Evidence-Based Reviews

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

Current Psychiatry. 2007 April;6(4):39-53

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.

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References

1. Markon J. Sleeping Va. driver convicted in crash; man had taken too much Ambien. The Washington Post, August 2, 2006. Accessed August 26, 2006 from LexisNexis Academic Database.

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4. Barclay L. Driving, other erratic behaviors reported after taking zolpidem. Available at http://www.medscape.com/viewarticle/528415. Accessed February 21, 2007.

5. Gottlieb DJ, Redline S, Nieto FJ, et al. Association of usual sleep duration with hypertension: the Sleep Heart Health Study. Sleep 2006;29(8):1009-14.

6. Gottlieb DJ, Punjabi NM, Newman AB, et al. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med 2005;165(8):863-7.

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8. Verispan VONA. Top 200 brand name drugs by units in 2005. Drug Topics 2006. Available at: http://www.drugtopics.com/drugtopics/data/articlestandard/drugtopics/102006/311294/article.pdf. Accessed February 22, 2007.

9. sanofi-aventis Ambien prescribing information. Available at: http://products.sanofi-aventis.us/ambien/ambien.html. Accessed February 21, 2007.

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“Sleep driving” blamed on the hypnotic zolpidem was used as a defense last year in Virginia in a criminal case involving impaired driving. The defendant’s attorney argued that the defendant should not be held criminally liable because he was “essentially unconscious” and the accident therefore was involuntary.

The “sleep driving” defense failed when testimony revealed the defendant had taken 5 times the recommended zolpidem dose before the accident. The judge found him guilty of a felony charge of driving under the influence of a sleep medication.¹

Sedative-hypnotics are increasingly being used to treat insomnia^2-4 and as a result some patients try to drive while under the drugs’ sedating effects. Also, new FDA-ordered labeling for all 13 available prescription sleep aids warns of potential risks of “complex sleep-related behaviors,” including driving, phoning, and eating while asleep (Box 1).

Hypnotics can improve quality of life and well-being by addressing insomnia’s complications—hypertension, diabetes, coronary artery disease, depression, and anxiety^5-7—but they also have been associated with impaired motor coordination and somnambulism. To help you and your patients weigh sleep medications’ relative risks and benefits, we report on clinical studies and court cases in the literature. Most of the data focus on zolpidem, by far the most prescribed hypnotic (Box 2).^8,9

Box 1

New labeling for hypnotics: Sleep-related behaviors

Labeling of all sedative-hypnotic drugs now carries FDA-ordered precautions about “sleep-driving and other complex behaviors” that may occur without the patient being fully awake. FDA cited reports of patients preparing and eating food, making phone calls, and having sex after taking a sedative-hypnotic, usually without memory of the event. A warning also was added about rare, potentially fatal anaphylactic reactions in patients taking first or later doses of sleep medications.

Steven Galson, MD, MPH, director of FDA’s Center for Drug Evaluation and Research, said the labeling changes were needed to inform patients and prescribers about the risks of sleep aids that “are well-tolerated and effective for many people.”

Source: Walsh S, Rawlings K. FDA requests label change for all sleep disorder drug products. Available at www.fda.gov/bbs/topics/NEWS/2007/NEW01587.html.

Zolpidem incidents and cases

In 2005, Americans filled 43 million prescriptions for sedative-hypnotics—26.5 million for zolpidem alone—compared with 29 million prescriptions in 2001.⁴ In addition to the new the FDA-requested warnings about sleep-related behaviors, zolpidem’s labeling cautions patients about operating heavy machinery, driving, or engaging in hazardous occupations after taking the drug. The manufacturer tells patients:

Clinical Point

Zolpidem affects performance and memory within the first 4 to 5 hours of administration

to ingest zolpidem only before going to bed
that they may experience residual sedation the following day.

Not all patients heed the precautions or follow dosing recommendations, however.

Impaired driving. Besides the “sleep driving” case in Virginia, a highly publicized zolpidem-related driving incident occurred May 4, 2006, when U.S. Representative Patrick Kennedy was involved in an accident after having taken zolpidem in combination with an antinausea medication. Another driving-related case has used zolpidem as a defense for impairment, but the court decided that the medication was not at fault because the defendant also had ingested alcohol.¹⁰

Other litigation. Although zolpidem-related impairment apparently has not been used successfully as a defense for a driving incident, class action suits alleging failure to disclose potentially harmful side effects have been filed against the manufacturer.

In Janet Makinen and others v. sanofi-aventis,¹¹ at least 500 plaintiffs claim zolpidem is related to sleep-driving, sleep-eating, and other somnambulistic behaviors. Plaintiffs allege negligence, breach of implied warranties, fraud, unfair trade practices, express warranty violations, strict liability, and consumer fraud violations. Other suits claim dangerous sleep-related side effects with zolpidem use.¹²

What clinical evidence shows

Driving impairment. Clinical studies have shown conflicting results about driving impairment associated with zolpidem. The literature falls into 2 categories, based on treatment duration:

Clinical Point

A 15-mg dose of zolpidem may cause greater acute impairment than the recommended maximum 10-mg dose

Zolpidem affects performance and memory within the first 4 to 5 hours of administration (Table 1).
Beyond 5 hours, no residual effects on performance have been identified (Table 2), and repeat nightly dosing has not caused impairment or tolerance.

Verster et al¹³ examined residual effects of benzodiazepines and the nonbenzodiazepines zolpidem, zopiclone (available in the United States as eszopiclone), and zaleplon on driving ability, as reported in studies of on-the-road driving, driving simulators, epidemiologic data, and closed-road driving. This review found that:

All sedative hypnotic benzodiazepines had statistically significant residual effects 10 to 11 hours after ingestion, with longer periods of impairment corresponding to medications with longer half-lives.
Zopiclone was associated with significant residual impairment for up to 10 hours after ingestion.
Zolpidem and zaleplon showed no significant impairment in driving 10 to 11 hours after ingestion. Impairment was found, however, when zolpidem was taken within 5 hours of driving.^14-18