Hypnotics and driving: FDA action, clinical trials show need for precautions
Drugs’ effects on performance and memory differ, depending on time since administration.
Table 1
Studies of zolpidem-associated driving skills impairment
(
| Author/design | Doses and timing | Driving skills assessments | Conclusions |
|---|---|---|---|
| Wilkinson, 199514 Blinded; 29 subjects | Zolpidem, 10 mg, 15 mg, and placebo in combination with an alcoholic drink (to reach a BAC of 0.08%) or placebo drink; testing 45 min, 130 min, and 230 min after administration | Visual backward masking test (approximates driving performance) and attention tests | Zolpidem produced significant impairment in combination with alcohol and when administered alone during peak effect assessment; alcohol did not potentiate zolpidem’s effects; additive effects of alcohol seen with 10-mg dose but not 15-mg dose of zolpidem |
| Rush et al, 199815 Double-blind, crossover; 9 subjects | Zolpidem, 7.5, 15, and 22.5 mg; quazepam, 15, 30, and 45 mg; triazolam, 0.1875, 0.375, and 0.5625 mg; testing ½, 1, 1½, 2, 2½, 3, 4, 5, and 6 hours after administration | Subject- and observer-rated questionnaires; tests of recall and delayed recognition | Performance-impairing effects of zolpidem were virtually indistinguishable from those of classic benzodiazepines, such as triazolam |
| Mattila et al, 199816 Randomized, placebo-controlled, double-blind, crossover; 12 subjects | Zolpidem, 15 mg; diazepam, 15 mg; oxazepam, 30 mg; zopiclone, 7.5 mg; alcohol testing before and 1, 3½, and 5 hours after administration | Simulated driving and other measures | Zolpidem impaired coordination, reaction, and cognition at 1 and 3½ hours; tracking remained impaired at 5 hours; all agents (especially zolpidem) impaired learning and memory |
| Mintzer et al, 199917 Double-blind, placebo-controlled; 16 subjects | Zolpidem, 15 mg/70 kg (dosed by subject weight); testing ½, 1, 2, and 3 hours after administration | Memory tasks (recall, fragment completion, recognition) | Zolpidem interfered with explicit but not implicit memory after administration; zolpidem produced a specific deficit in acquisition of contextual information |
| Verster et al, 200418 2-step randomized, placebo-controlled, double-blind, crossover; 30 subjects | Zolpidem, 10 mg and 20 mg; zaleplon, 10 mg and 20 mg; middle-of-the-night dosing; testing 4 hours after dosing | On-the-road driving and other tests of attention, learning, and thinking | Zolpidem, 10 mg and 20 mg, significantly impaired driving function; zolpidem, 20 mg, produced significant impairment on all psychomotor and memory tests; zaleplon, 10 mg and 20 mg, did not differ significantly from placebo |
| BAC: Blood alcohol concentration | |||
Studies of zolpidem-associated driving skills impairment
(>5 hours after dosing)
| Author/design | Doses and timing | Driving skills assessments | Conclusions |
|---|---|---|---|
| Fairweather et al, 199223 Randomized, placebo-controlled; 24 older volunteers taking no other medications | Zolpidem, 5 mg or 10 mg, or placebo taken before bedtime; testing 8.5 hours after administration | Numerous, including reactive time, memory, word recognition | Zolpidem consistently helped with sleep latency, with no residual performance deficits; no tolerance seen with repeated dosing |
| Bocca et al, 199924 Double-blind, crossover; 16 volunteers | Zolpidem, 10 mg; zopiclone, 7.5 mg; flunitrazepam,* 1 mg; and placebo given at 11 PM, with testing at 9 AM | Driving simulation and real time test drive; eye movements measured after driving tests | No residual effects with zolpidem; zopiclone impaired driving ability and increased saccadic latency; flunitrazepam impaired early morning driving and saccadic eye movements longer than zopiclone |
| Partinen et al, 200320 Randomized, placebo-controlled, double-blind, 3-period crossover; 18 women with insomnia | Zolpidem, 10 mg; temazepam, 20 mg; dosing at 2 AM, testing 5.5 hours after dosing | Driving simulation; delayed word recall and memory testing (FePsy test) | No statistically significant effects on driving ability with either drug; no significant differences in FePsy results compared with baseline or placebo |
| Staner et al, 200525 Randomized, placebo-controlled, double-blind, four-way crossover; 23 subjects with DSM-IV-TR diagnosis of insomnia | Zolpidem, 10 mg; zopiclone, 7.5 mg; lormetazepam,* 1 mg; 7 days of dosing; tests given 9 to 11 hours post-dosing | Driving simulation; EEG at rest and while driving | Zolpidem showed no impairment of driving ability and no EEG changes compared with placebo; driving impairment and EEG alterations were found with zopiclone and lormetazepam |
| * Hypnotics not approved in the United States but available elsewhere. | |||
Acute effects (
Combined with alcohol. Wilkinson14 conducted a randomized, 6-way crossover study in which subjects received 10- or 15-mg doses of zolpidem or placebo plus an alcoholic beverage (enough to obtain a blood alcohol concentration [BAC] of ~0.08%) or placebo beverage. Tests given shortly after patients took the study medications showed that zolpidem caused statistically significant impairment both in combination with alcohol and alone during peak drug effect—identified as 45 minutes after ingestion. Alcohol did not potentiate the impairment associated with zolpidem.
Using a similar design, Mattila et al16 compared acute performance impairment associated with zolpidem, diazepam, oxazepam, and zopiclone. In this randomized, double-blinded, crossover study, all comparison medications impaired antecedent learning and memory, but zolpidem given at 15 mg had the greatest effect. Zolpidem impaired coordination, reactive functioning, and cognitive skills at 1 and 3.5 hours after administration, and simulated driving test performance remained impaired at 5 hours (approximately two half-lives of the medication). Of note is that the 15-mg zolpidem dose used in this study was shown by Wilkinson et al14 to be more impairing than the recommended maximum 10-mg dose.
