Sleep attacks in patients taking dopamine agonists: reviewBMJ 2002; 324 doi: https://doi.org/10.1136/bmj.324.7352.1483 (Published 22 June 2002) Cite this as: BMJ 2002;324:1483
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LETTER TO THE EDITOR OF BMJ
Sleep attacks in patients taking dopamine agonists: from evidence to
varying degrees of association
Editor - Homann et al reviewed the evidence for the existence and
prevalence of sleep attacks (SA) in patients taking dopamine (DA) agonists
for Parkinson’s disease (PD), and the type of drugs implicated . We would
like to comment his report and its conclusion on the basis of our
knowledge of the pharmacology of piribedil.
Concerning piribedil only 3 SA events have been reported, one by
Feirreira , 2 by Montastruc et al in a pilot prospective
pharmacoepidemiologic study with 159 patients, where the piribedil sample
is recognized too small to allow any statistical significance.
Also, the number of 23 sleep-events for lisuride and piribedil,
reported by Homann, is not explained by the details of his report.
Moreover, on a pharmacological basis, it does not make any sense to
combine the reports on lisuride and piribedil, as they show quite
different structural and receptor profiles: lisuride is a D1D2 ergot DA-
agonist, piribedil a D2D3 non-ergot DA-agonist with alpha2-antagonistic
properties. These properties are expressed in an adrenergic outflow
increase in corticolimbic structures. It is this alpha-2 antagonist
quality which could make piribedil a poor candidate for inducing sleep
events or attacks. This is confirmed in human pharmacology and pre-
clinical studies showing an improvement of vigilance related parameters .
It is also important to underline that the definition of SA in the
review is different from the Frucht definition, the reference in the
twenty retained publications. The addition of “possible” SA to the
reference which specifies only “definite and probable” SA can easily
convert SE into SA.
The European Agency for the Evaluation of Medicinal Products has
recently initiated a review of all the dopamine agonists in February 2002
. It establishes that sleep disturbance can be a feature of PD and a drug-
disease interaction may contribute to such a disturbance. All dopamine
agonists, to varying degrees, have been associated with somnolence. These
adverse drug reactions are more frequently reported with ropinirole,
pramipexole and possibly cabergoline. Concerning levodopa, bromocriptine
and piribedil, the EMEA recognizes that they are associated very rarely
with excessive daytime somnolence and sudden sleep onset episodes, which
is related to the very low number of published cases.
Dept of Neurology
Ev Johannes-Hospital, Bielefeld Germany
Homann CN, Wenzel K, Suppan K, Ivanic G, Kriechbaum N, Crevenna R,
Ott E. Sleep attacks in patients taking dopamine agonists: review. BMJ
2002;324:1483-7. (22 June.)
Ferreira JJ, Galitzky M, Montastruc JL, Rascol O. Sleep attacks and
Parkinson’s disease treatment.
Montastruc JL, Brefel-Courbon C, Senard JM, Desboeuf K, Rascol O,
Lapeyre-Mestre M. Sudden sleep attacks and antiparkinsonian drugs: a pilot
prospective pharmacological study. Clin Neuropharmacol 2001;24:181-3.
Smith L.A., Tel C.B., Jackson M.J., Hansard M.J., Braceras R.,
Bonhomme C., Chezeaubernard C., Del Signore S., Rose S. and Jenner P.
(2002) Movement Disorders, 17(5): 887-901.
The European Agency for the Evaluation of Medicinal Products. CPMP
Position Statement. Dopaminergic substances and sudden sleep onset.
London, 28 February 2002. CPMP/578/02.
Competing interests: No competing interests
About half of all sleep related road crashes are caused by healthy
adults aged under 30 y [1,2]. As the UK’s main research centre into
driver sleepiness, we investigate many of these crashes. Most of these
drivers usually deny having fallen asleep, and the evidence pointing to
the crash being sleep-related has to come from other sources. There are
possible reasons for this denial, such as fear of prosecution and loss of
insurance indemnity. But it is more likely is that the driver genuinely
had no recollection of actually having fallen asleep. Sleep laboratory
studies show that people who fall asleep typically deny having been asleep
if awoken within a minute or two . As a driver cannot remain asleep
for more than a few seconds without having a near miss or crash, this may
account for why such recollection is poor in drivers having had these
crashes. We also find that these drivers usually deny any knowledge of
prior sleepiness, even if they do admit to having fallen asleep at the
wheel. That is, it was an “unforewarned sleep attack”, even in someone
who has been driving knowingly in a sleep deprived state. Although we
consider that such an assertion is often genuine, it is quite mistaken,
for reasons we will describe shortly. We make this point because without
adequate age matched healthy control groups, any claims [e.g. 4] that
Parkinson’s disease (PD) sufferers are more likely to experience
unforewarned sleep attacks whilst driving, should be treated with caution.
Few readers of the BMJ will have any clear recollection of how sleepy
they were last night or when precisely this sleepiness began.
Recollection becomes even more hazy if one has to think back two or three
nights. Hence, asking a driver who has fallen asleep at the wheel,
whether they can remember being sleepy beforehand, is rather pointless
when they have to think back days or weeks to the time of the crash.
Similarly, we humans have a poor recollection of other feeling states,
such as hunger and thirst. How many of us can remember how hungry we were
yesterday before lunch, and when this began, or how thirsty we were before
yesterday breakfast’s cup of tea ? Was lunch an unforewarned eating
attack ? It seems that human memory has not the capacity to remember such
Of course, this is no excuse for drivers falling asleep at the wheel.
If one monitors healthy drivers falling asleep, under safe driving
conditions, as we do , it is clear that they have excellent on-line
insight into their level of sleepiness. However, a minority consider that
despite reaching the stage of struggling to stay awake, by winding down
the window, turning up the radio etc (which by these very acts makes plain
to the individual that they are sleepy), they will maintain that they are
able to stay awake and drive competently.
The view that PD patients are particularly liable to have
unforewarned sleep attacks at the wheel was largely initiated by Frucht et
al. , who identifyied eight patients apparently experiencing sudden
“sleep attacks” when driving; five of whom apparently had no forewarning.
Fortunately, none of these sleep attacks resulted in any injury. Had
these attacks occurred spontaneously whilst driving, then more cases of
injury might have been expected, which suggests that the circumstances of
such sleep attacks need to be investigated further.
The work Frucht et al. illustrates other issues in this area. They
made no comparisons with age related healthy controls, to determine the
extent that falling asleep at the wheel could have been due to normal
ageing. Also, they provided no information about their many other PD
patients who drive, but had no such attacks. The authors attributed the
presumed sleep attacks to dopamine agonists, and that withdrawal of these
drugs alleviated such attacks. Of course, drivers who have had the
misfortune to fall asleep at the wheel usually are more careful not to
allow this to happen again. So it is possible that in these patients the
likelihood of a further “sleep attack” whilst driving would have
diminished anyway, with or without this medication being continued.
Finally, although Frucht et al. reported that none of these patients
had any history of sleep disturbance, none was actually examined for this,
and the evidence is only based on the patients’ own opinions. This is most
unreliable, and for example, in other patients without PD, but with severe
obstructive sleep apnoea when the sleep disturbance is debilitating, they
can be unaware of these particular symptoms and claim to sleep well. It
is likely that many PD patients do have sleep disturbances for one reason
or another [e.g. 7-12] and experience daytime sleepiness because of this.
Even so, one still should not consider any reported daytime sleep attack
to be spontaneous and unforewarned.
Many drivers including PD patients and other sufferers from sleep
disorders, fail to appreciate is that sleepiness portends sleep, which can
appear more rapidly than one realises, especially if the driver has
reached the more profound and self evident state of fighting off sleep. It
is possible, of course, that patients with such sleep disorders may
experience a more rapid onset of sleepiness during driving. However, this
would probably depend on the degree of sleep disturbance, and is a matter
that remains to be established. Nevertheless, given that healthy
individuals who fall asleep at the wheel usually do so because they are
sleep deprived then, to the extent to which this sleep loss is similar to
that of the patient with a sleep disorder, the manifestation and onset of
sleepiness may well be similar for both people. That is, one should not
necessarily single out these patients to be at greater risk of falling
asleep at the wheel than the foolish young man who drives without sleep in
the small hours of the morning. In sum, it is likely that most
“unforewarned sleep attacks” are more apparent than real, and may be just
as prevalent in healthy young male drivers as in PD patients. The
treatment for both groups is probably better education about the dangers
of driving when sleepy.
1. Horne JA ,Reyner LA. Sleep related vehicle accidents. Br Med J
2. Horne JA, Reyner LA.. Vehicle accidents related to sleep: a review.
Occup Environ Med 1999; 56: 289-294.,
3. Bonnet MH, Moore SE. The threshold of sleep: perception of sleep as a
function of time asleep and auditory threshold. Sleep. 1982; 5: 267-276.
4. Homann CN, Wenzel K, Suppan K, Ivanic G, Kriechbaum N, Crevenna R &
Ott, E. Sleep attacks in patients taking dopamine agonists: a review.
2002, Br Med J 2002; 324: 1483-86.
5. Reyner LA, Horne JA (1998) Falling asleep whilst driving: are drivers
aware of prior sleepiness? Int J Legal Med 1998; 111:120-123.
6. Frucht S, Rogers JD, Greene PD, Gordon MF, Fahn S. Falling asleep at
the wheel: motor vehicle mishaps in persons taking pramipexole and
ropinerole. Neurology 1999; 52: 1908-1910.
7. Factor SA, McAlarney T, Sanchez-Ramos JR & Weiner W. Sleep
disorders and sleep effect in Parkinson’s disease. Mov Disord 1990; 5:
8. Lees AJ, Blackburn NA, Campbell VL (1988) The night-time problem of
Parkinson’s disease. Clin Neuropharmacol 1988;11: 512-519
9. Pal PK, Calne S, Samii A & Fleming JAE. A review of normal sleep
and its disturbance in Parkinson’s disease. Parkinsonism Related Disord
10. Partinen M. Sleep disorder related to Parkinson’s disease. J Neurol
1997; 244 [suppl 1] S3-S6.
11. Rye DB, Bliwise DL, Dihenia B, Gurecki P. Daytime sleepiness in
Parkinson’s disease. J Sleep Res 2000; 9:63-79.
12. Tandberg E, Larsen JP, & Karlsen K. Excessive daytime sleepiness
and sleep benefit in Parkinson’s disease: a community based study. Mov
Disord 1999;14: 922-927.
Competing interests: No competing interests