haut de page

mise à jour du 22 mai 2003
Clinical Neuropharmacology
1990; v 13; n 3; p 264-267  lexique
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.


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.

  • Bès A et al Hypersensibilité dopaminergique dans la migraine: un test diagnostique ? La Nouvelle Presse Médicale1982; 11; 19
  • Blau JN Migraine postdromes: symptoms after attacks Cephalagia 1991 Nov; 11; 5; 229-31
  • Blin O, Azulay JP, Masson G, Aubrespy G, Serratrice G Apomorphine-induced yawning in migraine patients: enhanced responsiveness Clin Neuropharmacol 1991 Feb; 14; 1; 91-5
  • Cerbo R, Barbanti P, Buzzi MG, Fabbrini G, Brusa L, Roberti C, Zanette E, Lenzi GL Dopamine hypersensitivity in migraine: role of the apomorphine test Clin Neuropharmacol 1997 Feb; 20; 1; 36-4
  • Del Bene E, M Poggioni Video assessment of yawning induced by sublingual apomorphine in migraine Headache 1994; 34; 9; 536-8
  • Del Zompo M Dopamine Hypersensitivity in Migraine: Role in Apomorphine Syncope Headache 1995; 35; 222-224
  • Del Zompo M Association between dopamine receptor genes and migraine without aura in a Sardinian sample Neurology 1998; 51; 3; 781-6
  • Fanciullacci M, Alessandri M, Del Rosso A Dopamine involvement in the migraine attack. Funct Neurol 2000; 15 Suppl 3:171-81
  • Heinrichs L Linking olfaction with nausea and vomiting of pregnancy, recurrent abortion, hyperemesis gravidarum, and migraine headache Headache 2003; 43; 3; 304-5
  • Jacome D Compulsive yawning as migraine premonitory symptom Cephalalgia 2001 Jun; 21; 5; 623-5
  • Jacome D Primary yawning headache Cephalalgia 2001 Jul; 21; 6; 697-699
  • James MF,Smith J M et al Cortical spreading depression and migraine: new insights from imaging? Trends in Neurosciences May 2001; vol 24; n 5; p 266-271
  • Loder A What is the evolutionary advantage of migraine ? Cephalalgia 2002; 22; 624-632
  • Peres MF et al Hypothalamic involvement in chronic migraine J Neurol Neurosurg Psychiatry 2001; 71; 747-751
  • Peroutka SJ Dopamine and migraine Neurology 1997 Sep; 49; 3; :650-6
  • Pietrobon D, J Sriessnig Neurobiology of migraine Nature Neurosciences Reviews may 2003; vol 4; n°5; p386-398
  • Sabatini U et al Migraine attacks induced by subcutaneous apomorphine in two migrainous parkinsonian patients Clinical Neuropharmacology1990; 13; 3; 264-267
  • Szechtman H et al Sensitization and Tolerance to Apomorphine in Men: Yawning, Growth Hormone, Nausea, and Hyperthermia Psychiatry Research 1988, 23, 245-255