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

Abstract

Objective A evaluation of the effect of verapamil and other calcium channel blockers in cluster headache (CH) treatment and an investigation of possible effect mechanisms. Background Verapamil has been used in the prevention of CH for almost 3 decades, however, the mode of action and therapeutic target is still unknown. Methods A Pubmed search was conducted: “Verapamil”[Mesh] and “Cluster Headache”[Mesh]. We identified 5 relevant studies for CH. Publications were included if they made a substantial contribution within 3 prespecified areas: Efficacy (randomized controlled‐trials or open labels studies), safety, and mechanism of effect. Results Clinical effect: Clinical preventive treatment of CH with verapamil is based on 2 randomized controlled studies and 3 open‐label studies. In total, 183 CH patients participated. Verapamil 360 mg/day was used in both controlled studies. Half of the chronic patients experienced benefit from verapamil treatment and the attack burden of episodic patients was, on average, reduced by 1 attack/day. Open‐label studies support a dose‐dependent level of efficacy. Mechanism of effect: Human and animal studies indicate that verapamil may exert its effect by modulating circadian rhythms, perhaps in central pacemakers, and/or by affecting release of calcitonin gene‐related peptide. Conclusion Verapamil appears to be an effective prophylactic drug in the treatment of CH and despite the scarcity of controlled trials, it is still the drug of choice. A chronotherapeutic approach might increase the effect. More basic and pharmacokinetic research is needed before the mechanism can be fully understood.

Episodic and Chronic Cluster Headache: Differences in Family History, Traumatic Head Injury, and Chronorisk

“…Change in phenotype between eCH and cCH is common and demonstrates the plasticity of the disorder and underlying pathomechanisms. Already pioneered, CH is a ripe target for further development of chronotherapy.…”

Pharmacotherapy for Cluster Headache

“…Its mechanism of action remains to be elucidated, but current understanding is that verapamil exhibits its effect through CGRP-release modification and possible circadian rhythm modification. Blockade of presynaptic calcium channels prevents CGRP release [58], possibly inhibiting the CGRP-induced hyper-responsive state [59]. Furthermore, calcium channels appear to play a role in the circadian rhythm, which is hypothesised to play a major role in the pathophysiology of cluster headache.…”

Novel Analgesics with Peripheral Targets

“…Therefore, it has to be carefully considered whether there is an opportunity for systemic analgesic action [ 142 ]. Despite that, verapamil is a prophylactic option for cluster headache [ 143 ]. However, for migraine, L-type channel blockers and substances with a calcium-inhibitory component are considered [ 144 ].…”