Abstract
Cluster headache (CH), the most severe of the primary headache disorders, is characterized by unilateral pain localized over the territory of the first trigeminal division, along with prominent cranial autonomic symptoms such as conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, facial sweating miosis and ptosis (1). The management of CH can be difficult as the agents used for prophylaxis are either not easily tolerated for prolonged use or ineffective in many cases, especially in the chronic variant. Verapamil, lithium and methysergide constitute the first-line treatment options for the maintenance prophylaxis of CH (2). Despite the longstanding utilization of such medications, detailed knowledge of their mechanism of action is still lacking.
In this report we describe a patient affected by chronic CH who unexpectedly underwent a complete and sustained response to pramipexole prescribed for parkinsonism.
Case report
A 46-year-old, right-handed man was referred for a 2-year history of daily paroxysmal headaches. His symptoms started at the age of 26 and were characterized by recurrent bouts of head pain with onset during the night-time, awaking the patient between 02.00 and 03.00 h. Rarely headaches occurred in the afternoon. The pain, lasting 60–90 min, was strictly localized in the right supraorbital area, usually severe or excruciatingly severe, stabbing in quality and associated with ipsilateral lacrimation, nasal stuffiness and photophobia. During the spells the patient was agitated and forced to leave the bed and pace room-to-room. Less frequently, the pain was moderate in intensity, without associated symptoms, and spreading toward the middle of the forehead without crossing the midline. The bouts had occurred for 20 years, with a frequency of one or two daily, and a free interval no longer than 8 days. The patient had been administered flunarizine, amitryptiline and propranolol for a presumed diagnosis of migraine without benefit. During the attacks he took indomethacin with a slight reduction in pain duration. Six months before presentation he developed progressing clumsiness in the left hand. His wife noted that her husband often kept the left arm in a fixed position and that his face had become inexpressive. The patient’s past medical history included arterial hypertension, for which he had been taking bisoprolol and amlodipine.
The physical examination was unremarkable. The neurological examination revealed facial hypomimia with slight right eyelid ptosis, absent arm swing on the left side while walking, moderate bradikynesia in the left arm with a cogwheel rigidity. Tremor was absent. The cranial nerve, pyramidal, cerebellar and sensitive functions were normal. The laboratory examinations and brain magnetic resonance imaging with contrast material were normal. Diagnosis of chronic cluster headache and left-sided hemiparkinsonism was made. It was chosen to treat parkinsonian symptoms first, because they constituted a new-onset disturbance and a cause of considerable difficulties in the patient’s job. Pramipexole at an initial dose of 0.25 mg t.i.d. was prescribed, with an increment of 0.25 mg t.i.d. every week up to 1 mg t.i.d. Parkinsonian signs rapidly improved. Surprisingly, the pain bouts became less intense and frequent and completely ceased by the end of the second month of therapy. The patient was followed up for 1 year after starting the pramipexole therapy, during which time he remained pain free, with the exception of three single mild nocturnal spells. The therapy was not withdrawn since it was considered unethical.
Discussion
We describe a patient affected by a previously undiagnosed and not correctly treated chronic CH who became pain free after 20 years of almost uninterrupted bouts following therapy with the dopamine agonist pramipexole for Parkinson’s disease (PD). Although the drug has not been withdrawn to demonstrate the recurrence of the headache, and we cannot exclude that the response to pramipexole was the consequence of the case, the complete disappearance of the pain within 2 months after a period of 20 years seems to be more than simple coincidence.
Pramipexole is a nonergoline dopamine agonist with selective activity at dopamine receptors belonging to the D2 receptor subfamily (D2, D3, D4 receptor subtypes), with preferential affinity for the D3 receptor subtype and little interaction with adrenergic and serotoninergic receptors (3). Increasing evidence suggests that an alteration in D3 receptor function plays an important role in the aetiology of a variety of central nervous system disorders, including schizophrenia, PD and substance abuse. D3 receptors are present at many sites of the human brain, including the nucleus accumbens, the basal ganglia, parietal, temporal and occipital cortex, as well as substantia nigra, hippocampus and amygdala. Furthermore, D2 receptors are prevalent in the hypothalamus, raphe nuclei and periacqueductal grey matter (4), all areas theoretically involved in the pathophysiology of primary headaches.
Currently, the relationship between the primary headaches and the brain dopaminergic system is not completely understood. A growing body of evidence supports a possible role for dopamine in the pathophysiology of migraine. Most migraine symptoms are interpreted as the result of dopaminergic activation, such as those occurring during the premonitory (mood changes, yawning and food cravings), painful (nausea, vomiting and hypotension) and postdromal phases (drowsiness and tiredness) (5). Moreover, the neuroleptics, dopamine receptor antagonists, are effective therapeutic agents in migraine (6). On the other hand, reports concerning CH and the dopamine system are lacking and a clear relationship has not been demonstrated. At present, the only link existing between CH and dopamine is an open-label trial with olanzapine successfully employed in abortive therapy (7). In that case, an antidopaminergic property seemed to play a role in the positive response, the opposite of what occurred our case, where a dopamine agonist interrupted a chronic CH, even if other receptorial mechanisms with olanzapine, particularly the serotonin and histamine receptors antagonism, could not be excluded.
PD and primary headache disorders are both high-prevalence conditions. It has been reported that about two-thirds of parkinsonian patients previously affected by migraine manifest significant improvement in or remission of head pain after PD onset, because of a positive effect of nigral degeneration on the pathophysiological mechanism of migraine or by a prophylactic action of dopaminergic therapy (8). A relationship between PD and CH and their reciprocal influence on natural history have not been reported. In the case reported here, an analogue inverse influence between PD and CH is quite improbable, since parkinsonian symptoms persisted for 6 months without any improvement in frequence or intensity of CH bouts. Furthermore, the positive effect on the pain developed in a few weeks after pramipexole was introducted, and became complete by the end of the second month of therapy.
Finally, the basal ganglia are involved in the regulation of nociceptive inputs to the higher centres (9). In PD, pain is a common complaint and can precede diagnosis of the disease (10). In our patient pramipexole could have affected pain symptomatology by means of a modulatory effect mediated via the basal ganglia.
This small study has shown that pramipexole may relieve the symptoms of this very severe head pain syndrome. A larger study is necessary to confirm the true value of this preliminary observation.