Tim R.M. Leufkens

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 GABAA 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.

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

Abstract 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.

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.

Effects of anxiolytics on driving

Most of the currently used anxiolytic agents act via GABA or serotonin. The latter include drugs traditionally classified as antidepressants, which are reviewed in the next chapter. This chapter reviews the results of ten experimental studies investigating the effects of anxiolytics on driving performance using over-the-road tests. Results show that only the serotonergic drugs (buspirone, ondansetron and ritanserin) had a low potential for impairment. All GABA-agonists (diazepam, lorazepam, oxazepam, clorazepate, alprazolam, alpidem, suriclone) had moderate to severely impairing effects on driving in the doses studied. Impairment was clearly dose dependent, and increased on average with increasing blood concentrations. However, most studies analyzing correlations between drug concentrations in plasma and effects on driving performance found low and non-significant correlations, indicating that prediction of impairment from blood concentrations is problematic.

Insomnia, Hypnotic Drugs and Traffic Safety

Sleep medication helps patients who suffer from insomnia to fall asleep and maintain asleep, but unfortunately hypnotic drugs often have residual effects that may affect daily activities such as driving a car. Epidemiological studies show that patients who use sleep medication are at increased risk of becoming involved in traffic accidents. These studies show an increased traffic accident risk for patients using benzodiazepine hypnotics or zopiclone.

Electroencephalography during on-the-road driving in older untreated insomnia patients and normal sleepers

Insomniacs report decreased performance in daily routines, which may have detrimental consequences for car driving. We compared changes over time in driving performance (measured as Standard Deviation of Lateral Position - SDLP) and background EEG between 20 untreated insomnia patients (52-70 years old) and 21 normal sleepers (54-73 years old) during a 1h on-the-road driving test after a normal night of sleep, in the morning. SDLP did not differ between groups and increased slightly over time to similar degrees in both groups. EEG alpha and beta power were lower in insomniacs as compared to normal sleepers. Alpha and beta power slightly reduced during driving in normal sleepers but remained at a constant low level in insomniacs. Changes in EEG power and SDLP were not related. It is concluded that on-the-road driving performance does not differ between older insomniacs and older normal sleepers and that changes in spectral EEG measures of cortical arousal and in driving performance are not related.

Determinants of self-reported sleep quality in healthy sleepers and patients

Abstract A clear clarification of which objective variables are predictive of the subjective sleep experience, and furthermore, which variables of the subjective sleep variables are an adequate representation of the sleep quality score are missing. This may lead to people not identifying possible sleep problems or to people who feel misunderstood when the problem is not objectively observed. Data from the SIESTA database were used, which consists of two consecutive nights of polysomnography and includes subjective data of 156 healthy persons and 95 patients (age range 20–95). Among other things, the strongest significant correlations were found when the difference between nights was taken, for instance, between the subscore “Sleep Quality” of the Subjective sleep and awakening questionnaire (SSA-1) and total sleep time (r = .423, p < .001). For the mental disorder group, stronger correlations were observed between the absolute sleep measurements of night 1 and SSA-1 (wake time after sleep onset: r = .732, p < .001). The subscore “Sleep Quality” was sufficient as a representative for the subjective sleep quality score. Our findings indicate that intra-individual variability plays a role and to enhance the insight more nights are needed when investigating the association between subjective sleep quality and objective sleep measurements.