Hypnotics and driving: FDA action, clinical trials show need for precautions

Current Psychiatry. 2007 April;06(04):39-53

April 1, 2007|Current Psychiatry

Bradley Freeman, MD;Jason J. Buckland, DO;Gregg R. Dwyer, MD, EdD;Richard L. Frierson, MD

Drugs’ effects on performance and memory differ, depending on time since administration.

Clinical Point

Patients who scored poorly on driving tests alone 5.5 hours after taking 10-mg of zolpidem might have been more susceptible to the drug’s effects

A study from the University of Toronto¹⁹ that did not include zolpidem examined potential psychomotor performance deficits and sleepiness in a comparison of time-released melatonin, 6 mg; zaleplon, 10 mg; zopiclone, 7.5 mg; temazepam, 15 mg, and placebo. Tests were given to 9 men and 14 women, ages 21 to 53, just before drug administration and 7 hours later.

Zaleplon had the greatest effect on psychomotor performance, followed by temazepam and zopiclone. Aside from prolonged perceived sleepiness, melatonin and placebo did not interfere with performance testing.

Box 2

Zolpidem: Approved for ‘short-term’ insomnia

Zolpidem, a benzodiazepine receptor agonist, was the 7th most prescribed drug in the United States in 2005 (2006 data not available).⁸ It is FDA-approved for short-term treatment of insomnia, although “short-term” is not defined. Package labeling states:

This nonbenzodiazepine hypnotic has been shown to decrease sleep latency and increase sleep duration for up to 35 days in controlled clinical trials. Patients should be evaluated for a primary psychiatric or medical illness if insomnia does not remit after 7 to 10 days of treatment.

An imidazopyridine that acts as an agonist of GABA A¹, zolpidem produces sedation while avoiding anticonvulsant, anxiolytic, and muscle relaxation effects. Available in 5- and 10-mg tablets, the drug is rapidly absorbed in the GI tract and excreted primarily through the kidneys. Its half-life is approximately 2.5 hours (approximately 3 hours in elderly patients). The most common side effects are daytime drowsiness, dizziness, and diarrhea; others include asthenia, hiccup, and diplopia.⁹

Middle-of-the-night dosing. Effects of zolpidem and zaleplon on driving ability, memory, and psychomotor performance were compared by Verster et al¹⁸ in a randomized, controlled trial. The double-blind, 5-period crossover design measured the effects of middle-of-the-night use of zaleplon, 10 or 20 mg; zolpidem, 10 or 20 mg; or placebo on:

driving ability 4 hours after administration
memory and psychomotor performance 6 hours after administration.

As expected, subjects taking zolpidem showed impairment on all measures. The 10- and 20-mg doses significantly impaired driving 4 hours after ingestion, with the 20-mg dose—twice the recommended maximum dose—producing greater impairment. The 20-mg dose—but not the 10-mg dose—also significantly impaired memory and psychomotor function. Zaleplon did not impair driving ability, memory, or psychomotor testing.

Clinical Point

Performance impairment seen with zolpidem may be indistinguishable from a benzodiazepine effect, except that the duration is shorter

Partinen et al²⁰ used the recommended zolpidem dose in a similar study of after-midnight use by women with insomnia. The double-blind, randomized, controlled trial evaluated performance with a driving simulator and neuropsychological testing 5.5 hours after medication dosing. Patients taking zolpidem, 10 mg, showed no significant impairment when compared with those taking placebo. Some patients scored poorly on the driving tests alone, and the authors concluded that this group was more susceptible to zolpidem’s effect.

Memory. In a double-blind, placebo-controlled trial by Mintzner et al,¹⁷ zolpidem dosed by patient weight at 15 mg/70 kg:

significantly impaired explicit memory (requires conscious recollection for recall)
did not affect implicit memory (lack of conscious awareness in the act of recollection).

Explicit memory for material presented before drug administration and previously acquired knowledge was not affected. Zolpidem spared explicit and implicit memory for material presented before administration, but subjects had difficulty acquiring contextual information after the dose was given.

These findings support complaints of zolpidem-related anterograde amnestic episodes, which also occur with some benzodiazepines (such as midazolam).

Similar to benzodiazepines? Rush et al’s results²¹ support Mintzer’s assertion¹⁷ that zolpidem shares many side effects with benzodiazepines. Performance impairment associated with zolpidem—as rated by subjects and observers—is virtually indistinguishable from a benzodiazepine effect, except that the duration is shorter with zolpidem (5 hours), compared with up to 10 hours for benzodiazepines.

Logan and Couper²² reviewed police reports and toxicology profiles of individuals suspected of driving while impaired. Zolpidem was found in 29 subjects, 5 of whom showed no other substances. In those 5, zolpidem blood levels ranged from 0.08 to 1.40 mg/L and did not appear to correlate with the degree of impairment.

Residual effects (>5 hours)

Older patients. In a randomized, placebo-controlled trial by Fairweather et al,²³ zolpidem improved sleep latency in 24 subjects ages 63 to 80. No evidence of impairment in reactive time, memory, or word recognition was found 8.5 hours after nighttime dosing, and tolerance was not seen after 1 week of repeated dosing.

References

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