Sleep Attacks and the New Dopamine Agonists: Should Pramipexole and Ropinirole Be Used in Patients Who Drive?

Abstract & Commentary

Source: Frucht S, et al. Neurology 1999;52:1908-1910. Commentary on and subsequent correspondence.

In june 1999, drs. frucht, rogers, greene, gordon, and Fahn reported their experience with the new dopamine agonists pramipexole and ropinirole in Neurology. Eight of their patients with Parkinson’s disease (PD) experienced sudden episodes of sleep, causing serious motor vehicle accidents. Frucht et al serendipitously noticed that at the time of their accidents, all eight were taking pramipexole (Mirapex); one patient also had an accident while taking ropinirole (Requip). These events occurred over a period of 18 months following the release of pramipexole and ropinirole into the U.S. market. Frucht et al coined the term "sleep attack" to describe this syndrome, attempting to capture the sudden and unexpected nature of these events.

There were no obvious factors (patient age, duration of Parkinson’s treatment, dose or duration of exposure to pramipexole or ropinirole) that identified patients at risk for sleep attacks. In four of eight patients, the first attack occurred during driving. Only three of eight patients experienced somnolence from pramipexole prior to their accident. Frucht et al proposed that these events resembled a narcoleptic attack, and suggested the possibility that the drugs triggered these events by down-regulating dopaminergic input to the reticular-activating system.

Following its introduction into the U.S. market, pramipexole quickly became the most widely prescribed dopamine agonist for PD, and ropinirole also achieved a significant share of the agonist market. The publication of this paper generated heated responses from Pharmacia and SmithKline Beecham (the manufacturers of the drugs), as well as considerable debate from movement disorders specialists. Most of these opinions appeared recently in the correspondence of the January 2000 issue of Neurology.

Commentary

As the author of the original paper and summary letter of response, it would be unreasonable not to acknowledge that this paper generated significant controversy. What follows may be construed as a biased view of the issue. However, clinical reports over the last six months have lent considerable support to our original report. The central questions in this debate are listed below. I will summarize the arguments for and against each issue.

Critical Questions: The New Agonists

• Question 1: Are the new dopamine agonists (pramipexole and ropinirole) responsible for sleep attacks? Are sleep attacks different from sedation?

• Question 2: If so, how do these drugs trigger these events?

• Question 3: Are there risk factors that can reliably predict the occurrence of sleep attacks in patients taking these drugs?

• Question 4: Can pramipexole and ropinirole be used safely in patients who drive?

Answers

Answer 1: Several correspondents argued that the new dopamine agonists were not solely responsible for these events. They ascribed these attacks to the interaction of agonists with other medications, or to an underlying sleep disturbance commonly seen in PD. Several correspondents also questioned whether sleep attacks differed from sedation. They point to the known sedating effect of most dopaminergic agents, arguing that sleep attacks (if they exist) be viewed as a more severe form of sedation. This is a mistaken interpretation: "sleep attacks" have all been abrupt and sustained for seconds or more without prior anticipation.

In the six months following publication of our report, additional data have helped address these questions. More than 16 other Parkinson’s patients were subsequently reported who experienced sleep attacks during treatment with pramipexole. Margaret Hoehn reported nine of her patients also were involved in motor vehicle accidents. In a letter sent to the European Union, SmithKline reported sleep attacks in 16 Parkinson’s patients treated with Requip. Other observations are reported in press. It does not seem tenable to propose that these events do not occur, as they have now been reported at many centers by different neurologists. While it is true that dopaminergic agents are often sedating, similar events of sudden sleep were not reported with pergolide, despite more than a decade of worldwide use. One could ask why sleep attacks were not reported in the clinical trials of pramipexole or ropinirole. Whether events were observed but coded as sedation or whether events were even observed at all remains an open question.

Answer 2: The mechanism by which pramipexole or ropinirole triggers abrupt, unanticipated sleep is unknown. We advanced one possibility in our correspondence to Neurology. Pramipexole and ropinirole have enhanced affinity for the D3 subtype of dopamine receptors. This receptor has recently been shown to be important in a well-known animal model of narcolepsy. Further work is needed to resolve this issue.

Answer 3: Heated debate has addressed whether risk factors can reliably predict the development of sleep attacks. Several authors, including some of the correspondents, have proposed a maximum dose (typically 1.5 mg of pramipexole) or duration of exposure to the agonist that would safeguard against a sleep attack. Alternatively, direct and frequent questioning regarding sedation or episodes of sudden sleep is proposed as a safeguard against these events.

The data do not support these recommendations. In order to recommend a dose or duration of drug exposure that is safe, doctors should expect that if this dose is not exceeded, or if the drug is used for at least the safe period, no events should occur. Sleep attacks, however, have now been reported with doses of pramipexole below 1.0 mg per day. Events have also occurred more than one year after patients start the drug. Most disturbing, not all events are preceded by other events.

Answer 4: The most important issue facing a neurologist who prescribes pramipexole or ropinirole is whether these drugs can be used safely in patients who drive or perform other activities requiring constant alertness. For patients who do not drive, a sleep attack may be inconsequential; for patients who drive, it is potentially life threatening for both the patient and the public.

The European Medicines Evaluation Agency has formally recommended that patients who take these drugs abstain from driving. The Food and Drug Administration stopped short of this warning but amended the warning label of Mirapex (a similar change will probably be made shortly with Requip).

What is the proper recommendation? (There is no answer to this question at present.) It would seem prudent to discuss this issue fully with all patients who are currently taking these drugs or who begin taking them, and to fully document this conversation. Until more data are available, Neurology Alert urges its readers to prohibit recommending these drugs in patients who drive. —sf

The new dopamine agonist pramipexole (Mirapex) has:

a. become the most widely prescribed dopamine agonist for Parkinson’s disease in the United States.

b. caused the European Medicines Evaluation Agency to recommend that patients taking it abstain from driving.

c. possibly been linked to "sleep attacks" in patients taking the drug causing serious motor vehicle accidents.

d. caused the FDA to amend the warning label of the drug.

e. All of the above