Verapamil and Migraine Prophylaxis: Mechanisms and Efficacy HERBERT

G.

MARKLEY,

M.D.,

Worcester, Massachusetts

Calcium channel blockers have demonstrated efficacy in investigative use for prophylaxis of migraine and cluster headaches. In particular, verapamil, with its low side-effect profile, appears to be a promising alternative to the currently available agents for prophylactic treatment of chronic recurring headaches. Although its exact mechanisms of action in this application are unknown, verapamil exerts a vasodilatory effect on cerebral arteries and interacts with serotonergic systems involved in migraine pathogenesis. A review of studies from the past decade indicates that verapamil may be as effective as traditional therapies as prophylaxis for the major types of chronic recurring headache.

hronic recurring headaches of the migraine type affect 10% to 20% of the U.S. population [l]. Headaches requiring medical attention or restricted activity have been reported to occur in 0.8% of males and 1.5% of females. Almost 6 million days (2.8 days per 100 persons) are lost annually from work or school due to migraine-related disability [2]. The symptoms of migraine include anorexia, nausea or vomiting, lightheadedness, photophobia, visual disturbances (i.e., blurring, teichopsia, photopsia, or scotomas), scalp tenderness, and neurologic symptoms such as hemiparesis [3]. The headache is described as unilateral, frontotemporal, and dull or throbbing, and usually has a gradual onset. A family history of migraine is common, although individual headaches may be provoked by environmental factors [4]. Of the major classes of headache defined by the International Headache Society [5], three are especially common and disabling: migraine with aura (classic migraine), migraine without aura (common migraine), and cluster headache. Migraine with aura is accompanied by transient prodromal neurologic symptoms, including ataxia, dysphasia, scotomas, photopsia, and paresthesias [461. Migraine without aura does not have neurologic prodromes and may not be unilateral [4-61. Cluster headache, believed to be a nonmigrainous form of headache, causes a boring or stabbing pain that occurs in cycles. It is more common in men, in contrast to migraine which occurs more frequently in women, especially in association with the menstrual cycles. [l]

C

PATHOGENESIS OF MIGRAINE

~ From the Headache Center, Department of Neurology, The Medical Center of Central Massachusetts, and University of Massachusetts Medical School, Worcester, Massachusetts. Requests for reprints should be addressed to Herbert G. Markley, M.D., Director, Headache Clinic, and Assocrate Chief, Department of Neurology, The Medical Center of Central Massachusetts-Memorial, 119 Belmont Street, Worcester, Massachusetts 01605.

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The precise origin of these types of recurring chronic headache is not known. Our understanding of the pathophysiology involved is limited,‘in large part because of the lack of an adequate animal model of spontaneously occurring chronic headache. Both vascular and neurogenic theories have been postulated, and the possibility that several mechanisms underlie the disorder has not been ruled out. Vascular Etiology

A vascular origin for migraine was first suggested by Wolff and Graham [7], who observed that

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the administration of ergotamine reduced the amplitude of the pulsations of the superficial temporal artery in patients during migraine attacks. They theorized that the neurologic symptoms of migrainous aura were due to intense intracranial arterial vasoconstriction, which was followed by pulsatile headache produced by extracranial arterial vasodilatation that was potentially accentuated by the ischemia during the preceding prodrome. A number of later investigations of cerebral blood flow have supported this sequence of cerebrovascular events in migraine [8--141. “Spreading Neurologic Depression” The initial vascular theory was modified when neuroreceptor interactions were demonstrated in the aura phase. The migrainous aura phase lasts for about 20 minutes and is often characterized by brilliant expanding hallucinations followed by an expanding scotoma. The Harvard neuropsychologist K.S. Lashley, in 1941, described the movement of his own migrainous scotoma across his visual field and was able to map it onto the visual cortex. He found that it traversed cortical gyri at the rate of 3 mmimin and speculated that a wave front of intense neuronal excitation was propagating across the cortex, followed by a refractory period of complete neuronal inhibition producing the blind area [El. Shortly thereafter, Leao, a Brazilian physiologist, demonstrated similar electrical “spreading depression” of cortical activity in the exposed cerebral cortex of animals, initiated by such stimuli as hypoxia, trauma, or local application of potassium chloride [16]. Although a neuronal model of migraine was not proposed in the 1940s these findings supported a neuronal, i.e., dendritic, basis for migraine, rather than a vascular basis. Almost 4 decades later, Olesen and Lauritzen [17,18] conducted a series of experiments using the xenon-133 injection method to measure regional cerebral blood flow (rCBF) changes during migraine attacks. Attacks were shown to be initiated by a wave of focal hyperemia, which was followed by reduced occipitoparietal rCBF (oligemia) that gradually spread anteriorly during both the aura and headache phases of the migraine attack [1’7]. The spreading oligemia, however, was found to reach primary sensorimotor areas after focal symptoms from those areas had begun, and remained there long after those symptoms had subsided, leading the investigators to conclude that focal migraine symptoms and blood flow changes were probably secondary to a form of spreading neuronal depression, as had been described by Leao [18]. These results have been replicated in other laboratories [19,20] and by other methods, such as positron emission tomography [20], all showing a con-

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sistent decrease in neuronal activation and rCBF, which begins in the occipital region during the aura phase of migraine and spreads slowly forward over the ipsilateral hemisphere at the rate of about 3 mmimin. Welch et al Cl91 used regional nuclear magnetic resonance spectroscopy to show that the area of decreased perfusion was not acidotic, as would be expected if vasospasm and ischemia were the cause of the phenomenon. This supports the theory that decreased neuronal firing and the resulting reduced metabolism produces reduced rCBF (via local autoregulation), instead of the older theory that regional vasospasm produces regional ischemia. Serotonergic Discharge Our most recent understanding of the pathophysiology of migraine is based upon both human and animal research and raises the possibility that a neurogenic cause for migraine might explain not only the aura, but also the headache phase of the illness. The available evidence now suggests that migraine may be due to an intermittently occurring paroxysmal neuronal discharge from serotonergic neurons in the median raphe nucleus of the pons [21]. This nucleus projects strongly to the ipsilatera1 occipital cortex, where the initial discharge is believed to initiate a wave of spreading excitation, followed by depression of neuronal activity that spreads anteriorly at a rate of 2 to 3 mmimin. An efferent pathway via the trigeminal nerve complex has been described [22], which may cause the changes in blood flow observed through the external carotid artery and its branches during the aura phase and which may also cause local arterial tenderness through the release of substance P, the “pain neurotransmitter.” Local arterial tenderness is probably not the cause of most intense migraine pain, however. The median raphe and adjacent locus ceruleus nuclei exert direct central effects upon pain transmission pathways via serotonergic and noradrenergic systems, and connect richly to the central pain relays of endorphinergic neurons in the periaqueductal gray nucleus of the midbrain [23-251. The nucleus raphe magnus also originates a serotonergic tract traveling caudad to medullary and spinal levels to synapse in the substantia gelatinosa, where it modifies afferent pain information carried by substance P fibers. These synaptic connections can modify pain information entering at trigeminal and cervical spinal levels and can produce changes in pain threshold. The cause of pain may be very similar to the central cause of pain in causalgia, an intense pain observed with “phantom limb syndrome” after amputation of a limb. Although research is shedding light on the role of serotonin (5-HT) in migraine pathogenesis [23,24],

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These data suggest that an important mechanism of these antimigraine agents may be their interactions with 5-HT receptors.

TABLE I Prophylactic Drug Therapy Used in Treating Migraine p blockers

Traditional Therapies

F/~~~op

Atenolol Metoprolol Tricvclic and nontricvclic antidewessants Amitriptyline ’ Nortriptyline lmlpramine Desipramine Doxepin Ergot preparations Ergotamine Methysergide Nonsteroidal anti-inflammatorv druas fNSAlDs) Calcium channel blockers ’ I Verapamil Nifedipine Diltiazem Flunarizine Nimodipine

TABLE II Potencies of Antimigraine Subtypes [28]

Drug

Drugs at Serotonin Receptor

5.HT,,

5-HT antagonists Methysergide Cyproheptadine Amitriptyline p blocker Propranolol Calcium channel blockers Verapamil Nifedipine Diltiazem

;; 1,800

5.HT,

5.7 2.2 23

160

4,100

2,100

140 320 2,400

>100,000 >100,000

?adioligand studies were performed in human frontal cortex.

5- HT = serotonin.

Traditional agents for migraine prophylaxis have been p blockers (e.g., propranolol), ergot preparations (e.g., methysergide), and tricyclic antidepressants (e.g., amitriptyline). Beta blockers appear to be effective-perhaps in as many as 80% of patients-because they block excessive cerebral vasodilatation [29-311, but they do not influence prodromal symptoms [29] and may worsen the severe vasoconstriction occurring in classic or complicated migraine. Ergot compounds, used to manage acute attacks, change the caliber of the smooth muscle of the cerebral arterial wall; methysergide is a 5:HT antagonist. Tricyclic antidepressants bind to specific receptors on platelets and neurons [32,33] and block 5-HT reuptake into neurons [33]. While these conventional therapies satisfactorily control migraine in many patients, they often lead to side effects that may significantly limit their usefulness in certain individuals. For example, p blockers may cause drowsiness and depression in both men and women and impotence in some men, and they are generally contraindicated in patients with congestive heart failure or asthma. The potential for vascular toxicity with ergot alkaloids [34-361 and fibrotic complications with long-term methysergide use [37] may prevent their use in many patients. Similarly, the muscarinic anticholinergic properties of the tricyclic antidepressants may preclude their use in patients with cardiovascular disorders or prostatism. Calcium Channel Blockers

in central pain pathways [25], and in changing central pain threshold [22], further investigation is required to clarify these mechanisms.

Since 1981, numerous studies [3,6,38-451 have shown that calcium channel blockers are effective in prophylaxis of migraine. Results with calcium channel blockers appear to be comparable to those PROPHYLACTICDRUGTREATMENTOF MIGRAINE achieved with standard migraine therapy such as Despite questions that remain regarding the propranolol. Like coronary arteries, cerebral arterpathogenesis of migraine, various drug therapies ies depend on the binding of extracellular calcium have been found empirically to be effective in pre- [45-481 for regulation of cell function, including venting migraine attacks (Table I). The pharmacovascular smooth muscle contraction, neurotranslogic effects of these prophylactic antimigraine mitter and hormone secretion, and enzyme activity drugs are diverse, although each may affect vascu- [4,48,49]. Calcium channel blockers inhibit the enlar smooth muscle, and most block 5-HT, adrenertrance of extracellular calcium into cephalic vascugic, or prostaglandin pathways [41. Recent studies lar smooth muscle and block intracerebral vasoconof interactions between antimigraine drugs and striction induced by vasoactive neurotransmitters, subtypes of 5-HT receptors have shown that pro- such as 5-HT and norepinephrine [50,51]. The abilphylactic antimigraine agents display a high or ity of calcium channel blockers to block the 5-HT receptor subtypes is considered an essential conmoderate affinity for 5-HTIA and/or 5-HT, receptor subtypes in the human brain (Table II) [26-281. tributing factor to their efficacy in migraine.

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tients had 50% or greater improvement (Figure 1). Mild constipation occurred in six patients (43%). Improvement was due to a significant decrease in frequency and duration of headaches with verapamil. The mean number of headaches per week dropped from 3.4 with placebo to 2.8 with verapamil, and the mean duration of each headache decreased from 10.6 to 8.7 hours. A remarkable decrease in weekly headache score from a mean of 226 to 2.9 was seen in one patient who was treated with placebo for 8 weeks, followed by verapamil, 40 mg qid (Figure 2). This patient became headache-free on verapamil and continued to receive it as prophylactic migraine therapy. Twelve of 19 patients given long-term prophylaxis with calcium channel blockers were headache free or considerably improved.

t-test

t = 3.02 df=13

Mean = 72.6

PLACEBO

ON CALCIUM ANTAGONISTS

VERAPAMIL 80 mg tid

Figure 1. Improvement in weekly headache score (intensity of headache times duration of attack) from a mean of 116.4 to 72.6 was shown in patients receiving verapamil (80 mg tid). ReprInted with permission from [3].

Common/Classic Migraine Solomon and colleagues [52] evaluated the efficacy of verapamil, 80 mg qid, as migraine prophylaxis in 12 patients with classic or common migraine. Ten of the 12 patients (83%) had fewer migraines during verapamil therapy, with a mean decrease in migraine frequency of 49%. A 36% mean reduction in headache unit index (i.e., headache severity divided by number of days observed) was also observed. No major side effects were reported.

VERAPAMILIN MIGRAINEPROPHYLAXIS The initial rationale for the use of verapamil in headache management was the drug’s effeet on dilatation of cerebral arteries, preventing the cerebral vasoconstriction believed to mark the onset of the migraine attack [3]. However, verapamil has demonstrated moderate affinity for the 5-HT subtype receptors on cerebral blood vessels and brain neurons [28], suggesting that it may act via additional mechanisms other than direct vasodilatation. In fact, in the prophylaxis of migraine, verapamil’s interaction with serotonergic systems may be more important than its vascular mechanisms. Chronic Migraine In a double-blind, placebo-controlled, crossover study [3], verapamil (240 mg/d) was administered for 8 weeks to 14 patients who had had chronic headaches (several headaches per week) for an average of 13 years. Ten patients (71%) had an improvement in weekly headache score (intensity of headache x duration of the attack), and four pa-

0 n=5 .

(unpaired

\

0 =0 0 s!s \

Mean 104.4

0

l

NO DRUG

t-test

t = 5.11 df = 73 p

Verapamil and migraine prophylaxis: mechanisms and efficacy.

Calcium channel blockers have demonstrated efficacy in investigative use for prophylaxis of migraine and cluster headaches. In particular, verapamil, ...
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