Sleep-Wake Survival Dynamics in People with Insomnia.

INTRODUCTION: Assessing objective measures of sleep fragmentation could yield important features reflecting impaired sleep quality in people with insomnia. Survival analysis allows the specific examination of the stability of NREM sleep, REM sleep and wake. The objective of this study was to assess the differences between survival dynamics of NREM sleep, REM sleep and wake between people with insomnia and healthy controls. METHODS: We analyzed retrospective polysomnography recordings from 86 people with insomnia and 94 healthy controls. For each participant, survival dynamics of REM sleep, NREM sleep and wake were represented using Weibull distributions. We used lasso penalized parameter selection in combination with linear regression to analyze the difference between participant groups with respect to the Weibull scale and shape parameters, while correcting for age, sex, total sleep time and relevant interaction effects. RESULTS: Significant effects of group were found for the NREM scale parameter, and for the wake scale and shape parameters. Results indicated that people with insomnia had less stable NREM sleep and more stable wake after sleep onset compared to healthy controls. Additionally, the altered distribution of wake segment lengths indicated an increased difficulty to fall asleep after longer awakenings in the insomnia group. However, these differences were mainly observed in younger participants. Significant effects of group for the survival parameters of REM sleep were not found. CONCLUSION: As illustrated by our results, survival analysis can be very useful for disentangling different types of sleep fragmentation in people with insomnia. For instance, the current findings suggest that people with insomnia have an increased fragmentation of NREM sleep, but not necessarily of REM sleep. Additional research into the underlying mechanisms of NREM sleep fragmentation could possibly lead to a better understanding of impaired sleep quality in people with insomnia, and consequently to improved treatment.

Assessing sleep-wake survival dynamics in relation to sleep quality in a placebo-controlled pharmacological intervention study with people with insomnia and healthy controls.

RATIONALE: The mechanisms underlying impaired sleep quality in insomnia are not fully known, but an important role for sleep fragmentation has been proposed. OBJECTIVES: The aim of this study is to explore potential mechanisms of sleep fragmentation influencing alterations of perceived sleep quality. METHODS: We analyzed polysomnography (PSG) recordings from a double-blind crossover study with zopiclone 7.5 mg and placebo, in elderly participants with insomnia complaints and age-matched healthy controls. We compared survival dynamics of sleep and wake across group and treatment. Subsequently, we used a previously proposed model to estimate the amount of sleep onset latency (SOL) misperception from PSG-defined sleep fragmentation. Self-reported and model-estimated amount of SOL misperception were compared across group and treatment, as well as model prediction errors. RESULTS: In the zopiclone night, the average segment length of NREM sleep was increased (group F = 1.16, p = 0.32; treatment F = 8.89, p < 0.01; group x treatment F = 0.44, p = 0.65), while the segment length of wake was decreased (group F = 1.48, p = 0.23; treatment F = 11.49, p < 0.01; group x treatment F = 0.36, p = 0.70). The self-reported and model-estimated amount of SOL misperception were lower during the zopiclone night (self-reported group F = 6.08, p < 0.01, treatment F = 10.8, p < 0.01, group x treatment F = 2.49, p = 0.09; model-estimated F = 1.70, p = 0.19, treatment F = 16.1, p < 0.001, group x treatment F = 0.60, p = 0.55). The prediction error was not altered (group F = 1.62, p = 0.20; treatment F = 0.20, p = 0.65; group x treatment F = 1.01, p = 0.37). CONCLUSIONS: Impaired subjective sleep quality is associated with decreased NREM stability, together with increased stability of wake. Furthermore, we conclude that zopiclone-induced changes in SOL misperception can be largely attributed to predictable changes of sleep architecture.

Modeling sleep onset misperception in insomnia.

OBJECTIVES: To extend and validate a previously suggested model of the influence of uninterrupted sleep bouts on sleep onset misperception in a large independent data set. METHODS: Polysomnograms and sleep diaries of 139 insomnia patients and 92 controls were included. We modeled subjective sleep onset as the start of the first uninterrupted sleep fragment longer than Ls minutes, where parameter Ls reflects the minimum length of a sleep fragment required to be perceived as sleep. We compared the so-defined sleep onset latency (SOL) for various values of Ls. Model parameters were compared between groups, and across insomnia subgroups with respect to sleep onset misperception, medication use, age, and sex. Next, we extended the model to incorporate the length of wake fragments. Model performance was assessed by calculating root mean square errors (RMSEs) of the difference between estimated and perceived SOL. RESULTS: Participants with insomnia needed a median of 34 minutes of undisturbed sleep to perceive sleep onset, while healthy controls needed 22 minutes (Mann-Whitney U = 4426, p < 0.001). Similar statistically significant differences were found between sleep onset misperceivers and non-misperceivers (median 40 vs. 20 minutes, Mann-Whitney U = 984.5, p < 0.001). Model outcomes were similar across other subgroups. Extended models including wake bout lengths resulted in only marginal improvements of model outcome. CONCLUSIONS: Patients with insomnia, particularly sleep misperceivers, need larger continuous sleep bouts to perceive sleep onset. The modeling approach yields a parameter for which we coin the term Sleep Fragment Perception Index, providing a useful measure to further characterize sleep state misperception.

Effects of Between- and Within-Subject Variability on Autonomic Cardiorespiratory Activity during Sleep and Their Limitations on Sleep Staging: A Multilevel Analysis.

Autonomic cardiorespiratory activity changes across sleep stages. However, it is unknown to what extent it is affected by between- and within-subject variability during sleep. As it is hypothesized that the variability is caused by differences in subject demographics (age, gender, and body mass index), time, and physiology, we quantified these effects and investigated how they limit reliable cardiorespiratory-based sleep staging. Six representative parameters obtained from 165 overnight heartbeat and respiration recordings were analyzed. Multilevel models were used to evaluate the effects evoked by differences in sleep stages, demographics, time, and physiology between and within subjects. Results show that the between- and within-subject effects were found to be significant for each parameter. When adjusted by sleep stages, the effects in physiology between and within subjects explained more than 80% of total variance but the time and demographic effects explained less. If these effects are corrected, profound improvements in sleep staging can be observed. These results indicate that the differences in subject demographics, time, and physiology present significant effects on cardiorespiratory activity during sleep. The primary effects come from the physiological variability between and within subjects, markedly limiting the sleep staging performance. Efforts to diminish these effects will be the main challenge.

Residual effects of low-dose sublingual zolpidem on highway driving performance the morning after middle-of-the-night use.

STUDY OBJECTIVE: To evaluate next-morning driving performance after middle-of-the-night use of zolpidem 3.5 mg in a buffered sublingual formulation (ZST). DESIGN: Single-center, four-period, randomized, double-blind, placebo-controlled, crossover study. SETTING: Maastricht University, The Netherlands. PARTICIPANTS: Forty healthy volunteers (20 females). INTERVENTIONS: Single dose of ZST administered in the middle of the night at 3 and 4 h before driving, zopiclone 7.5 mg at bedtime 9 h before driving, and placebo. MEASUREMENTS: Performance in a 100-km standardized highway driving test in normal traffic measuring standard deviation of lateral position (SDLP) - an index of weaving. Drug-placebo changes in SDLP > 2.5 cm were considered to reflect clinically relevant driving impairment. RESULT: For ZST, Max McNemar symmetry analyses showed that the proportion of drivers classified as impaired was increased 3 h after dosing (P < 0.012), but not 4 h after dosing. Mean increases in SDLP from placebo, although statistically significant, were small (1.46 cm [P < 0.0001] at 3 h and 0.83 cm [P = 0.0174] at 4 h). The morning after zopiclone, 45% of the drivers were classified as impaired with a mean increase in SDLP of 2.46 cm (P < 0.0001). There were no significant sex differences in effects of ZST and zopiclone. CONCLUSION: Zolpidem 3.5 mg in a buffered sublingual formulation has a minimal risk of impairing driving performance in the morning ≥ 4 hours after middle-of-the night use. When taken 3 hours before driving, the drug may have impairing effects so caution should be exercised if medication is taken other than as indicated. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT01106859; Trial Name: Driving Performance After Middle of the Night Administration of 3.5 mg Zolpidem Tartrate Sublingual Tablet; http://clinicaltrials.gov/ct2/show/NCT01106859.

Zopiclone's residual effects on actual driving performance in a standardized test: a pooled analysis of age and sex effects in 4 placebo-controlled studies.

BACKGROUND: In many European countries, Canada, and Japan, the nonbenzodiazepine zopiclone is now among the most frequently prescribed hypnotic drugs. This finding can be explained by the growing view among physicians that zopiclone is more effective and safer than conventional benzodiazepines. However, in 4 studies using similar procedures, it has been shown that zopiclone 7.5 mg causes moderate to severe impairment in driving performance. OBJECTIVE: The goal of the present article was to review these studies and analyze the pooled data to determine whether the severity of effects is modified by the sex and age of the subjects. METHODS: The driving data of the placebo and zopiclone 7.5 mg evening treatment periods from a total of 4 studies conducted at Maastricht University were included in this pooled analysis. All studies were conducted according to balanced double-blind, crossover designs. The effects on driving were always measured the next morning, between 10 and 11 hours after administration, by using a standardized highway driving test. A total of 101 healthy volunteers of both sexes in equal proportions (with no reports of insomnia) participated. Subjects comprised young volunteers (age range, 21-45 years) in 3 studies and older volunteers (age range, 55-75 years) in the fourth study. RESULTS: Results show that zopiclone 7.5 mg has significant and clinically relevant performance-impairing effects on driving in the morning, until 11 hours after bedtime ingestion. The effects did not differ between male and female subjects and did not increase with age, at least until 75 years. The effects of zopiclone 7.5 mg are comparable to the effects of a mean blood alcohol concentration between 0.5 and 0.8 mg/mL, which has been associated with a 2- to 3-fold increase in the risk of becoming involved in a traffic accident. CONCLUSIONS: We concluded that patients using an evening dose of zopiclone 7.5 mg should avoid activity in skilled work and participation in traffic the morning after intake. General practitioners' beliefs regarding the beneficial safety profile of zopiclone may need adjustment, and patients using zopiclone 7.5 mg should be warned accordingly. There is no need to differentiate warnings about zopiclone's residual impairing effects depending on the sex of the patient.

Highway driving in the elderly the morning after bedtime use of hypnotics: a comparison between temazepam 20 mg, zopiclone 7.5 mg, and placebo.

A major problem related to hypnotic drug use is residual sedation the morning after bedtime administration. This constitutes a particular safety hazard for patients who have to drive a car the next morning. Information on the severity of residual effects is mainly derived from studies conducted with young healthy volunteers. However, most users of hypnotics are older people who may be more sensitive to drug effects. The aim of this study was to evaluate the residual effects the morning after evening doses of temazepam 20 mg and zopiclone 7.5 mg on driving performance in healthy elderly drivers. Eighteen healthy elderly drivers (10 females and 8 males; mean age, 64.3 years) participated in a double-blind, 3-way crossover study. Treatments were single oral doses of temazepam 20 mg, zopiclone 7.5 mg, and placebo administered at bedtime. Subjects performed a standardized highway driving test between 10 and 11 hours after hypnotic intake. Before and after the driving test, cognitive performance was assessed. Driving performance did not differ between temazepam and placebo but was significantly impaired after zopiclone 7.5 mg (P < 0.002). The results of the laboratory tests were in line with the effects on driving of both hypnotics. Temazepam 20 mg is unlikely to impair driving 10 hours or more after bedtime administration in healthy elderly aged 75 years or younger. Zopiclone 7.5 mg moderately impairs driving in the elderly at least until 11 hours after administration. The magnitude of impairing effects in the elderly was comparable with those found previously in younger volunteers.

Highway driving performance and cognitive functioning the morning after bedtime and middle-of-the-night use of gaboxadol, zopiclone and zolpidem.

Gaboxadol is a selective extrasynaptic GABA(A) receptor agonist previously in development for the treatment of insomnia. Due to its short half-life (1.5-2 h) it is expected to be free from residual effects the next morning. The present study assessed the residual effects of evening and middle-of-the-night administration of 15 mg of gaboxadol on cognitive, psychomotor and driving performance. Twenty-eight healthy volunteers entered the study with 25 (12 women; mean age 31.4 years) completing a double-blind, placebo-controlled, active-referenced five-way cross-over study. Each treatment night subjects ingested one capsule at 23:00 hours and one at 04:00 hours. Treatments were placebo at both times, 15 mg gaboxadol or 7.5 mg zopiclone followed by placebo, and placebo followed by 15 mg gaboxadol or 10 mg zolpidem. Effects on cognition and psychomotor performance were assessed between 07:30 and 08:30 hours and on driving between 09:00 and 10:00 hours. Driving, as measured by standard deviation of lateral position in an on-the-road driving test, was almost significantly (P < 0.07) impaired after evening administration of gaboxadol for the all-subjects-completed set (n = 25) but significantly (P < 0.05) in the full analysis set (n = 28). Effects of all other active treatments on driving were significant. Evening administration of gaboxadol had minor effects on divided attention only, whereas middle-of-the-night administration impaired performance significantly in all tests except memory. Zolpidem and zopiclone impaired performance significantly in every test except tracking after zopiclone; 15 mg of gaboxadol can produce minor residual effects on driving after evening administration. Administration later at night is associated with moderately impairing residual effects on driving and psychomotor performance but not on memory.

Cognitive, psychomotor and actual driving performance in healthy volunteers after immediate and extended release formulations of alprazolam 1 mg.

RATIONALE: Alprazolam extended-release (XR) is approved for the treatment of panic disorder. This sustained formulation is absorbed in a delayed manner and is therefore expected to produce fewer and less severe side effects than its immediate release equivalent (alprazolam IR). The effect of alprazolam XR on potentially dangerous daily activities, such as driving a car, is expected to be less as compared to alprazolam IR. OBJECTIVES: The present study was designed to compare the effects of alprazolam XR (1 mg) and alprazolam IR (1 mg) on actual driving ability and cognitive function. METHOD: Eighteen healthy volunteers (aged 20-45 years) participated in a double-blind, placebo-controlled, three-way crossover study. At 4 h post-dose, subjects performed a standardized driving test on a primary highway in normal traffic. Cognitive and psychomotor tests were assessed 1, 2.5, and 5.5 h post-dose. Memory functioning was measured only 1 h after administration. RESULTS: Both formulations severely impaired driving performance between 4 and 5 h after administration. The magnitude of impairment in the driving test observed with alprazolam XR was about half that observed with alprazolam IR. Laboratory test results were in line with the driving data. CONCLUSIONS: The acute impairing effects of alprazolam XR 1 mg on driving and psychomotor functions were generally less, as compared to its immediate-release equivalent, but still of sufficient magnitude to increase the risk of becoming involved in traffic accidents.