High-Dose Verapamil in Episodic and Chronic Cluster Headaches and Cardiac Adverse Events: Is It as Safe as We Think?

Abstract

Cluster headache (CH) is a primary headache disorder with relatively effective treatments. Although few sufficiently controlled trials are available, verapamil is recommended as the first-line prophylactic drug for CH by the French Headache Society (with a low level of evidence, level B) and by the EFNS (European Federation of Neurological Societies, level A). Daily doses of more than 480 mg (and up to 1200 mg daily) are frequently used off-label, while 360 mg daily is the only dosage to have demonstrated its effectiveness in a double-blind trial against placebo, and the usual label posology used by cardiologists is 240 mg daily in hypertension. We report the case of a 19-year-old man who was self-reported to our cardiology consultation for dyspnea and asthenia for 18 months. His medical history consisted of CH crisis for 4 years treated by verapamil 720 mg/day for 18 months with relatively good efficiency. His electrocardiogram (ECG) showed a sinus bradycardia at 40 bpm with a first-degree atrio-ventricular block. Evolution was favorable after progressive verapamil discontinuation. Analysis performed on the French Pharmacovigilance Database between July 1, 2000 and December 1, 2014 found four other cases of cardiac adverse events related to high-dose verapamil used in CH prevention (two cases of syncope with complete atrio-ventricular block with verapamil 1200 and 240 mg daily, respectively, one syncope related to sick sinus syndrome with verapamil 360 mg daily, and one case of sinus bradycardia with verapamil 720 mg daily). Although available studies seem to demonstrate an apparent good tolerance, this off-label practice should not be considered as standard of care and requires strict cardiac monitoring, as suggested by the Agence Nationale de Sécurité du Médicament (ANSM) in a recent re-evaluation of the benefit/risk ratio of high-dose verapamil used in CH prevention.

Verapamil and Cluster Headache: Still a Mystery. A Narrative Review of Efficacy, Mechanisms and Perspectives

“…The negative inotrope and chronotrope effects of verapamil are a concern for the neurologist when treating CH patients with “neurological dosages” of verapamil, which are roughly twice those used in cardiac diseases . Verapamil has been shown to induce cardiac side effects in otherwise healthy patients with no history of cardiac disease and can induce a slight reduction in blood pressure in normotensive patients . In a review, including 217 CH patients treated with verapamil (mean dose 512 mg/day [range 20‐1200 mg/day]), electrocardiography (ECG) descriptions were provided for 108 (mean dose 587 mg/day [range 240‐1200 mg]).…”

Phase Specific Pain Localization in Cluster Headache Patients.

“…Results from previous international cross-sectional surveys on CH describe demography (2,5,6), clinical characteristics including symptoms (2,4,6,7), and diagnostic and therapeutic challenges (8)(9)(10). Current pharmaceutical management of CH(11) − (12) including preventive treatment involves substances like triptans, prednisolone, lithium, verapamil and others which, especially when used by patients in high doses over long periods of time, have the potential for side effects like cardiac events (13), fatigue, nausea, tremor, depression, increased serum glucose and others (12).…”

“…Retroorbital pain is reported by 86% (n: 545/631) of patients. Periorbital pain localization can be further discriminated into the medial (5) and lateral (19) corners of the eye as well as supra- (11,18) and infraorbital (13,20) regions.…”

Pain localization in cluster headache patients: Onset, peak, and radiation

“…34-44) were less frequently reported. Significant differences between peak pain and radiation pain were found for orbital and periorbital (points5,11,12,18,19), frontal (point10,17), and temporal(point 25) locations (Figure 3).| 445 3.6 | Radiation Pain radiation was reported by 70% (n:444/631, cCH: 72% [n:152/406], eCH: 68% [152/226]) of the participants. The most frequently reported pain locations for onset and peak pain were periorbital.…”

“…periods of time, has potential side effects and risks such as cardiac events, 17 fatigue, nausea, tremor, depression, increased serum glucose and others. 14 Local treatments like neuromodulatory approaches 13,[18][19][20] are other options, especially for patients in whom systemic pharmacotherapy is ineffective or contraindicated.…”