Abstract
We report a SUNCT patient who showed both a precipitation and worsening of symptomatic periods after treatment with L-type calcium channel blockers. This pharmacological response may provide us with important clues for understanding the pathophysiology of SUNCT, and hopefully to find a remedy for the victims of this syndrome. This observation could also support a verapamil trial in SUNCT patients as a precipitating of attacks.
Introduction
Although many efforts have been made to reduce the suffering of patients with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), there is no uniformly effective treatment (1). Some benefit may seemingly be obtained from carbamazepine (e.g. (1)), lamotrigine (2–4) or gabapentin (5, 6). The possibility that some drugs might even worsen the symptoms has been suspected during this extensive therapeutic search.
Early in 1995 it was reported that calcium channel blockers, particularly verapamil, tended to worsen SUNCT symptoms (1). Our most recent diagnosed SUNCT patient has the particular trait of having taken calcium channel blockers before the onset and during all his three symptomatic periods. This case substantiates previous observations and suggests an involvement of calcium channels in the pathophysiology of SUNCT syndrome.
Case report
The patient is a 69-year-old male retired physician, who gave a history of arterial hypertension, IgG lambda monoclonal gammopathy, chronic anxiety, adrenal adenoma, renal cysts, prostatic hypertrophy, bilateral chronic glaucoma, duodenal ulcers, and cholelithiasis. He was on regular treatment with losartan, paroxetin, and timolol eye drops. Four months before coming to our clinic he noticed sudden and brief tingling paraesthesias on his right frontal region provoked by gently touching this skin area. In the following days he developed sudden and brief episodes of stabbing pain on the same location associated with ipsilateral eye redness. Symptoms could appear spontaneously or be elicited by different precipitating mechanisms, such as blowing the nose, touching right ala nasi, bending forward, or making strong mental efforts, such as playing chess. Two weeks before coming for evaluation symptoms worsened. The patient described 10–15 attacks per day of intense pain on his right eyebrow or right periorbital region associated with marked lacrimation and conjunctival injection on the symptomatic side. Attacks lasted about 2 min and could be provoked by the same mechanisms mentioned above. The patient himself related worsening with the onset of anti-hypertensive treatment with amlodipine, 5 mg daily, 2 weeks before. The symptoms dissappeared 6 days after withdrawing this drug. Ten years and 18 months ago he had suffered from similar symptoms, including brief and recurrent episodes of pain, conjunctival injection and lacrimation in his right eye. On both occasions symptoms started a few days after initiating anti-hypertensive treatment with verapamil 80 mg tid, lasted for about 45 days, and dissappeared a few days after its discontinuation. Routine blood tests showed a slight hyperglycaemia (125 mg/dl). Serum immunoelectrophoresis demonstrated a monoclonal IgG lambda band. Brain magnetic resonance imaging (MRI) and angio-MRI scans showed no significant abnormalities. A computed tomography scan of the paranasal sinuses revealed a right frontal osteoma.
Discussion
SUNCT has been treated with calcium channel antagonists: one patient with nifedipine (1), 11 patients with verapamil (1, 5, 7–10), one with diltiazem (1), and two with flunarizine (11, 12). Although one patient claimed to have been ameliorated by nifedipine (1), and another patient improved while taking a combination of verapamil and carbamazepine (10), four SUNCT patients treated with verapamil seemingly experienced a worsening of attacks (1).
SUNCT seems to behave inversely to cluster headache as far as response to prophylactic treatment with verapamil is concerned. This drug may worsen symptoms in the former whereas its preventive efficacy is well acknowledged in the latter. A further and interesting development is that in our patient calcium channel blockers not only worsened but also seemed to prime the onset of SUNCT symptomatic periods. This striking response might have important clinical and pathophysiological implications.
L-type calcium channels are activated by large depolarizations and remain open for a long time before inactivating (13). Within the nervous system they are located primarily on the cell bodies and proximal dendrites of neurones (13). Dihydropiridines such as verapamil, nifedipine and diltiazem block L-type calcium channels (14). The effects of these drugs on the nociceptive systems are uncertain. Experimental studies in animals suggest an anti-nociceptive effect mediated through opioid pathways (15, 16). Different studies indicate that this action could be restricted to antagonists of N-type calcium channels (17). Others have reported either tolerance or hypersensitivity of opioid receptors according to the duration of treatment (18). Clinical studies in humans have not shown any benefit from a combination of opiates and antagonists of L-type channels (19, 20). Calcium channel blockers might even suppress the anti-nociceptive effects of nicotinic and endothelin-1 pathways (21, 22). The precipitation of symptoms in our patient could be related to inhibition of nicotinic or endothelin-1 anti-nociceptive pathways, or induction of tolerance in opioid receptors. Accordingly, it could be worthwhile trying agonists of nicotinic, endothelin-1 or opioid systems in SUNCT patients. Despite previous discouraging results with opiates (1), additional trials with drugs with different profiles on the opioid receptors may be pertinent. High doses or prolonged administration of these drugs might be needed in order to overcome an eventual tolerance in the opioid systems (18).
Lamotrigine not only inhibits sodium currents, but also acts on calcium currents. In particular, it seems to inhibit N-type instead of L-type calcium channels (23). The distribution and functions of these two types of channels are quite different. Thus, the documented benefit of lamotrigine and the possible negative effects of verapamil in SUNCT patients are probably mediated at different levels.
Present and previous evidence should encourage investigators to keep be vigilant for further reports on negative effects of calcium channel blockers in SUNCT. Such pharmacological responses may provide us with important clues for understanding the pathophysiology of SUNCT, and hopefully to find a reliable remedy for the victims of this syndrome. This finding may also open the doors for a verapamil trial in SUNCT patients as a pharmacological precipitation of attacks in a similar fashion to nitroglycerine is administered to trigger cluster headache attacks.