A common feature of Ca²⁺ antagonists is to block the transmembrane influx of Ca²⁺ across cell membranes through slow, voltage-dependent channels, of which several types exist in cardiac muscle and vascular smooth muscle (21,33,76). Therefore, the antagonists are also called slow channel inhibitors, or Ca²⁺⁻ entry blockers, which are more accurate terms because they characterize the nature of the drug. For historical reasons, however, calcium antagonist is still the preferred term (76). Most of the antagonists in concentrations sufficient to inhibit the vascular and cardiac functions do not impair the Ca²⁺ influx in peripheral neural and vascular endothelial cells (21,73), but flunarizine cildipine and α-eudesmol, a P/Q-type Ca²⁺ channel antagonist, act prejunctionally on adrenergic nerves (6,28) or the release of substance P and calcitonin gene-related peptide (CGRP) from sensory nerves (5). The calcium antagonists are a heterogenous group of drugs (Fig. 56-1) with several subtypes blocking different types of Ca²⁺ channels (76).

The calcium antagonists have relatively selective effects on cerebral arteries compared with that on peripheral arteries (8,54,59,75). One reason may be that they are highly dependent on extracellular calcium for their activation; however, results from in vitro studies of this selectivity vary considerably among species. Thus, for nimodipine, the difference in potency for inhibiting the contraction of cerebral and peripheral arteries in animal studies was of the order of several thousand-fold (54,75), whereas in humans this difference was recently reported to be only about 10-fold (30). A novel Ca²⁺ antagonist dotarizine that also has antiserotonergic property diminished the vasoconstrictory of hyperventilation on cerebral vessels, suggesting it to be useful as a prophylactic medication in migraine therapy (34,35).

The other pharmacologic property of calcium antagonists considered possibly beneficial in migraine is the cytoprotective effect, that is, protection against excessive Ca²⁺ influx/release during cerebral ischemia. This cytoprotective effect has been demonstrated convincingly in animal studies for both flunarizine and nimodipine (36). It has also been suggested that calcium antagonists may be effective in migraine prophylaxis by inhibiting cortical spreading depression (CSD) (see Chapter 22). In one study in rats using a high dose of flunarizine (40 mg/kg intraperitoneally), flunarizine increased the threshold for CSD (77). A later study with the same dose but a modified technique failed to reproduce this result (44). In another study, an oral dose of 20 mg/kg flunarizine had no effect on CSD (24).

The brain contains a high density of binding sites for calcium antagonists (22), and the drugs have central nervous system (CNS) effects that could be relevant for their effect in migraine. In humans, experimental evidence has been found that nimodipine can affect neurotransmission (29), and flunarizine has proven efficacy as an add-on drug for epilepsy (53,74). In addition, the side effects of flunarizine, such as sedation, weight gain, Parkinsonism, and depression, strongly suggest interaction with CNS neurotransmitters. In addition, flunarizine has antihistaminic effects (74).

Cerebral arterial vasospasm is unlikely to occur in migraine, and flunarizine, the best proven calcium antagonist for migraine, exerts minimal calcium antagonistic effect on cerebral vessels in therapeutic doses (30). This drug does, however, appear to impair the synthesis and release of nitric oxide, a substance possibly responsible for migraine pain (see Chapter 40), from perivascular nerves (6) and possibly endothelium in cerebral vasculatures. Interferences with the release of sensory transmitters, substance P and CGRP, by α-eudesmol may also be involved in migraine prophylaxis (5). On the other hand, nimodipine in doses used in migraine prophylaxis can exert an effect on cerebral vessels (30), but it has only minor or no prophylactic effect (vide infra). The cytoprotective effect of calcium antagonists is probably irrelevant, because the most convincing effect of calcium antagonists is in migraine without aura (69), in which cerebral blood flow is normal during attacks (see Chapter 35). The mechanism of action of calcium antagonists in migraine prophylaxis is most likely through their interaction with CNS neurotransmission.

The half-life of verapamil is 3 to 7 hours (27), and the drug is given in three daily doses. Sustained-release preparations of verapamil can be given once or twice daily. Flunarizine has a terminal elimination half-life of 18 days (74) and is given once daily.

Verapamil has been evaluated for migraine prophylaxis in three small, double-blind, crossover trials (43,63,64). In total, only 41 patients were evaluable in these trials; therefore, the results cannot be applied directly to the general migraine population.

In two trials, verapamil (240 and 320 mg daily) was better than placebo (43,64), and in one study verapamil (320 mg) had an effect that was similar to that of long-acting propranolol (120 mg daily) but also similar to that of placebo (63). In two double-blind trials, probably performed simultaneously, 320 mg/d of verapamil had better results than 240 mg daily compared with placebo control (62), but the lack of randomization precludes drawing any conclusions.

In conclusion, the scientific proof for a prophylactic effect of verapamil in migraine is almost nonexistent, and its use in migraine prophylaxis in some countries is based on open clinical studies that indicated some efficacy of the drug (61).