Migraine attacks
induced by subcutaneous apomorphine in two
migrainous parkinsonian patients
U Sabatini, O Rascol, A Rascol, JL
Montastruc
Laboratoire de Pharmacologie
Médicale et Clinique, INSERM U317,
Faculté de Médecine, 37,
allées Jules Guesde, 31073 Toulouse
Cédex
Increased responses to catecholamines in
migraine patients are well established. In some
cases, it has been possible to demonstrate a
peripheral dopaminergic hypersensitivity but to
our knowledge, although nonspecific headache is
sometimes considered as a possible side effect
of antiparkinsonian drugs, no description of a
true migraine attack induced by a dopaminergic
drug has yet been reported. We describe the
occurrence of a typical migraine attack after
the subcutaneous injection of apomorphine in two
migrainous parkinsonian patients.
Case 1 A 66-year-old woman was
admitted to our Parkinson's disease clinic for
antiparkinsonian drug re-equilibration. Since
puberty, she had a long history of true common
migraine (positive familial history, headache
attacks lasting 10-48 h, occurring once or twice
a month, without prodromes, pulsatile, with uni-
or bilateral topography, and accompanied by
neurovegetative symptoms such as nausea or
vomiting). She never used preventive treatments
and classical analgesics had moderate efficacy
on the symptoms of the attacks. Since her
menopause, in 1975, she noticed that her
migraine attacks had completely disappeared. At
the same period, she presented with the first
signs of Parkinson's disease and she started
DOPA therapy in 1978. Since 1983, abnormal
movements and motor fluctuations required
frequent changes in antiparkinsonian treatments.
In 1989, the patient entered the hospital
because of a complex extrapyramidal
symptomatology including gait disturbance
(freezing), wearing-off phenomena, early morning
dystonia, and peak dose facial dystonia with
generalized dyskinesia. She was treated at that
time by L-DOPA (100 mg + 25 mg of benserazide
five times a day), bromocriptine (2.5 mg five
times a day), and trihexyphenidyl (2 mg three
times a day). Because of the complex association
of symptoms, antiparkinsonian drugs were stopped
for 24 h in order to observe the patient while
"off." An -apornorphine test" (10 mg
subcutaneously) was then performed in order to
observe the patient while "on." Oral domperidone
was prescribed 2 days befère the test (20
mg/day in three divided doses) to avoid
peripheral dopaminergic side effects.
Apomorphine switched the patient "on" within 20
min. This effect lasted 1 h, with no significant
change in blood pressure but during this period
the patient progressively experienced headache.
Pain was bilateral and pulsatile; its intensity
increased during the next hours to become strong
enough to keep the patient in bed with nausea,
asthenia, pallor, and photophobia. The attack
lasted 3 days, with intense headache and
vomiting. Usual analgesics had only a moderate
effect. The patient spontaneously described
these symptoms as typical of her past migraine
attacks. One week later, she refused another
apomorphine injection, fearing to precipitate a
new attack. With a follow-up of 10 months, the
patient did not suffer from any other recurrent
headache.
Case 2 A 54-year-old woman was
admitted to our Parkinson's disease clinic in
order to confirrn the diagnosis of early
Parkinson's disease. She had a typical history
of common migraine (monthly migraine attacks
with bilateral and pulsatile headache lasting 2
days, associated with nausea and photophobia).
Her migraine was known since puberty and attacks
frequently occurred during menstrual periods.
Since menopause, 5 years ago, migraine attacks
had disappeared and she was totally free of any
kind of headache. During the 2 years preceding
her hospitalization, the patient noticed a
global slowing with mild gait impairment. She
was aware of moderate difficulties in her home
care work. Clinical examination, without any
concomitant treatment, evidenced an
akinetohypertonic parkinsonian syndrome
predominant on the right side. In order to
assess the sensitivity of the symptoms to
dopaminergic drugs, an apomorphine test (3 mg
subcutaneously) was performed after domperidone
pretreatment (60 mg/day 2 days before).
Apomorphine improved the extrapyramidal symptoms
but the patient also reported the concomitant
occurrence and progressive worsening of a
bilateral pulsatfle headache associated with
nausea and photophobia. When asked, she was
convinced that these symptoms strikingly
mimicked her past migraine attacks. The syndrome
lasted 1 day and disappeared after a night of
sleep. After informed consent was obtained from
the patient, three other subcutaneous injections
were performed: the first and third ones
consisted of placebo (saline) injections while
the second one consisted of 1 mg of apomorphine.
Each subcutaneous injection was administered in
a single-blind way with a 3 day interval between
each injection. Placebo injections had no
effect. On the contrary, after 1 mg of
apomorphine, while this dose was insufficient to
elicit any detectable antiparkinsonian effect,
headache occurred with the same clinical
symptoms as previously described.
DISCUSSION
These two migrainous patients exhibited
typical symptoms of common migraine attacks
following the subcutaneous injection of
apomorphine. Nausea is extremely frequent after
apomorphine injections. However, this common
side effect differs from the present
observations because headache is absent, nausea
does not usually last more than 1 or 2 h
according to the short half-life of the drug,
and it is prevented by domperidone. Then,
according to the clinical description of the
present cases, we assume that the symptoms that
we observed were true migraine attacks and were
différent from the well-known
gastrointestinal side effects induced by
dopaminergic agents. The relationship of these
attacks with apomorphine must then be discussed.
It is, of course, possible to consider the
possibility of a spontaneous recurrence of
migraine attacks. In our opinion, however, two
arguments invalidate this hypothesis: first, the
occurrence by chance of a spontaneous attack at
this very moment seems to be unlikely because
the two patients did not experience any headache
since their menopause, Le., during the
preceeding 15 and 5 years; second, in case 2,
the attacks were clearly associated with the
apomorphine injections while the placebo
injections had no effect. This last remark also
disagrees with the hypothesis that the attacks
could have been induced by a nonspecific
precipitation by the prevailing stress factors.
In fact, the injection of 1 mg of apomorphine,
devoid of any motor effect and clinically
indistinguishable from placebo, induced the
attack while placebo did not. Therefore,
according to the French unexpected or
toxié drug reaction assessment, the role
of apomorphine is convincing.
Headache is not a side effect frequently
ascribed to apomorphine. In our experience, it
was a rare symptom among the other well-known
side effects (nausea, sedation, orthostatic
hypotension) that we observed in patients
treated with this drug. In parkinsonian
patients, unspecified headache has been reported
in few cases after dopaminergic treatments like
parenteral lisuride, oral pergolide, or
bromocriptine. This last drug induced trigeminal
neuralgia attacks in a patient with a pituitary
tumor. In a double-blind, placebo-controlled
study, headache was reported to be no more
frequent in the bromocriptine than in the
placebo group (3/108 patients vs. 2/108
patients). None of these cases corresponds to a
well-documented migraine attack.
Several arguments suggest a possible
involvement of dopamine in migraine
pathophysiology. Dopaminergic agonists induce
exaggerated dopaminergic peripheral side effects
such as vomiting and hypotension in migraine
patients. Dopaminergic antagonists are proposed
as antimigraine drugs. Apomorphine and other
dopaminergic drugs increase cerebral blood flow
and have a cerebral vasodilator effect that
could fit with the vascular hypothesis of
migraine. It is thus conceivable that, since it
has already been reported for other drugs like
reserpine, apomorphine was able to trigger true
migraine attacks in our parkinsonian but also
migrainous patients.
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