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

Abstract

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.

Keywords: Driving; hypnotics; sex; zolpidem sublingual; zopiclone.

Figure 1

Study design. PBO, placebo; ZOP, zopiclone 7.5mg; ZST, zolpidem 3.5 mg sublingual formulation. *Randomized 1:1 to receive placebo at 3 or 4 h before driving in ZOP and PBO conditions.

Figure 2

Highway driving test. (A) Subjects drive a specially instrumented vehicle for approximately 1 h over a 100-km primary highway circuit, accompanied by a licensed driving instructor having access to dual controls. The subject's task is to drive with a steady lateral position between the delineated boundaries of the slower (right) traffic lane, while maintaining a constant speed of 95 km/h. (B) A camera on top of the car continuously registers the lateral position of the car on the road with respect to the left lane delineation. (C) The standard deviation of lateral position (SDLP, in cm) is an index of road-tracking error or “weaving”. SDLP scores increase compared with placebo after the use many sedating drugs including low doses of alcohol.

Figure 3

Individual and mean (horizontal lines) drug-placebo changes in driving performance as measured by the standard deviation of lateral position (SDLP). Change scores following administration of zolpidem 3.5 mg sublingual formulation (ZST) 4 h before driving (ZST 4 h), ZST 3 h before driving (ZST 3 h), and zopiclone 7.5 mg (ZOP), are shown separately for males (squares) and females (circles). Dotted lines show thresholds for impaired and improved driving: changes above 2.5 cm reflect impaired drivers, and changes below -2.5 cm reflect improved drivers. SDLP changes of three tests that were terminated prematurely are indicated by triangles.