Falling asleep at the wheel: Motor vehicle mishaps in persons taking pramipexole and ropinirole

Subjects and methods.

Among PD patients monitored at three movement disorders centers, we identified 8 who had sustained automobile accidents. All 8 were receiving pramipexole following its introduction in July 1997. One patient experienced a similar side effect while taking ropinirole. After their accidents, each patient underwent a structured telephone interview to elicit information on their prior driving records, details of the accident, sleep history, and other effects of these drugs.

Results.

The patients’ clinical histories are summarized in the table. All 8 were men. Their average age was 65.1 years (range 54 to 83) and average duration of illness was 6.4 years (range 2.5 to 13). At the time of their accidents, patients had been taking pramipexole for an average of 7 months (range 1 to 14) at an average dosage of 2.9 mg/day (range 1 to 4.5). Under treatment with levodopa and agonist therapy, all patients were at Stage II PD (Hoehn & Yahr). They had normal cognition, excellent driving records, and no history of sleep disturbances. All 8 fell asleep while driving an automobile, several while driving on the highway. In 3 of the 9 accidents, an accompanying passenger verified the events. Fortunately, no patients were injured. At the time of their accidents, most patients were taking carbidopa/levodopa, and none were taking more than 3 medications for PD. One patient was taking a low-dose bedtime sedative: 0.5 milligrams of clonazepam.

Four patients taking pramipexole experienced sleep attacks during other activities, such as business meetings and phone calls. There was no history of sleep attacks before the use of pramipexole and ropinirole. Other drug-induced side effects included hallucinations (2) and increased libido (1). After the accidents, pramipexole was discontinued in 6 patients and reduced in 2. No further sleep attacks occurred in any patient. One patient subsequently treated with 16 mg/day of ropinirole experienced a similar sleep attack while driving, and the ropinirole was discontinued. Patients described sudden, irresistible, overwhelming sleepiness without awareness of falling asleep.

Discussion.

Eight PD patients experienced sleep attacks resulting in accidents while taking pramipexole; one of them also experienced a separate event while taking ropinirole. Although we did not routinely survey our PD patients regarding motor vehicle accidents, we were surprised by the number of those events during the 18 months pramipexole had been available for routine clinical use. In clinical trials of pramipexole and ropinirole for the treatment of PD, insomnia and sedation were reported, but sleep attacks were not. This may have been caused by lack of recognition by patients or physicians, failure to differentiate somnolence from sleep attacks, or a difference in patient profile between participants in clinical trials and those in our series. Although data are not available for the incidence of sleep attacks in patients taking other dopamine agonists or carbidopa/levodopa, we believe that the number of patients who experienced this worrisome side effect while taking pramipexole is too high to explain by chance alone. There were no obvious factors (age, duration of treatment, dose, or duration of exposure to pramipexole or ropinirole) that identified patients at risk for sleep attacks.

We believe that pramipexole and ropinirole were responsible for the sleep attacks for several reasons. All attacks occurred after patients began taking pramipexole or ropinirole and stopped after the drugs were discontinued. All of our patients needed to drive; therefore, we did not rechallenge them with the drugs because of the unacceptable risk. Since these incidents, patients have been monitored while not taking these drugs (typically at least several months) without a recurrence of attacks.

Although PD patients have disordered sleep architecture,4 this form of sleep attack has not been previously described, to our knowledge. Despite an average duration of illness of 6.4 years and treatment with carbidopa/levodopa and other dopamine agonists, no patient had experienced a previous sleep attack. The mechanism of sleep attacks and disturbance in arousal mechanisms from pramipexole and ropinirole is unknown. The ascending reticular activating system is frequently involved pathologically in PD,4 and the dopamine system is important in narcolepsy and in normal arousal states. These attacks resembled narcolepsy, occurring acutely and without warning. Although the mechanism of narcolepsy is not fully understood, standard medicines for narcolepsy (amphetamine, methamphetamine, methylphenidate, and pemoline) may act by increasing central dopamine.5 We propose that pramipexole and ropinirole may have triggered sleep attacks by downregulating dopaminergic input to the reticular activating system, possibly by acting on presynaptic receptors, which are stimulated by lower doses of these agents. Further work, including polysomnography and continuous EEG monitoring of patients taking and not taking these medicines, is needed to define the effect of these drugs on sleep and arousal in PD.