Verapamil and Cluster Headache: Still a Mystery

A Narrative Review of Efficacy, Mechanisms and Perspectives

Anja S. Petersen, MD; Mads C. J. Barloese, MD, PhD; Agneta Snoer, MD; Anne Mette S. Soerensen, MD; Rigmor H. Jensen, MD, DMSc


Headache. 2019;59(8):1198-1211. 

In This Article

Abstract and Introduction


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.


Verapamil is the first line treatment in the prevention of cluster headache (CH) attacks.[1] Discovered by the German physiologist Fleckenstein in the mid-1960s,[2] it was developed because of the vasodilatory effect, and along with other calcium channel blockers (CCB) it was widely used to treat cardiovascular diseases. CH is a primary headache with severe unilateral pain of which the majority of the patients experience bouts separated by pain-free periods.[3,4] The waxing and waning of episodic CH (eCH) create some difficulty in designing and completing trials of preventive therapy. Thus, there are no large scale randomized controlled trials (RCT) of verapamil's effect in the treatment of CH and prevention of CH attacks is still an off-label use of verapamil. However, in addition to the reviewed studies, verapamil has been field tested by headache specialists all over the world and our clinical experience is that most patients are satisfied with this treatment.

Migraine and CH treatment with CCBs began in the early 1980s based on the assumption that CCB could prevent vasospasms and abolish possible painful vasodilation.[5] Decades have passed since verapamil was introduced and vasospasms are no longer believed to be a generator of CH attacks. However, verapamil's mode of action in CH is unknown[6] and understanding the mechanism of action might also elucidate the CH pathophysiology.

There are no currently available reviews of verapamil with a focus on efficacy and mechanism of action. Existing reviews focus on treatment of CH in general and 1 review compares verapamil therapy in a cardiological and neurological context and critically evaluates the mode of action.[6] However, this review does not propose new hypothesis on mechanism of effect.

The aim of this review is to conduct a narrative evaluation of the effect of verapamil and other CCBs in CH treatment and an investigation of possible effect mechanisms. Based on our results, we aim to propose new perspectives for optimizing and/or personalizing treatment with verapamil.