Specific calcium channel blockers were originally intended for use in cardiovascular disease but show great promise as prophylactic agents in the treatment of migraine. Diltiezam,²⁷⁰ verapamil,²⁷¹ nifedipine,²⁷² nimodipine,^273-275 and flunarizine²⁷⁶ have all been reported to be effective in migraineurs.  The mechanism of action of this class of drug in headache is unknown but may relate to their antivasoconstrictor activity²⁷⁷ or to non‑vascular processes such as inhibition of platelet aggregation, serotonin release,²⁷¹ or serotonin and histamine receptor blockade.  Calcium entry blockers do not necessarily share common molecular structures and may act at different sites on the calcium channel.  For instance, nimodipine, nifedipine and nitrendipine are dihydropyridines, flunarizine is a piperazine derivative and verapamil is structurally related to papaverine.  It is now known that many other drugs have calcium channel blocking activity including some useful for migraine, such as amitriptyline and cyproheptadine.²⁷⁷

Data suggest that there may be a delay of up to 8 weeks before any response to these agents is seen ^270,273,274   Verapamil may be an exception with improvement occurring within one or two weeks of initiation.  At the current time verapamil is my first choice for most patients with migraine headaches.   Therapy is initiated with 80mg/d for 2 days, then 80mg 2/d for two days, and then 80mg 3/d for two days, and then switch to the 240mg sustained release form.  Sometimes patients report an initial increase in headache and headache improvement often requires weeks of treatment.  The dose of verapamil may then be increased to 240mg sustained release in the morning and 120mg sustained release in the evening, and later to 240mg sustained release twice per day.   The primary side effect of verapamil is constipation which may be avoided with the use of stool softeners.  Other side effects vary and depend upon the individual drug, but do include dizziness, headache (particularly with nifedipine), depression, vasomotor changes, tremor, orthostatic hypotension, and bradycardia.  Calcium channelers are especially useful in patients with comorbid hypertension and in patients with a contraindication to beta-blockers, such as asthma and Raynaud’s disease.  These agents, particularly verapamil, may have a particular advantage in patients with prolonged aura or vertibular vascular migraine. There is little comparative data on the efficacy of various calcium channel blockers.