Driving, Other Erratic Behaviors Reported After Taking Zolpidem

Laurie Barclay, MD

March 24, 2006

March 24, 2006 — Zolpidem (Ambien), a nonbenzodiazepine, sedative-hypnotic prescribed for the short-term treatment of insomnia, has been associated with increased numbers of impaired driving incidents in Wisconsin during the past several years. Although the label directs patients to take zolpidem only when able to devote a full 8 hours to sleep, and cautions against operating heavy machinery or motor vehicles, the patients involved in these incidents have driven while under the influence of zolpidem. Some of these drivers have expressed their belief that they were "sleep-driving," saying they have no memory of the driving incident.

"A 'typical' Ambien driver will demonstrate erratic, unsafe driving, often with wide lane deviations, many crashes or near–head on collisions, or unpredictable, bizarre driving maneuvers," Laura J. Liddicoat, BS, supervisor of the Toxicology Section at the Wisconsin State Laboratory of Hygiene (WSLH) in Madison, told Medscape. "Their physical symptoms include a profound loss of balance, so pronounced that the standardized field sobriety tests, such as the walk-and-turn and one-leg-stand, are usually discontinued for fear that the subjects will fall or otherwise harm themselves. Cognitive abilities are greatly reduced; subjects are often confused, disoriented, have a slow, delayed response and reduced short-term memory as displayed by needing instructions repeated numerous times and not recalling recent driving events."

At the 58th annual meeting of the American Academy of Forensic Sciences on February 28, Ms. Liddicoat discussed 6 cases of impaired driving related to zolpidem. These cases were identified from drivers stopped for impaired driving with alcohol concentrations below 0.10 g/100 mL, which is the testing protocol at WSLH. Blood levels of zolpidem in these drivers ranged from 190 to 4440 ng/mL. The peak of a single dose of zolpidem is about 110 to 115 ng/mL, according to the drug's package insert. Drivers with a level of 190 ng/mL had 3 or 4 other drugs detected.

"Even more concerning is that these blood levels were most likely post-peak, given the medication half-life and the logistics of having somebody's blood level drawn," Rafael Pelayo, MD, a sleep expert not involved with Ms. Liddicoat's report, told Medscape. Dr. Pelayo is an assistant professor of psychiatry and behavioral sciences at the Stanford University Medical Center in California.

From 1999 to 2004, zolpidem was detected in 187 impaired driving cases in Wisconsin, which includes 46 cases in 2003 and 46 cases in 2004. In 2005, there were 53 cases. While this indicates a slight increase over the previous year, the number of cases submitted and tested at WSLH also increased, so the higher number may reflect increased Driving Under the Influence of Drugs (DUID) enforcement efforts.

In some states, zolpidem has been among the top 10 drugs in blood levels for DUI, according to an article in The New York Times. In Wisconsin, zolpidem was ranked at 19 of 20 in 2004 and at 17 of 20 in 2005, behind diphenhydramine (ranked at 12 or 13), alprazolam (ranked fourth), and diazepam (ranked third).

"Ambien has been in the 'Top 20' drugs (other than ethanol) detected in Wisconsin drivers for each of the last 7 years," Ms. Liddicoat said. "This is an amazing accomplishment for a drug that has a very short half-life, and when taken as directed will be completely eliminated during the expected 8-hour sleep period."

Part of the reason behind zolpidem's increased role in DUI may relate to its widespread use. Last year, 26.5 million prescriptions were written for zolpidem in the United States, at a cost of $2.2billion, and zolpidem accounted for 84% of prescriptions written for the top 3 best-selling sleep-promoting agents (the others are eszopiclone [Lunesta] and zaleplon [Sonata]).

"Driving under the influence of incorrect use of hypnotics is not unique to any particular drug," Dr. Pelayo said. "It is odd that after more than a decade of use, [zolpidem] is getting so much attention without any recent published papers. I am not aware of any peer-reviewed data that singles out one nonbenzodiazepine from another."

Whether the zolpidem-impaired driving incidents represent "sleep-driving" or merely amnesia for the events after zolpidem ingestion is not clear. Although zolpidem has not been reported to have a significant residual effect on memory or on driving skills when subjects have been tested the morning after taking a single 10-mg dose, it produces severe deficits in psychomotor performance and cognitive abilities when patients attempt to drive within 5 hours of use.

"It is difficult for me to determine whether there is true 'sleep-driving,' or whether the reported individuals have no recollection of behavior that has occurred," Philip M. Becker, MD, medical director of the Sleep Medicine Institute, Presbyterian Hospital of Dallas in Texas, told Medscape. "Agents that are active at the benzodiazepine receptor are known to disturb memory, particularly around peak blood levels. In the case of Ambien, peak blood levels are 1 to 2 hours after ingestion."

Although many of the recent media reports refer to "sleep-driving," Ms. Liddicoat feels that such
references are misleading, based on her experiences with the Wisconsin cases.

"I won't use the term 'sleep-driving' as I have not seen studies that describe this condition," Ms. Liddicoat said. "In virtually all of the Ambien cases we've looked at, the impaired driving has been the result of misuse, or abuse, of the drug. All of the cases that I have personal knowledge of involved people that were not in bed sleeping prior to driving and took Ambien while intending to stay awake and be active."

Erratic behaviors reported after taking zolpidem are not limited to impaired driving, but have included sleepwalking, eating, drinking alcohol, belligerent outbursts, urinating in inappropriate places, agitation, confusion, dazed appearance, slurred speech, incoordination, and poor balance. Usually patients have no memory of these incidents and are at a loss to explain subsequent events, such as why food is missing from the refrigerator or why alcohol bottles are half empty.

"These rare incidents are typically associated with alcohol, polypharmacy and/or excessive doses," Dr. Pelayo said. "It should be well known that excessive amounts of nonbenzodiazepine agonists can behave like benzodiazepines when the dose is increased beyond the recommended amount."

Factors associated with zolpidem-impaired driving include not going to bed immediately after taking the drug, attempting to drive too soon after taking it, high blood levels, or ingestion with other drugs and/or alcohol.

"The interaction between zolpidem levels and abnormal behavior is dose-dependent and also is influenced by other sedating compounds, including alcohol," Dr. Becker explained. "Some patients also took the medication well before bedtime, rather than the recommendation that it is taken as you lie down for bed. If alcohol is consumed with any dosage of zolpidem, it increases the risks of abnormal behavior."

Reports of these bizarre behaviors while under the influence of zolpidem have raised concerns that the drug's label warnings should be more explicit. However, better patient education by physicians and pharmacists may also be needed, according to the experts interviewed by Medscape. This education should cover not only safe use of hypnotic agents and potential adverse effects, but also general management of insomnia. However, thorough, clear labeling and adequate patient education may not address deliberate misuse of the drug.

"Individuals who take excess amounts [of zolpidem] or combined with alcohol often have other motives [than controlling insomnia] for their behavior," Dr. Becker pointed out.

US Food and Drug Administration (FDA) official Kimberly Rawlings told Medscape that the label warnings for zolpidem do indicate that patients should follow all directions to avoid unnecessary adverse effects; take zolpidem right before getting into bed; not drink alcohol on the same evening that they plan to take zolpidem (or any other hypnotic); not take more than the prescribed dose; not increase doses or stop taking hypnotic drugs without consulting a physician; and use caution when getting out of bed, driving, or operating other machinery.

"Special concerns that patients should be aware of include memory loss or amnesia," Ms. Rawlings said. "Patients are advised to take Ambien only when they are able to get a full night's sleep (7-8 hours) before they need to be active again."

The FDA will be monitoring carefully for adverse events and will continue its review of adverse events associated with zolpidem. In the meantime, Ms. Rawlings stressed the need for good physician-patient communication regarding using the drug safely and finding the optimal dose for each patient.

The reason that patients are not following drug labeling is unclear. Dr. Pelayo suggested that "the overall safe track record for these meds may perhaps make some patients less cautious." Dr. Becker noted that patients who have previously taken older hypnotic agents may be accustomed to a longer period of latency, typically 30 to 60 minutes, before sleepiness occurs. Zolpidem, which is rapidly absorbed and fast-acting, may therefore take effect before they have gone to bed.

"I do not believe the problem is labeling — it may be an issue of education," Dr. Becker said.
"Abnormal behaviors can occur even on the normal doses of zolpidem. Physicians must make patients aware of this possibility, responding to any reports that a patient should offer about such abnormal behavior. Certainly pharmacists can play an important role in communicating the appropriate use of medications."

Dr. Becker cautioned against making any changes regarding health policy based on these reports.
"Unforeseen consequences would be far more likely," he concluded. "Insomnia is a disorder that requires further research and broader understanding. More specific hypnotic agents may become available for specific patients, although research will have to determine how effective these agents may be for a particular patient."

Disclosures: Dr. Pelayo has consulted or received honoraria from Sanofi (the maker of Ambien), Sepracor (Lunesta), Takeda, and Neurocrine. Dr. Becker is a consultant to Sanofi-Aventis, as well as a member of its speakers bureau and recipient of some of the company's research grants.

Reviewed by Gary D. Vogin, MD


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