory impairment, using a free-recall procedure. Results showed sleep improvements with 15 mg temazepam compared with placebo-sleep quality (mean score, 3.3 +/- 0.9 vs 2.9 +/- 0.8; P = 0.03), total sleep time (6.9 +/- 1.0 hours vs 6.3 +/-1.3 hours; P = 0.02), number of awakenings (1.5 +/- 1.3 vs 2.0 +/- 1.2; P < 0.001), and sleep-onset latency (25 +/- 22 minutes vs 37 +/- 25 minutes; P = 0.03). Improvements were seen with diphenhydramine treatment compared with placebo on the number of awakenings only (mean, 1.7 +/- 1.1 vs 2.0 +/- 1.2; P < 0.05). Numbers of adverse events reported were similar after all treatments, although there was 1 fall during temazepam treatment. Findings indicate that temazepam is more effective than diphenhydramine when compared with placebo at the doses tested, although this advantage is mitigated by the risk of falls associated with temazepam use. The choice of agent to use in the elderly must consider these relative benefits and risks.     

The effects of temazepam and ethanol on human psychomotor performance

Summary We have studied the effects of temazepam, alone and in combination with ethanol, on psychomotor performance in six healthy men and women using a battery of five microcomputer-based tasks before and 30, 90, and 150 min after treatment.The tests were pursuit tracking, divided attention, two four-choice reaction time tests and tapping rate. The entire battery required 25 min. The subjects also reported their mood at each testing time using a computerized bipolar mood scales test.Temazepam (15 mg) plus ethanol (peak blood concentration of 11 mmol·1^–1) significantly impaired divided attention, tracking, and reaction time over a 3 h period. There was significant impairment versus placebo for each drug alone on some of the tests.Plasma and urine concentrations of temazepam and temazepam glucuronide were measured, but there was no significant temporal correlation between impairment and drug or metabolite concentration in either plasma or urine.The subjects knew when they had taken ethanol, but could not discriminate temazepam from ethanol whether alone or in combination. The subjects rated their performance similarly after each of the four treatment conditions.The performance on the tracking, divided attention, and PAB reaction time tasks used in this study was impaired by a combination of Tmazepam and ethanol in doses which may not cause impairment when each is given alone.     

Effect of temazepam on blood pressure regulation in healthy elderly subjects.

1. Blood pressure regulation was studied in 12 healthy elderly subjects after double-blind randomised administration of placebo, 15 mg and 30 mg temazepam at 10.00 h and 22.00 h. 2. Supine and standing heart rate and blood pressure were measured after daytime administration and supine measurements were obtained during sleep. 3. Temazepam caused a fall in systolic blood pressure and an increase in heart rate after morning administration. These changes were greater in the standing position and were dose-dependent; for standing blood pressure and heart rate 1 h after administration there was a 7 mm Hg fall and 6 beats min-1 increase after 15 mg temazepam and a 10 mm Hg fall and 8 beats min-1 increase after 30 mg temazepam. Temazepam magnified the fall in systolic blood pressure and increase in heart rate that occurred with standing. Temazepam enhanced the fall in systolic blood pressure that occurred during sleep (mean +/- s.d.; placebo: -23 +/- 10 mm Hg, 15 mg temazepam: -31 +/- 13 mm Hg, 30 mg temazepam: -36 +/- 14 mm Hg). 4. These changes in blood pressure regulation caused by temazepam may have clinical importance in some elderly individuals.     

Evaluation of temazepam and diphenhydramine as hypnotics in a nursing-home population

Seventeen nursing home residents with sleeping problems were enrolled in a randomized, double-blind, crossover trial of temazepam 15 mg, diphenhydramine (DPH) 50 mg, and placebo. Each drug was given for five consecutive nights with a 72-hour washout period between drugs. Subjects were assessed three times weekly with tests of psychomotor and cognitive function and four times weekly with observer sleep diaries and morning sleep questionnaires. Three subjects failed to complete the study. By report of the subjects, DPH resulted in shorter sleep latency than did placebo (t = 2.77, p less than 0.05). On the fifth night, use of DPH was associated with longer duration of sleep than temazepam (t = 2.88, p less than 0.05). No significant difference in tests of neurologic function was noted although, compared with placebo, subjects performed more poorly on seven of eight tests while taking temazepam and five of eight tests while taking DPH. Several instances of daytime hypersomnolence were noted in subjects taking temazepam and DPH, but none in subjects given placebo.     

Temazepam as a hypnotic in osteoarthritic patients

The effects of nocturnal temazepam elixir on 14 male osteoarthritic patients and 16 age- and sex-matched healthy controls were investigated in a double-blind parallel groups study. Temazepam produced a number of significant changes in objective sleep. In the osteoarthritic patients temazepam reduced the duration of awakenings, percentage stage 0, percentage stage 1, percentage stages (0+1) and increased percentage stage 2 and REM latency. In the controls temazepam reduced the duration of awakenings, percentage stage 0, percentage stages (0+1) and increased percentage stage 2, sleep efficiency and REM latency. During the drug period, seven out of 15 subjects receiving temazepam reported improved sleep, compared with one out of 15 placebo subjects. There was no evidence to suggest that temazepam caused any unwanted side-effects or affected the duration of morning stiffness in osteoarthritic patients. Temazepam produced no significant impairment of early morning psychomotor performance or significant withdrawal effects in either patients or controls.     

Effects of temazepam on memory and psychomotor performance: a dose-response study

In a randomised, three-period crossover study, psychomotor performance and memory were tested and mood assessed for 3 h after single doses of placebo (PL), 20 mg temazepam (T20) or 30 mg temazepam (T30) were given to six healthy females aged 21-23. A composite measure of psychomotor speed showed a dose-dependent slowing (Page's L trend test: p < 0.001; sign test PL vs T20 and T30 vs T20: p < 0.05). The number of errors in the performance of tasks was increased, significantly in the case of some measures. Explicit memory (Buschke Selective Reminding Task) showed significant impairment of long-term but not short-term memory (Page's L trend test: p < 0.05). The form of the dose-response curve was positively accelerating, with the difference in performance between T20 and T30 at least as great as that between PL and T20. Visual Analogue Scales showed a decrease in a factor representing functional integrity (Page's L trend test: p < 0.05;) sign test (PL vs T20: p < 0.05), but no changes in mood. These results show that 30 mg is a useful extension of the dose range of temazepam, being well tolerated and that it produces a substantially greater impairment of performance than 20 mg. Copyright 2001 John Wiley & Sons, Ltd.     

Limited memory impairment after temazepam

In order to examine the effects of temazepam on memory, a battery of cognitive tests and analogue mood ratings were given to healthy volunteers after oral administration of 5, 10 and 30 mg. The lowest dose had no effect and 10 mg only significantly increased self-ratings of well-being. Temazepam (30 mg) significantly improved recall of items learned prior to drug administration, but impaired recall and recognition of word lists acquired after drug administration. However, when retrieval was assessed indirectly using a backwards reading task there was no impairment, indicating that automatic information processing was unaffected. Temazepam (30 mg) significantly reduced self-ratings of anxiety and increased those of sedation. It also significantly impaired performance in symbol copying, digit-symbol substitution and number cancellation tasks. It is striking that, at a dose that was sedative and impaired many aspects of performance, temazepam nonetheless improved retrieval of items learned prior to drug administration. © 1998 John Wiley & Sons, Ltd.     

Effects of antihistamines,chlormezanone and alcohol on psychomotor skills related to driving

Summary The effects of diphenhydramine, meclastine, and chlormezanone, alone or in combination with alcohol, on psychomotor skills related to driving have been investigated in 300 healthy volunteers. A choice reaction test and two coordination tests were employed. — Diphenhydramine caused sedation, partly independent of the dose, and slightly impaired psychomotor performance. Some subjects were exceptionally sensitive to diphenhydramine induced impairment of skills. It enhanced the effects of alcohol. — Meclastine did not impair psychomotor performance. A 1.5 mg dose did not enhance the effects of alcohol, but 3 mg did, although it was less potent than 50 mg of diphenhydramine. — Chlormezanone 200 mg had a relaxing effect which became apparent as a shortened reaction time at 30 min. Chlormezanone 400 mg did not affect psychomotor performance, nor did it enhance the effects of alcohol on psychomotor skills.     

Acute Effects of Temazepam and Nitrazepam on Psychomotor Skills and Memory

Abstract Twelve pretrained healthy students ingested temazepam, nitrazepam, and placebo, each double blind at one-week intervals in randomized order. Reactive and co-ordinative skills and critical flicker fusion were measured before each drug intake and 1,2,3,6 and 8 hours after it. Short-term memory and paired association learning were measured at 1, 3 and 8 hours. The psychomotor responses to drugs were modified by a sequence effect (not at zero tests) which effect varied depending on the drug and parameter. In multivariance analysis it was included to reveal drug effects. Nitrazepam 10 mg increased reaction and co-ordination errors and also impaired learning and memory. Temazepam 10 mg impaired co-ordinative skills; on a whole it differed from nitrazepam but hardly from placebo. Temazepam 20 mg impaired co-ordination, and learning and memory. Both temazepam 20 mg and nitrazepam were experienced sedative. All drug effects were clearest during the first 3 hours, nitrazepam also impaired learning at 8 hours. Temazepam 20 mg seems suitable as a hypnotic.     

Acute effects of temazepam and nitrazepam on psychomotor skills and memory.

Twelve pretrained students ingested temazepam, nitrazepam, and placebo, each double blind at one-week intervals in randomized order. Reactive and co-ordinative skills and critical flicker fusion were measured before each drug intake and 1, 2, 3, 6 and 8 hours after it. Short-term memory and paired association learning were measured at 1, 3 and 8 hours. The psychomotor responses to drugs were modified by a sequence effect (not at zero tests) which effect varied depending on the drug and parameter. In multivariance analysis it was included to reveal drug effects. Nitrazepam 10 mg increased reaction and co-ordination errors and also impaired learning and memory. Temazepam 10 mg impaired co-ordinative skills; on a whole it differed from nitrazepam but hardly from placebo. Temazepam 20 mg impaired co-ordination, and learning and memory. Both temazepam 20 mg and nitrazepam were experienced sedative. All drug effects were clearest during the first 3 hours, nitrazepam also impaired learning at 8 hours. Temazepam 20 mg seems suitable as a hypnotic.     

The effects of single and repeated administration of ebastine on cognition and psychomotor performance in comparison to triprolidine and placebo in healthy volunteers

OBJECTIVE: The cognitive and psychomotor effects of 10 mg, 20 mg and 30 mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10 mg (as a verum) and placebo in 10 healthy volunteers in a double-blind, randomised cross-over study. METHODS: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1 h, 2 h, 4 h and 8 h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ). RESULTS: Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p < 0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the difference with placebo reaching statistical significance on day 1, 8 h post-dose (p < 0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8h on day 1 (p < 0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4 h and 8 h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2 h and 4 h following triprolidine administration on day 1 and ebastine (30 mg) was rated as sedative 4 h following administration on day 5. The perceived sedative activity of ebastine 30 mg was also reflected in the subjective reports on the LSEQ on day 1 (p < 0.05). CONCLUSIONS: These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10-20 mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10 mg.     

Double-blind evaluation of the efficacy and safety of temazepam in outpatients with insomnia.

1 The efficacy and safety of temazepam 30 mg, compared with glutethimide 500 mg and placebo, were evaluated in double-blind conditions in a 4-day study in 75 outpatients with a history of insomnia. 2 Temazepam and glutethimide were rated by the patients as effective and significantly superior to placebo for general quality of sleep, time required to fall asleep, frequency of nocturnal and early morning awakenings, and duration of sleep. 3 Residual effects reported for temazepam and glutethimide immediately after awakening and during the day were similar to or less than those reported for placebo.     

The acute and sub-chronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance, and weal and flare

AIM: To compare the central and peripheral H1 inhibitory effects of acute and sub-chronic doses of levocetirizine (L-CTZ), cetirizine (CTZ), loratadine (LOR) and promethazine (PRM) versus placebo, using a battery of psychomotor and cognitive tests together with measures of the weal and flare reaction. PRM was included in the study as a positive internal control to validate the sensitivity of the psychometric test battery to the CNS effects of the various treatments. METHODS: Twenty healthy volunteers (18-50 years) received L-CTZ 5mg, CTZ 10 mg, LOR 10 mg, PRM 30 mg and placebo once daily for four days in a five-way, double-blind, crossover study. For each treatment condition, subjects were assessed using a psychometric test system and a pinprick weal and flare response to 100 mg/ml histamine solution at baseline and at 1, 2, 3 ,4, 6, 8, 10 and 122 hours post-dose on days 1 and 4. The psychometrics comprised critical flicker fusion (CFF), choice reaction time (CRT), a continuous tracking task (CTT) and subjective rating scales for sedation (LARS). On days 2 and 3, subjects took their medication at pre-designated times while out of the unit. RESULTS: The verum (PRM) established the sensitivity of the test battery: a significant overall reduction in CFF thresholds on both days 1 and 4 (p < 0.05); an overall significant increase (impairment) in recognition, motor and total reaction times on day 1 (p < 0.05); a significant impairment of both the tracking accuracy and reaction time aspects of the CTT task on day 1 (p < 0.005) and significantly higher ratings of subjective sedation on day 1 (p < 0.05). L-CTZ, CTZ and LOR were not distinguishable from placebo in any of the objective and subjective tests at any time point on either day 1 or day 4. With regards to the peripheral inhibitory effects, L-CTZ inhibited both the weal and flare reaction, with maximum inhibition (almost 100%) occurring within two hours of drug ingestion. CTZ also showed evidence of potent peripheral inhibition of histamine, whereas PRM, and especially LOR, showed only a weak weal and flare reaction which had completely attenuated at day 4. CONCLUSIONS: In a study where the psychometric assessments were shown to be sensitive to impairment, L-CTZ 5 mg was found following both initial and repeated doses, but also to be demonstrably free from disruptive and sedative effects on objective measures of psychomotor and cognitive function. Similarly, CTZ showed evidence of pronounced antihistaminic activity and significantly reduced weal and flare scores after both acute and repeated doses, again without evidence of cognitive or psychomotor impairment. LOR also was non-sedative but the antihistaminic reaction was demonstrably weak.     

The effects of acute doses of dothiepin (25, 50, and 75 mg) versus placebo on psychomotor performance and cognitive function

Sixteen healthy volunteers received dothiepin 25 mg, 50 mg, 75 mg and placebo in a double-blind crossover study. Each subject received the four treatments once, with a 6-day washout period between test days. On each occasion psychomotor performance and cognitive function were measured 30 min before dosing and 1, 2, 4, 6 and 8 h after drug administration. The test battery comprised: Critical Flicker Fusion, Choice Reaction Time, Continuous Tracking and Short Term Memory. Subjective ratings of sedation were measured using Line Analogue Rating Scales. Dothiepin at the subtherapeutic dose of 75 mg was shown to produce statistically significant impairment (p<0·05) on several of the variables investigated. These included CFF at the 2- and 4-h test points, TRT at the 2-h test point and LARS at the 2- and 4-h test points. Lower doses also produced impairment of cognitive function and psychomotor performance as measured by the present test battery. © 1997 John Wiley & Sons, Ltd.     

The Effects of Single and Repeated Administration of Ebastine on Cognition and Psychomotor Performance in Comparison to Triprolidine and Placebo in Healthy Volunteers

Summary

Objective:The cognitive and psychomotor effects of 10?mg, 20?mg and 30?mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10mg (as averum) and placebo in 10 healthy volunteers in a double-blind, randomised crossover study.

Methods: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1?h, 2?h, 4?h and 8?h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ).

Results: Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p?<?0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the I difference with placebo reaching statistical significance on day 1,8?h post-dose (p?<?0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8?h on day 1 (p?<?0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4?h and 8?h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2?h and 4?h following triprolidine administration on day 1 and ebastine (30?mg) was rated as sedative 4?h following administration on day 5. The perceived sedative activity of ebastine 30?mg was also reflected in the subjective reports on the LSEQ on day 1 (p?<?0.05).

Conclusions: These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10–20?mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10?mg.     

Temazepam,but not zolpidem,causes orthostatic hypotension in astronauts after spaceflight

Insomnia is a common symptom, not only in the adult population but also in many astronauts. Hypnotics, such as temazepam (a benzodiazepine) and zolpidem (an imidazopyridine), are often taken to relieve insomnia. Temazepam has been shown clinically to have hemodynamic side effects, particularly in the elderly; however, the mechanism is not clear. Zolpidem does not cause hemodynamic side effects. The purpose of this study was to determine whether the use of different hypnotics during spaceflight might contribute significantly to the high incidence of postflight orthostatic hypotension, and to compare the findings in astronauts with clinical research. Astronauts were separated into three groups: control (n = 40), temazepam (15 or 30 mg; n = 9), and zolpidem (5 or 10 mg; n = 8). In this study, temazepam and zolpidem were only taken the night before landing. The systolic and diastolic blood pressures and heart rates of the astronauts were measured during stand tests before spaceflight and on landing day. On landing day, systolic pressure decreased significantly and heart rate increased significantly in the temazepam group, but not in the control group or in the zolpidem group. Temazepam may aggravate orthostatic hypotension after spaceflight when astronauts are hemodynamically compromised. Temazepam should not be the initial choice as a sleeping aid for astronauts. These results in astronauts may help to explain the hemodynamic side effects in the elderly who are also compromised. Zolpidem may be a better choice as a sleeping aid in these populations.     

A comparison of the acute behavioral effects of triazolam and temazepam in normal volunteers

Two experiments were conducted to assess the acute behavioral effects of triazolam and temazepam in healthy, non-drug abusing men in double-blind, placebocontrolled, crossover trials, where all subjects received all possible doses. These drugs were compared to examine allegations that triazolam produces greater behavioral impairment than temazepam. Drug effect were assessed during 4-h sessions using measures of recall, learning, psychomotor performance, and subject ratings assessing drug effects and abuse potential. In experiment 1, triazolam (0.25 and 0.5 mg/70 kg) produced greater behavioral impairment than temazepam (15 and 30 mg/70 kg). However, triazolam also produced greater increases than temazepam in subject ratings of drug strength, drunkenness and sleepiness, suggesting the dose ranges compared may not have been clinically equivalent. Experiment 2 was conducted to assess whether a higher dose of temazepam than tested in experiment 1 would produce levels of behavioral impairment comparable to those observed with triazolam in experiment 1. In experiment 2, the temazepam dose was increased to 60 mg/70 kg while the triazolam dose was 0.5 mg/70 kg which was the highest dose tested in experiment 1. These doses produced comparable increases in subject ratings of drug strength, drunkenness and sleepiness, but temazepam produced significantly more behavioral disruption than triazolam. These findingsdo not support the position that triazolam produces greater behavioral impairment than temazepam, and may even suggest that across a wide range of doses triazolam isless disruptive than temazepam.     

Improved hypnotic treatment using chlormethiazole and temazepam

The effects of a single 384 mg oral dose of chlormethiazole were compared with those of 20 mg of temazepam and placebo in healthy old and young women (mean ages 72.9 and 24.7 years respectively). Both drugs were effective hypnotics and had no detectable pharmacological action the next morning. Even four hours after administration performance of a simple psychomotor test was not impaired and sway (measured by an ataxiameter) was not increased in either age group. Pharmacokinetic studies showed that chlormethiazole was rapidly absorbed, distributed, and eliminated by both groups, so that minimal plasma concentrations existed 11 hours after administration. Temazepam, however, was less quickly absorbed and distributed, especially in the young group, and substantial amounts remained in the plasma 11 hours after administration. No unwanted effects occurred after temazepam, but 17 of the 20 subjects suffered from nasal irritation after taking chlormethiazole. Thus hangover effects may be avoided in elderly subjects after they have taken hypnotic drugs, and temazepam and chlormethiazole allow sleep to be interrupted safely.     

The psychomotor and cognitive effects of a new antihistamine,mizolastine, compared to terfenadine,triprolidine and placebo in healthy volunteers

Eighteen healthy volunteers received mizolastine 5 mg, 15 mg or 45 mg, terfenadine 60 mg, triprolidine 10 mg or placebo in a 6-way crossover, double blind study. Following each dose, subjects performed a series of tests of cognitive function and psychomotor performance at 1, 3, 5, 8 and 24 hours post-dose. The test battery included critical flicker fusion, choice reaction time, tracking, Stroop and Sternberg memory tests and assessment of subjective sedation.Sedative effects and a concomitant reduction in psychomotor and cognitive function were observed following triprolidine, terfenadine and the highest dose of mizolastine, 45 mg, e.g. triprolidine reduced CFF threshold by 1.5 Hz and increased reaction time by 50 ms, impairments comparable to those caused by blood alcohol concentrations of 50 mg%, the legal limit in many countries. Mizolastine 5 mg did not differ significantly from placebo and at 15 mg differed only at one test point at one time.It may be concluded that mizolastine (5 mg and 15 mg) is free from disruptive effects on cognitive function and psychomotor performance, in contrast to terfenadine 60 mg, triprolidine 10 mg and mizolastine 45 mg.