Efficacy and Safety of Doxepin 1 mg and 3 mg in a 12-week Sleep Laboratory and Outpatient Trial of Elderly Subjects with Chronic Primary Insomnia.

STUDY OBJECTIVES: to evaluate the efficacy and safety of doxepin 1 mg and 3 mg in elderly subjects with chronic primary insomnia. DESIGN AND METHODS: the study was a randomized, double-blind, parallel-group, placebo-controlled trial. Subjects meeting DSM-IV-TR criteria for primary insomnia were randomized to 12 weeks of nightly treatment with doxepin (DXP) 1 mg (n = 77) or 3 mg (n = 82), or placebo (PBO; n = 81). Efficacy was assessed using polysomnography (PSG), patient reports, and clinician ratings. Objective efficacy data are reported for Nights (N) 1, 29, and 85; subjective efficacy data during Weeks 1, 4, and 12; and Clinical Global Impression (CGI) scale and Patient Global Impression (PGI) scale data after Weeks 2, 4, and 12 of treatment. Safety assessments were conducted throughout the study. RESULTS: DXP 3 mg led to significant improvement versus PBO on N1 in wake time after sleep onset (WASO; P < 0.0001; primary endpoint), total sleep time (TST; P < 0.0001), overall sleep efficiency (SE; P < 0.0001), SE in the last quarter of the night (P < 0.0001), and SE in Hour 8 (P < 0.0001). These improvements were sustained at N85 for all variables, with significance maintained for WASO, TST, overall SE, and SE in the last quarter of the night. DXP 3 mg significantly improved patient-reported latency to sleep onset (Weeks 1, 4, and 12), subjective TST (Weeks 1, 4, and 12), and sleep quality (Weeks 1, 4, and 12). Several global outcome-related variables were significantly improved, including the severity and improvement items of the CGI (Weeks 2, 4, and 12), and all 5 items of the PGI (Week 12; 4 items after Weeks 2 and 4). Significant improvements were observed for DXP 1 mg for several measures including WASO, TST, overall SE, and SE in the last quarter of the night at several time points. Rates of discontinuation were low, and the safety profiles were comparable across the 3 treatment groups. There were no significant next-day residual effects; additionally, there were no reports of memory impairment, complex sleep behaviors, anticholinergic effects, weight gain, or increased appetite. CONCLUSIONS: DXP 1 mg and 3 mg administered nightly to elderly chronic insomnia patients for 12 weeks resulted in significant and sustained improvements in most endpoints. These improvements were not accompanied by evidence of next-day residual sedation or other significant adverse effects. DXP also demonstrated improvements in both patient- and physician-based ratings of global insomnia outcome. The efficacy of DXP at the doses used in this study is noteworthy with respect to sleep maintenance and early morning awakenings given that these are the primary sleep complaints of the elderly. This study, the longest placebo-controlled, double-blind, polysomnographic trial of nightly pharmacotherapy for insomnia in the elderly, provides the best evidence to date of the sustained efficacy and safety of an insomnia medication in older adults.

Low-dose sublingual zolpidem tartrate is associated with dose-related improvement in sleep onset and duration in insomnia characterized by middle-of-the-night (MOTN) awakenings.

STUDY OBJECTIVES: To evaluate the efficacy and safety of low-dose, sublingual zolpidem tartrate when taken during a scheduled middle-of-the-night (MOTN) awakening in subjects with insomnia characterized by difficulty returning to sleep following MOTN awakenings. DESIGN: Randomized, double-blind, placebo-controlled, 3-way crossover study. METHODS: Each treatment period consisted of 2 consecutive nights of dosing separated by a washout of 5 to 12 days. Subjects were awakened 4 h after lights out, dosed with sublingual zolpidem tartrate (3.5 mg or 1.75 mg) or placebo, kept awake for 30 min, and then returned to bed for an additional 4 h. Sleep parameters were assessed by polysomnography (PSG) and post-sleep questionnaires. SETTING: Five sleep laboratories. PARTICIPANTS: Adults (24 males, 58 females, mean age 45.9 y) with a diagnosis of DSM-IV primary insomnia and a history of prolonged MOTN awakenings. Baseline difficulties with MOTN awakenings were confirmed by a 10-day screening sleep diary and PSG screening. RESULTS: Low-dose sublingual zolpidem tartrate demonstrated significant dose-related decreases in latency to persistent sleep and total sleep time (P < 0.001) compared to placebo after MOTN dosing. All subject reports paralleled PSG observations. Neither dose showed next-morning impairment on the DSST or ratings of sleepiness. The 3.5-mg dose produced improvements in reports of sleep quality (P < 0.001), ability to function, and level of refreshed sleep (P < 0.05 for both dosages) compared to placebo. Sublingual zolpidem tartrate lozenges were generally safe and well tolerated. CONCLUSIONS: Low-dose sublingual zolpidem tartrate may be suitable for treatment of patients who have difficulty resuming sleep after MOTN awakenings.

Efficacy and safety of as-needed, post bedtime dosing with indiplon in insomnia patients with chronic difficulty maintaining sleep.

OBJECTIVE: To evaluate the efficacy and tolerability of immediate release indiplon capsules in patients with chronic insomnia using an "as-needed" dosing strategy in response to difficulty falling back to sleep following a middle of the night, nocturnal awakening. METHODS: Adult outpatients (N=264; 71% female; age, 46 years) who met DSM-IV criteria for primary insomnia, with average total sleep time (TST) < 6.5 hours and >8 nights in the past month with nocturnal awakenings, were randomized to 4 weeks of double-blind treatment with 10 mg or 20 mg indiplon capsules, or placebo. The primary endpoint was latency to sleep onset post-dosing after a middle of the night awakening (LSOpd). Secondary endpoints included patients' subjective assessment of total sleep time (sTSTpd). Next day residual effects were evaluated by a 100 mm Visual Analog Scale (VAS) rating of sleepiness. RESULTS: Both doses of indiplon significantly reduced LSOpd at all time-points. Compared to placebo (45.2 min), the 4-week least squares (LS) mean LSOpd was 36.5 min in the indiplon 10 mg group (P = 0.0023) and 34.4 min in the indiplon 20mg group (P < 0.0001). The 4-week LS mean sTSTpd was higher in the indiplon 10 mg group (253 min) and 20mg group (278 min) compared to placebo (229 min; P < 0.01 for both comparisons). There was no increase observed in VAS ratings of next-day sleepiness for either dose of indiplon when compared to placebo. Indiplon was well-tolerated at both doses. CONCLUSIONS: Patients with chronic insomnia with nocturnal awakenings achieved significant and sustained improvement in sleep parameters while utilizing an as-needed post bedtime dosing strategy with indiplon capsules. Indiplon was well-tolerated, with no self-rated, next-day residual effects.

Long-term nightly treatment with indiplon in adults with primary insomnia: results of a double-blind, placebo-controlled, 3-month study.

OBJECTIVES: To evaluate the efficacy and safety of indiplon in primary insomnia. DESIGN: Randomized, double-blind, placebo-controlled, 3-month study. SETTING: Multi-center outpatient setting. PATIENTS: N=702 (61% female; mean age 46 years) who met DSM-IV criteria for primary insomnia of at least 3 months' duration. INTERVENTIONS: Indiplon 10 mg (n=236), indiplon 20 mg (n=233), or placebo (n=233). MEASUREMENTS: Subjective assessment of each of the following: latency to sleep onset (sLSO), total sleep time (sTST), number of awakenings after sleep onset (sNAASO), wake time after sleep onset (sWASO), sleep quality, Insomnia Severity Index (ISI), and global improvement. RESULTS: Treatment with indiplon resulted in significant improvement relative to placebo at all time points for the primary endpoint, sLSO. Mean sLSO at Month 1 for each treatment group was: 10 mg (34.0 +/- 1.3 mins), 20 mg (33.0 +/- 1.3 mins), and placebo (48.7 +/- 1.9 mins; P <0.0001 for both comparisons); efficacy was sustained through Month 3. Both doses of indiplon resulted in significant improvement in sleep maintenance and duration endpoints, sTST and sWASO, as well as sleep quality, ISI, and global improvement at all assessment time points. CONCLUSIONS: In patients with chronic insomnia, long-term nightly treatment with 10 mg and 20 mg doses of indiplon resulted in significant and sustained efficacy in sleep onset, maintenance, and duration, and significant associated improvement in both daytime functioning and quality of life.

A pilot study evaluating acute use of eszopiclone in patients with mild to moderate obstructive sleep apnea syndrome.

OBJECTIVE: To evaluate the effects of eszopiclone on measures of respiration and sleep using polysomnography in patients with mild to moderate obstructive sleep apnea syndrome (OSAS). METHODS: This double-blind, randomized crossover study included patients (35-64 years) with mild-to-moderate OSAS [apnea and hypopnea index (AHI) range 10 and 40]. Patients received either eszopiclone 3mg or placebo for two consecutive nights, with a 5-7 day washout between treatments. Continuous positive airway pressure (CPAP) was not allowed on nights in the sleep laboratory. RESULTS: The primary endpoint, mean total AHI, was not significantly different from placebo (16.5 with placebo and 16.7 with eszopiclone; 90% confidence interval (CI) -1.7, 1.9). No significant differences in total arousals, respiratory arousals, duration of apnea and hypopnea episodes, or oxygen saturation were noted. Significant differences in spontaneous arousals (13.6 versus 11.4 for placebo and eszopiclone, respectively; 90% CI -3.7, -0.7), sleep efficiency (85.1% and 88.4%; p=0.0075), wake time after sleep onset (61.8 and 48.1 min; p=0.0125), and wake time during sleep (55.9 and 43.2 min; p=0.013) were noted after eszopiclone treatment. Eszopiclone was well tolerated. CONCLUSIONS: In this pilot study, eszopiclone did not worsen AHI, and it improved sleep maintenance and efficiency. Further study is warranted to determine whether eszopiclone could improve CPAP compliance or next-day function in patients with OSAS.

A polysomnography study of eszopiclone in elderly patients with insomnia.

OBJECTIVE: To evaluate the safety and efficacy of eszopiclone 2 mg in elderly patients (aged 64-86 years) with chronic insomnia. METHODS: This was a randomized, double-blind, placebo-controlled 2-week study. Patients meeting DSM-IV criteria for primary insomnia and screening polysomnography criteria (wakefulness after sleep onset [WASO] >or= 20 min and latency to persistent sleep >or= 20 min) were randomized to 2 weeks of nightly treatment with eszopiclone 2 mg (n = 136) or placebo (n = 128). Efficacy was assessed using polysomnography (Nights 1, 2, 13, and 14) and patient reports (Nights 1-14); safety was assessed using adverse events, clinical labs, physical examination, and vital signs. The mean of all efficacy results during the double-blind period was used for the efficacy analysis. RESULTS: Results indicated that eszopiclone was associated with significantly shorter sleep onset, less WASO, higher sleep efficiency, more total sleep time, and greater patient-reported quality and depth of sleep scores than placebo (p < 0.05 for all) with a trend in patient-reported morning sleepiness (p = 0.07). Other measures of daytime functioning (ability to function, daytime alertness, and sense of well-being) were not significantly different between the two treatment groups. Among patients who napped, eszopiclone patients reported fewer naps (p = 0.03) and less cumulative naptime (median: 98 min placebo, 70 min eszopiclone, p = 0.07). Unpleasant taste, dry mouth, somnolence, and dizziness were higher in the eszopiclone group (12.5%, 8.8%, 6.6%, and 6.6%, respectively) than in the placebo group (0%, 1.6%, 5.5%, and 1.6%, respectively). CONCLUSION: In this study, eszopiclone was well tolerated and produced significant improvements in both polysomnographic and patient-reported measures of sleep maintenance, sleep induction, and sleep duration in elderly patients with chronic primary insomnia.

The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study.

OBJECTIVE: This study examined the effects of milnacipran on polysomnographic (PSG) measures of sleep and subjective complaints in patients with fibromyalgia and disturbed sleep. METHODS: This was a single-site, double-blind, placebo-controlled, two-period crossover PSG study. Eligible subjects (aged 28-72 y) were randomized (1:1) to milnacipran (100 mg/d) or placebo for crossover period 1, and vice versa for period 2. Each crossover period comprised a dose-escalation and dose-maintenance phase, with a 2-w taper/washout between periods. In-laboratory PSGs were collected at baseline, and at the end of each treatment period. The primary endpoints were the difference in PSG-recorded wake after sleep onset (WASO), number of awakenings after sleep onset (NAASO), and sleep efficiency (SE) between 4 w of maintenance treatment with milnacipran and placebo. Other PSG measures, subject-rated sleep, fatigue, physical functioning, and pain were assessed. Post hoc analysis was performed in subjects showing at least 25% reduction in pain from baseline in the Brief Pain Inventory Score (responders). RESULTS: Of 19 subjects randomized, 15 completed both periods. Subjects treated with milnacipran showed no significant improvements in WASO and NAASO, but showed reduced SE (p = 0.049). Milnacipran did not show significant improvement in other PSG parameters or subjective endpoints. Two thirds of completers met responder criteria and additionally showed a significant improvement in daily effect of pain (p = 0.043) and subjective sleep quality (p = 0.040). CONCLUSION: The data suggest that milnacipran is not sedating in most patients with fibromyalgia and improvements in sleep are likely a result of pain improvement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT01234675.

A 2-week efficacy and safety study of eszopiclone in elderly patients with primary insomnia.

STUDY OBJECTIVES: Evaluate the efficacy of eszopiclone in primary insomnia. DESIGN/SETTING: Randomized, double-blind, placebo-controlled multicenter in outpatient setting with weekly visits. PARTICIPANTS: Two-hundred thirty one men and women aged 65 to 85 years (mean age 72.3 years) with primary insomnia, as defined by the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition. INTERVENTIONS: Eszopiclone 1 mg (n = 72), eszopiclone 2 mg (n = 79), or placebo (n = 80) nightly for 2 weeks. MEASUREMENTS/RESULTS: Efficacy was assessed using an interactive voice response system. Following the predefined hierarchical testing strategy, the eszopiclone 2-mg group had a significantly shorter sleep latency compared with placebo over the double-blind period (P = .0034). The eszopiclone 2-mg group had significantly longer total sleep time (P = .0003) and eszopiclone 1-mg group had significantly shorter sleep latency (P < or = .012) compared with placebo. The eszopiclone 1-mg group was not significantly different from placebo on total sleep time or any other secondary efficacy endpoint. Secondary analyses indicated that the eszopiclone 2-mg group had significantly less wake after sleep onset; significantly fewer and shorter in duration daytime naps; and significantly higher ratings of sleep quality and depth, daytime alertness, and sense of physical well-being compared with placebo (P < .05). Eszopiclone was well tolerated. The most frequent treatment-related adverse event was unpleasant taste. CONCLUSION: Nightly treatment with eszopiclone 1 mg effectively induced sleep, while the 2-mg dose was effective in inducing and maintaining sleep. Eszopiclone was well tolerated in elderly patients with primary insomnia, and the sleep efficacy was accompanied by significantly less napping and significantly higher ratings of daytime alertness, sense of physical well-being, and several quality-of-life parameters at the higher dose.

The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial.

BACKGROUND: While melatonin agonists are known to regulate circadian sleep rhythms, it is not clear whether melatonin agonists have a direct soporific effect. It has been suggested that melatonin's soporific effect is secondary to its ability to induce hypothermia. beta-Methyl-6-chloromelatonin is a high-affinity melatonin receptor agonist that is not associated with hypothermia. The purpose of the present study was to determine if the melatonin agonist beta-methyl-6-chloromelatonin has a direct soporific effect in subjects with primary insomnia. METHOD: A double-blind, placebo-controlled, crossover safety and efficacy study of 20 mg, 50 mg, and 100 mg of beta-methyl-6-chloromelatonin and placebo was conducted in subjects with DSM-IV-TR primary insomnia. Of 84 subjects screened, 40 progressed to randomly receive each of 3 beta-methyl-6-chloromelatonin doses or placebo on each of 2 consecutive nights with 5-day washout periods between treatments. The effect of treatment on both polysomnographic and subjectively measured sleep parameters, next-morning psychomotor performance, and safety measures was determined. The primary outcome measure was latency to persistent sleep measured by polysomnography. RESULTS: A significant effect of beta-methyl-6-chloromelatonin on the primary efficacy variable, latency to persistent sleep, was observed (p = .0003). The 20-mg dose resulted in a significant 31% improvement in sleep latency compared with placebo, while significant 32% and 41% improvements were observed at the 50-mg and 100-mg doses, respectively (20 mg, p = .0082; 50 mg, p = .0062; 100 mg, p < .0001). Similarly, a significant effect of beta-methyl-6-chloromelatonin on subjective measures of time to fall asleep occurred (p = .0050), with significant improvement observed at both the 50-mg and 100-mg doses (p = .0350 and .0198, respectively) and a trend toward improvement observed at the 20-mg dose (p = .0582). Adverse events were mild to moderate in severity and did not differ in frequency between beta-methyl-6-chloromelatonin and placebo treatments. CONCLUSION: beta-Methyl-6-chloromelatonin significantly decreases both objective and subjective measures of sleep latency in subjects with primary insomnia. Thus, these data suggest that mel-atonin agonists may exert a direct soporific effect, as previous research indicates that beta-methyl-6-chloromelatonin is not associated with changes in body temperature, heart rate, or blood pressure.

Effects of temazepam 7.5 mg and temazepam 15 mg on sleep maintenance and sleep architecture in a model of transient insomnia.

OBJECTIVE: To compare the effects of temazepam 7.5 mg and temazepam 15 mg on sleep maintenance during the last third of the night (last 160 min) and on sleep architecture throughout the night. RESEARCH DESIGN AND METHODS: This was a retrospective analysis of a previously reported double-blind, randomized, uncontrolled, parallel-group, multicenter study. Healthy subjects with previous but no current complaints of transient insomnia were enrolled. Transient insomnia was induced in the sleep laboratory by means of the 'first night' effect and by implementing a 2-h phase advance. The effects of both doses of temazepam on polysomnographic measures of sleep were evaluated for 1 night. The primary, prospectively-defined analysis of this study showed that 7.5-mg and 15-mg doses of temazepam had equivalent effects on latency to persistent sleep, total sleep time, and the number of sleep interruptions recorded over an 8-h period. Both doses were well tolerated. The post hoc analysis reported here compared these 2 doses for their effects on sleep maintenance and architecture. Sleep efficiency during the last third of the night was designated as the primary endpoint. The methodology for this analysis was fully defined and documented prior to re-analysis of the database for these parameters. RESULTS: Sixty-five subjects received temazepam 7.5 mg and 66 received temazepam 15 mg. No statistically significant differences between doses were detected for sleep efficiency or number of sleep interruptions during the last third of the night. Sleep architecture (measured over 8 h) did not differ significantly between groups. CONCLUSIONS: The 7.5-mg and 15-mg doses of temazepam were equally effective for maintaining sleep during the last third of the night. Continuity of sleep throughout the night, as reflected by sleep architecture, was also similar regardless of dose. In keeping with current practice guidelines, initiation of treatment with temazepam for transient insomnia should begin with the 7.5 mg dose.

Self-reported sleep in postmenopausal women.

OBJECTIVE: We aimed to find how self-reported sleep (measured by the St. Mary's Hospital Sleep Questionnaire) in postmenopausal women having hot flash activity was related to objective sleep (actigraphy), psychological and somatic symptoms [Women's Health Questionnaire (WHQ)], and cognitive test performance (computerized tests). A secondary aim was to find if self-reported sleep showed expected correlations with hyperarousal (Hyperarousal Scale). DESIGN: Drug trial baseline data from 88 healthy, postmenopausal women were retrospectively analyzed. Multivariate regression was used to adjust for confounder variables and test whether differences in self-reported sleep measures were systematically associated with differences in objective sleep, WHQ symptom measures, or cognitive test performance scores. RESULTS: Increased self-report scores for low sleep quality were associated with an increased risk of WHQ symptoms and reduced cognitive test performance. Self-reported sleep measures showed little correlation with their analogous objective measures. Self-reported low sleep quality proved most closely associated with the WHQ symptoms of tiredness, clumsiness, and difficulty concentrating. Women whose self-reported sleep-onset latency times were longer than the median overestimated their objective sleep onset time by 30 min, whereas the other women underestimated theirs by 15 min (P < 0.0001). Women whose self-reported total sleep was longer or shorter than the median, respectively, underestimated objective sleep times by 9 and 71 min (P < 0.0001). High hyperarousal scores were associated with underestimations of objective sleep. CONCLUSION: Self-reports of lower sleep quality were associated with increased WHQ psychological and somatic symptom measures and decreased cognitive test performance more than with differences in objective sleep. Self-reported trouble sleeping may signal problems independent from objectively low sleep quality, such as subjective distress or diminished cognitive function.

The pharmacokinetics of sodium oxybate oral solution following acute and chronic administration to narcoleptic patients.

This trial was conducted to evaluate the pharmacokinetics and safety of a sodium oxybate (gamma-hydroxybutyrate [GHB]) oral solution in narcoleptic patients after acute and chronic treatment. An open-label, two-period, two-treatment study design was used. Trial subjects included 13 patients with polysomnographically confirmed narcolepsy. The patients were administered a bedtime dose of 4.5 g of sodium oxybate while in a sleep research center. They were subsequently treated with sodium oxybate at the nightly dose of 4.5 g for 8 weeks. The patients then returned to the sleep center and were again treated with the 4.5-g sodium oxybate dose at bedtime. Blood samples (5 mL) were collected at 18 time points before and up to 7 hours after both the first dose of sodium oxybate and following 8 weeks of dosing. Plasma samples were analyzed for oxybate content by a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Noncompartmental methods were applied in the determination of pharmacokinetic parameters from each patient's plasma oxybate concentration versus time curve. No serious adverse events were recorded, and all patients completed the study. Headache, enuresis, and leg cramps were reported as adverse experiences. With both acute and chronic dosing, sodium oxybate was rapidly absorbed and eliminated with an apparent half-life of about 40 minutes. The only changes observed in the kinetics of oxybate after 8 weeks of treatment were a 13% and 16% increase in peak concentration (C(max)) and systemic exposure (AUC), respectively. The pharmacokinetics of sodium oxybate in narcoleptic patients were not changed in any clinically significant manner when the drug was chronically administered. The drug was well tolerated.

Effect of zolpidem on sleep in women with perimenopausal and postmenopausal insomnia: a 4-week, randomized, multicenter, double-blind, placebo-controlled study.

BACKGROUND: Although most adults in the United States obtain less sleep than they need, women report more sleep deprivation throughout their lifetime than do men. The prevalence of self-reported sleep difficulty increases as women make the transition from the premenopausal to the postmenopausal period. OBJECTIVE: The purpose of this study was to assess the clinical efficacy and safety of zolpidem as a treatment for insomnia in perimenopausal and postmenopausal women. METHODS: Women who were perimenopausal or postmenopausal for >or=6 months, who had developed insomnia in conjunction with menopausal symptoms, and who had difficulty maintaining sleep or had nonrestorative sleep for >or=6 months were eligible for this 4-week, multicenter study. Sleep maintenance difficulty had to occur an average of >or=3 nights per week and had to be accompanied by >or=2 nocturnal hot flashes, hot flushes, or night sweats. Patients were randomized in a double-blind fashion to 1 of 2 treatment groups--zolpidem 10 mg or placebo. Capsules were provided in weekly blister cards, and patients were instructed to take 1 capsule each night at bedtime. Patients recorded estimates of their sleep quality and quantity and daytime functioning on daily morning and evening questionnaires, and made weekly global assessments of sleep. RESULTS: The study included 141 women (mean age +/- SD, 50.8 +/- 4.5 years; age range, 39-60 years). Increases in reported total sleep time were significantly greater in the zolpidem group than in the placebo group (P < 0.01) for each treatment week. Wake time after sleep onset and number of awakenings decreased significantly in the zolpidem group compared with the placebo group (P < 0.05). Each week, approximately twice as many patients in the zolpidem group as in the placebo group reported improved sleep (P < 0.001 for each week). The improvement in sleep-related difficulty with daytime functioning was significantly greater in the zolpidem group than in the placebo group (P < 0.05). The effects of zolpidem did not diminish with the duration of treatment. CONCLUSIONS: Zolpidem 10 mg/d was effective and well tolerated in the treatment of menopause-related insomnia in perimenopausal and postmenopausal women.

Comparison of temazepam 7.5 mg with temazepam 15 mg for the treatment of transient insomnia.

OBJECTIVE: To demonstrate the equivalent efficacy of temazepam 7.5 mg and temazepam 15 mg for the treatment of transient insomnia. RESEARCH DESIGN AND METHODS: This was a double-blind, parallel group, multicenter study. Healthy male and female subjects with previous but not current complaints of transient insomnia were enrolled. Transient insomnia was induced in the sleep laboratory by means of the 'first night' effect and by implementing a 2-h phase advance. The effects of both doses of temazepam on polysomnographic (PSG) measures of sleep were evaluated for one night. Latency to persistent sleep (LPS) and total sleep time (TST) were designated as the primary efficacy endpoints. RESULTS: One hundred and thirty-one subjects completed the study: 65 received the 7.5-mg dose, and 66 received the 15-mg dose. Treatment groups begin with the lowest effective dose, i.e., 7.5 mg. were well matched based on background demographics. No statistically significant differences between doses were detected for LPS, TST,or any other objective (PSG) measure of sleep. Furthermore, both doses were found to be clinically equivalent for LPS and TST based on predetermined criteria. Temazepam was well tolerated, and no significant differences between doses were found for adverse event (AE) incidence, mean score on the Digit Symbol Substitution Task, or mean scores on questions related to tolerability from the Leeds Sleep Evaluation Questionnaire. CONCLUSIONS: The 7.5-mg and 15-mg doses of temazepam were equally effective for the treatment of transient insomnia. In keeping with current practice guidelines, initiation of treatment with temazepam for transient insomnia should

Comparative efficacy of zolpidem and temazepam in transient insomnia.

This study compared hypnotic effects of zolpidem 10 mg, temazepam 15 mg and placebo in healthy adults. Two factors expected to promote insomnia, the 'first night effect' and a 2-hour phase advance, were combined in a single night laboratory-based double-blinded protocol. This was a multi-center study, with data collected in 13 sleep laboratories. Subjects with normal sleep histories and without prior sleep laboratory experience were randomly assigned to treatment groups. Medications were administered 15 min before lights out, with polysomnographic monitoring for 7.5 h. Subjective questionnaires and performance tests, digit symbol substitution test (DSST) and symbol copying test (SCT), were administered at study entry and after arising. 630 subjects completed the study and provided data analyzed using repeated measures ANOVAs. Neither agent significantly reduced objective sleep latency relative to placebo. Zolpidem reduced awakenings and wake after sleep onset (WASO); temazepam did not. Both agents improved sleep efficiency and most subjective sleep measures relative to placebo, with zolpidem superior for five of six subjective outcome measures compared to temazepam. SCT, morning sleepiness and morning concentration were not altered by any treatment. Zolpidem significantly reduced morning DSST performance; temazepam did not. Zolpidem 10 mg provided greater subjective hypnotic efficacy than temazepam 15 mg in this model of transient insomnia, with reduced polysomnographic awakenings and WASO. Impairment of DSST was seen with zolpidem but not temazepam. Copyright 2001 John Wiley & Sons, Ltd.

Efficacy and safety of doxepin 6 mg in a model of transient insomnia.

INTRODUCTION: The efficacy and safety of doxepin (DXP) 6mg tablets were evaluated in healthy adults in a model of transient insomnia. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled study in healthy adults using a model of transient insomnia. A first-night effect combined with a 3-h phase advance was implemented to induce transient insomnia in healthy adults. Subjects received a single night time dose of placebo (PBO; N=282) or DXP 6mg (N=283) in a sleep laboratory. Efficacy was evaluated objectively (polysomnography; PSG) and subjectively (morning questionnaire). Consistent with the model utilized, the primary endpoint was latency to persistent sleep (LPS); secondary PSG endpoints included wake after sleep onset (WASO; key secondary endpoint), total sleep time (TST), wake time after sleep (WTAS) and sleep efficiency (SE; overall, by quarter of the night and hourly); secondary subjective endpoints included latency to sleep onset (LSO), subjective WASO (sWASO), subjective TST (sTST) and sleep quality. RESULTS: DXP 6mg demonstrated statistically significant improvements in LPS (13min decrease versus PBO; p<0.0001), WASO (39min less than PBO; p<0.0001), TST (51min more than PBO; p<0.0001), WTAS (p<0.0001), overall SE (p<0.0001), SE in each quarter of the night (p<0.0001) and SE in each of the 8h (p⩽0.0003), all versus PBO. Additionally, DXP 6mg significantly improved subjective variables including LSO (p<0.0001), sWASO (p=0.0063), sTST (p<0.0001), and sleep quality (p=0.0004), versus PBO. There was no consistent evidence of next-day residual sedation and also minor sleep stages alterations. The incidence of adverse events was comparable to placebo. CONCLUSIONS: In this model of transient insomnia, DXP 6mg demonstrated significant improvements in sleep onset, sleep maintenance, sleep duration and sleep quality, and also appeared to reduce early morning awakenings. These data suggest that DXP 6mg may be effective and well tolerated in adults experiencing transient insomnia.

Biomechanical comparison of a new staple technique with tension band wiring for transverse patella fractures.

BACKGROUND: The tension band wiring technique is the most common method of transverse patella fracture fixation. Since post-operative instabilities have been reported for this technique, alternative osteosynthesis solutions are of interest. We investigated the biomechanical behaviour of a new staple technique for treatment of transverse patella fractures in a cadaveric model. METHODS: Eight human cadaveric knees with femur and tibia including soft tissue were used. A transverse osteotomy of the patella was created. Each specimen was fixed consecutively with tension band wiring and two Nitinol compression staples. Testing was performed by pull on the quadriceps tendon between a 90 degrees flexed position and full knee extension for up to 5,000 cycles. FINDINGS: At 1,000 cycles, fracture site displacements in flexion and extension were significantly smaller for the staple group at the ventral aspect of the patella as compared to the tension band wiring group. With a failure criterion of 2mm fracture site displacement, cycles until failure were significantly smaller for the staple group. INTERPRETATION: This study provides evidence based on a cadaveric model that compression staples have a promising potential to treat transverse patella fractures.

Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebo-controlled crossover study.

OBJECTIVES: Evaluate efficacy and safety of the histamine-H1 antagonist doxepin at doses of 1 mg, 3 mg, and 6 mg in elderly adults with primary insomnia. DESIGN: A randomized, double-blind, placebo-controlled, crossover design was used in this population of elderly adults with primary insomnia (DSM-IV). Each treatment period consisted of 2 polysomnographic (PSG) assessment nights with a 5- or 12-day drug-free interval between periods. The study was conducted from September 2004 to January 2005. SETTING: Sleep laboratories in 11 sleep centers in the United States. PARTICIPANTS: Elderly adults with primary insomnia. INTERVENTION: Doxepin 1 mg, 3 mg, and 6 mg. MEASUREMENTS: Efficacy was assessed using PSG and patient-reported measures. RESULTS: Seventy-six patients were randomly assigned. All 3 doxepin doses produced dose-related significant improvements in PSG-determined wake time during sleep (p < .0001), wake time after sleep onset (p < .0001), total sleep time (p < .0001), and overall sleep efficiency (p < .0001) versus placebo. At the 3-mg and 6-mg doses, sleep efficiency was significantly improved during all thirds of the night (p < .05). There was a dose-related decrease in patient-reported sleep latency, with the 6-mg dose achieving statistical significance in latency to sleep onset (p = .0181). The pattern of the remaining subjective efficacy results was consistent with PSG. All 3 doxepin doses had side effect profiles comparable to placebo, with no spontaneously reported anticholinergic effects, no memory impairment, and no significant next-day residual effects. CONCLUSIONS: In this 2-night study of elderly adults with primary insomnia, doxepin doses of 1 mg, 3 mg, and 6 mg were well tolerated and produced significant improvement in objective and subjective sleep maintenance and duration endpoints that persisted into the final hour of the night. Positive effects on patient-reported sleep onset were observed at the highest dose. All 3 doxepin doses had a safety profile comparable to placebo. These data demonstrate that doxepin was efficacious in improving sleep in elderly adults.

Effects of desloratadine and alcohol coadministration on psychomotor performance.

OBJECTIVE: This study was set up to evaluate the effects of desloratadine 7.5 mg daily, with and without alcohol, on sedation and psychomotor performance. RESEARCH METHODS: In a double-blind, placebo-controlled, four-way crossover trial, 25 adult patients were randomized to desloratadine 7.5 mg, desloratadine 7.5 mg plus alcohol, placebo, or placebo plus alcohol. Alcohol was weight adjusted to an average blood alcohol concentration of 0.1%. Assessments included the modified Romberg test, Stanford Sleepiness Scale, Digit Symbol Substitution Test, Serial Add Subtract Reaction Time Test, and the Psychomotor Vigilance Test. The primary variable was the mean score of each of the five tests averaged over the treatment period, expressed as the mean percent change from baseline. RESULTS: Across these assessments, differences between desloratadine alone or with alcohol versus placebo alone or without alcohol, were not significant, whereas most differences between desloratadine and placebo alone versus desloratadine and placebo with alcohol were significant (p < 0.01). Thus, with or without alcohol, desloratadine 7.5 mg does not increase sedation or impair psychomotor performance. Most adverse events (AEs) were mild-to-moderate in severity, with the most frequently reported individual AEs being headache, fatigue, nausea, vomiting, and dry mouth. The study does have potential limitations. The measures used are restricted to a particular profile of the known effects of alcohol only, and the relatively high doses of alcohol used alone demonstrate effects on psychomotor function and attention. CONCLUSIONS: A single dose of desloratadine does not potentiate alcohol-mediated CNS impairment. Desloratadine alone or in combination with alcohol was safe and well tolerated.

Effects of synthetic conjugated estrogens A on sleep quality in postmenopausal women with nocturnal diaphoresis and/or hot flushes: a pilot study.

In a single-center, double-blind, placebo-controlled pilot study, patients who received 0.625 mg daily of synthetic conjugated estrogens A experienced a statistically significant reduction in the average number of hot flushes and galvanic skin responses. The polysomnographic change in sleep measures did not reach statistical significance, but the data suggest an overall improvement in sleep quality in the treatment group.