MIGRAINE

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CHAPTER 56 MIGRAINE

Migraine is a primary episodic headache disorder characterized by various combinations of neurological, gastrointestinal, and autonomic changes. The word migraine is derived from the Greek word “hemicrania” (Galen, circa 200 AD).¹ Diagnosis is based on the headache’s characteristics and associated symptoms.² The International Headache Society diagnostic criteria for headache disorders (1988)³ have been revised (2004) and describe a total of seven subtypes of migraine.⁴ Data in this chapter⁵ are from the Technical Reports of the Agency for Healthcare Policy and Research,⁶^–⁹ the U.S. Headache Consortium Guidelines,^10,¹¹ and the triptan metaanalysis.¹²

EPIDEMIOLOGY

Migraine prevalence rates are similar and stable in European countries and in the United States.¹³ In the United States, according to one study, 17.6% of women and 6% of men had had one migraine attack in the previous year.¹⁴ A second study 10 years later had similar prevalence estimates (Fig. 56-1).¹⁵ Migraine prevalence varies by age, gender, race, and income. Before puberty, migraine prevalence is approximately 4%.¹⁶ After puberty, the prevalence increases more rapidly in girls than in boys. It increases until approximately age 40, then declines. The prevalence is lowest among Asian-Americans, intermediate among African-Americans, and highest among white persons.¹⁶ In the United States, migraine prevalence decreases as household income increases.^14,^16,¹⁷

Figure 56-1 Adjusted age-specific prevalence of migraine by sex.

(From Lipton RB, Stewart WF, Diamond S, et al: Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001; 41:646-657.)

Migraine substantially affects quality of life. The World Health Organization ranks migraine among the world’s most disabling medical illnesses.¹⁸ Approximately 28 million Americans have severe, disabling migraine headaches.¹⁵ Migraine’s annual cost to employers is approximately $13 billion, and related annual medical costs exceed $1 billion.¹⁶ Instruments to quantify migraine disability include the Migraine Disability Assessment Scale¹⁹ and the Headache Impact Test.²⁰

PATHOPHYSIOLOGY

Genetics

Migraine is a group of familial disorders with a genetic component. Familial hemiplegic migraine (FHM) is an autosomal dominant disorder characterized by attacks of migraine, with and without aura, and hemiparesis. The gene has been mapped to chromosome 19p13 in approximately two thirds of cases.^21,²² The defect arises from at least 10 different missense mutations in the CACNA1A gene, which codes for the α₁ subunit of a voltage-dependent P/Q Ca²⁺ channel.²³ The same gene is associated with episodic ataxia with cerebellar vermix atrophy.²¹ P-type neuronal Ca²⁺ channels mediate 5-hydroxytriptamine (5-HT) and excitatory neurotransmitter release. Dysfunction may impair 5-HT release and predispose patients to migraine attacks or impair their self-aborting mechanism. Voltage-gated P/Q-type calcium channels mediate glutamate release, are involved in cortical spreading depression (CSD), and may be integral in initiating the migraine aura (Fig. 56-2).²⁴ A second gene has been mapped to chromosome 1q21-23. The defect is due to a mutation in the α₂ subunit of the Na/K pump.²⁵

Figure 56-2 Cortical spreading depression (CSD). The relationship between CSD and headache in migraine with aura. CSD releases H⁺, K⁺, and other agents, including arachidonic acid (AA) and nitric oxide (NO), in the extracellular space of the neocortex. These agents diffuse toward local blood vessels and depolarize perivascular trigeminal terminals, which, in turn, causes activation of the caudal portion of the trigeminal nucleus (TGN) in the brainstem. At the same time, collateral axons of activated neurons in the trigeminal ganglion (TGG) release proinflammatory peptides in the meninges and their vessels, which leads to a local inflammatory reaction. The activation from the superior salivatory nucleus (SSN) and reaching meningeal blood vessels via the sphenopalatine ganglion (SPG). The perception of pain is mediated by higher order projections from the TGN. The dashed lines between TGN, SSN, and regions generating the pain indicate that these connections either are unknown or have not been depicted.

Aura

The migraine aura was believed to be caused by cerebral vasoconstriction and the headache by reactive vasodilation.²⁶ This explained the headache’s throbbing quality and its relief by ergots. It is now believed that the migraine aura is caused by neuronal dysfunction, not ischemia; ischemia rarely, if ever, occurs. Headache often begins while cortical blood flow (CBF) is reduced²⁷^–²⁹; thus, headache is not caused by simple reflex vasodilation.^30,³¹

The migrainous fortification spectrum corresponds to an event moving across the cortex at 2 to 3 mm/minute.³² Noxious stimulation of the rodent cerebral cortex produced a spreading decrease in electrical activity that moved at 2 to 3 mm/minute (CSD).³³ CSD is characterized by shifts in cortical steady-state potential; transient increases in potassium, nitric oxide, and glutamate levels; and transient increases in CBF, followed by sustained decreases.²⁷

The aura is associated with an initial hyperemic phase followed by reduced CBF, which moves across the cortex (spreading oligemia).³⁴ Olesen and colleagues^34,³⁵ found 17% to 35% reductions in posterior CBF, which spread anteriorly at 2 to 3 mm/minute. It crossed brain areas supplied by separate vessels and is thus not caused by segmental vasoconstriction.³⁵ Reduced CBF persisted from 30 minutes to 6 hours, and then CBF slowly returned to baseline or even increased. The rates of progression of spreading oligemia are similar to those of migrainous scotoma and CSD, which suggests that they are related.^31,^33,³⁶

Additional studies ^28,^29,³⁷^–⁴⁰ support the hypothesis that CSD produces the aura.²⁷ During visual auras, CBF decreased 15% to 53%, cerebral blood volume decreased 6% to 33%, and mean transit time increased 10% to 54% in the occipital cortex contralateral to where the aura was experienced. The perfusion defect moved anteriorly.²⁹ The absence of diffusion abnormalities suggests that ischemia does not occur during the aura.⁴¹

Blood oxygenation level–dependent (BOLD) functional magnetic resonance imaging (MRI) reflects the relative concentration of deoxyhemoglobin in venous blood. Visual stimulation was used to trigger headache in migraineurs.³⁷ A wave of increased BOLD signal (reflecting hyperoxygenated blood) and then decreased BOLD signal (possibly reflecting neuronal metabolic flow coupling) propagated into the contiguous occipital cortex at 3 to 6 mm/minute. When visual stimulation was used to test the visual cortex response, the BOLD signal and the BOLD response to visual activation diminished after progression of the visual aura.³⁰

Magnetoencephalography demonstrates changes that are consistent with CSD in migraineurs but not in controls.^42,⁴³ Using transcranial magnetic stimulation (which applies magnetic fields of increasing intensity) to evaluate occipital cortex excitability, Aurora and associates⁴⁴ and Young and coworkers,⁴⁵ but not Afra and colleagues,⁴⁶ found that phosphenes were generated in migraineurs at lower thresholds than in controls and that it was easier to visually trigger headaches in subjects with lower thresholds. Other evidence of increased central nervous system (CNS) excitability comes from studies of visual and brainstem auditory evoked potentials.⁴⁷ Migraine with aura may be caused by neuronal hyperexcitability, which perhaps arises from cortical disinhibition.

Headache

Headache probably results from the activation of meningeal and blood vessel nociceptors in combination with a change in central pain modulation. Headache and its associated neurovascular changes are subserved by the trigeminal system. Reflex connections to the cranial parasympathetic nerves form the trigeminoautonomic reflex. Activation results in vasoactive intestinal polypeptide release and vasodilation.³¹

Trigeminal sensory neurons contain substance P, calcitonin gene–related peptide (CGRP), and neurokinin A.⁴⁸ Stimulation results in release of substance P and CGRP from sensory C-fiber terminals⁴⁹ and neurogenic inflammation.⁵⁰ The neuropeptides interact with the blood vessel wall, producing dilation, plasma protein extravasation, and platelet activation.⁵¹ One study suggests that neurogenic inflammation occurs in humans.⁵² Neurogenic inflammation sensitizes nerve fibers (peripheral sensitization) that then respond to previously innocuous stimuli, such as blood vessel pulsations,⁵³ causing, in part, the pain of migraine.⁵⁴ Central sensitization can also occur. After meningeal irritation, expression of c-fos (a marker for neuronal activation) occurs in the trigeminal nucleus caudalis⁵⁵ and in the dorsal horn at the C₁ and C₂ levels.^56,⁵⁷

Superior sagittal sinus stimulation results in release of CGRP but not substance P.⁵⁸ This is important: Levels of CGRP, not substance P, is elevated in external jugular venous blood during migraine.⁵⁹ Sumatriptan reduced elevated CGRP levels in a migraine attack and in experimental animals during trigeminal ganglion stimulation.^60,⁶¹ CGRP may play a role in migraine headache.^62,⁶³ A potent specific CGRP antagonist⁶⁴ has been reported to be effective in acute migraine treatment.⁶⁵

Applying an “inflammatory soup” to the dura sensitizes second-order trigeminovascular neurons (increased spontaneous activity and response to mechanical and thermal skin stimulation).⁵³ Triptans administered early prevented central sensitization: Dural and facial receptive fields did not expand; spontaneous activity, mechanical sensitivity, and thermal sensitivity did not increase. Late triptan intervention did not reverse central sensitization but shrank the expanded dural receptive fields and normalized intracranial mechanosensitivity. Central sensitization may play a key role in maintaining the headache.^66,⁶⁷

Affected patients often develop cutaneous allodynia (nonpainful stimuli are experienced as painful) during migraine attacks because of trigeminal sensitization.⁶⁶ Triptans can prevent but not reverse cutaneous allodynia.⁶⁷ Cutaneous allodynia can be used to predict triptans’ effectiveness.⁶⁶ In the absence of allodynia, triptans completely relieved the headache and blocked the development of allodynia. In 90% of attacks with established allodynia, triptans provided little or no headache relief and did not suppress allodynia. However, late triptan therapy eliminated peripheral sensitization (throbbing pain aggravated by movement), even when pain relief was incomplete and allodynia was not suppressed.⁶⁶ Early intervention may work by preventing cutaneous allodynia and central sensitization.

Brainstem activation occurs in migraine without aura. On positron emission tomography, patients with right-sided migraine headache showed increased regional CBF in the left brainstem.⁶⁸ Sumatriptan relieved the headache and associated symptoms but did not normalize brainstem regional CBF. This suggests that activation is caused by factors other than, or in addition to, increased activity of the endogenous antinociceptive system. A second report corroborated these findings.⁶⁹

A link exists between the migraine aura and headache. CSD activates trigeminovascular afferents, causing a long-lasting increase in middle meningeal artery blood flow and plasma protein extravasation within the dura mater.⁷⁰ CSD results in upregulation of inducible nitric oxide synthetase and inflammatory cytokines. This mechanism couples meningeal blood flow and neurogenic inflammation to CSD but does not explain headache ipsilateral to the aura.^31,⁷⁰

Serotonin (5-HT) Receptors and Migraine Treatment

There are seven classes of 5-HT receptors: 5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆, and 5-HT₇.⁷¹ In humans, there are five 5-HT₁ receptor subtypes: 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E, and 5-HT_1F.⁷² The 5-HT_1B receptor is located on intracranial blood vessels and CNS neurons. The 5-HT_1D receptor is located on CNS neurons and trigeminal nerve endings. The 5-HT_1F receptors are located on trigeminal nerve endings.⁷³ Ergots and triptans act at the 5-HT_1B, 5-HT_1D, and, in part, 5-HT_1F receptors. They constrict extracerebral intracranial vessels, inhibit trigeminal neurons, and block transmission in the trigeminal nucleus. They minimally constrict human coronary arteries. They block plasma protein extravasation⁵⁰ by activating prejunctional trigeminal 5-HT_1D and 5-HT_1F heteroreceptors, blocking neuropeptide release. Plasma protein extravasation can be also be blocked by nonsteroidal anti-inflammatory drugs (NSAIDs),⁷⁴ γ-aminobutyric acid (GABA) agonists,^75,⁷⁶ neurosteroids,⁷⁷ substance P antagonists,⁷⁸ and the endothelin antagonist bosentan.⁷⁹ Dihydroergotamine and the centrally penetrant triptans label the nuclei in the brainstem and spinal cord that are involved in pain transmission and modulation.⁸⁰ The caudal trigeminal nucleus is activated by stimulation of the sagittal sinus, and this activity is transmitted to the thalamus. Ergots and triptans suppress this activation.

Conclusion

The migraine aura is probably caused by CSD. Headache probably results from activation of meningeal and blood vessel nociceptors in combination with a change in central pain modulation. Headache and its associated neurovascular changes are subserved by the trigeminal system. Stimulation results in the release of substance P and CGRP from sensory C-fiber terminals and neurogenic inflammation.⁵¹ Neurogenic inflammation sensitizes nerve fibers (peripheral sensitization), which then respond to previously innocuous stimuli, such as blood vessel pulsations, causing, in part, the pain of migraine. Central sensitization of trigeminal nucleus caudalis neurons can also occur. Central sensitization may play a key role in maintaining the headache. Brainstem activation also occurs in migraine without aura, partly as a result of increased activity of the endogenous antinociceptive system. The migraine aura can trigger headache; CSD activates trigeminovascular afferent vessels. Stress can also activate meningeal plasma cells via a parasympathetic mechanism, leading to nociceptor activation.⁸¹

Migraine may be a result of a change in processing of pain and sensory input. The aura is triggered in the hypersensitive cortex (as a result of CSD). Headache is generated by central pain facilitation and neurogenic inflammation. Central sensitization, mediated in part by supraspinal facilitation, can occur. Decreased antinociceptive system activity and increased peripheral input may be present.

DESCRIPTION OF THE MIGRAINE ATTACK

The migraine attack can consist of premonitory, aura, headache, and resolution phases. Premonitory symptoms occur in 20% to 60% of migraineurs, hours to days before headache onset. They may include psychological, neurological, constitutional, or autonomic features, such as depression, cognitive dysfunction, and bouts of food cravings.⁸² Migraineurs who reported having premonitory symptoms were able to accurately predict 72% of their full-blown headaches. The most common premonitory symptoms were feeling tired/weary (72%), difficulty concentrating (51%), and stiff neck (50%). Poor functioning was commonly predictive of headache.⁸³

Aura

The migraine aura consists of focal neurological symptoms that precede, accompany, or (rarely) follow an attack. Aura usually develops over 5 to 20 minutes; lasts less than 60 minutes; can be visual, sensory, or motor; and may involve language or brainstem disturbances.³ Headache usually follows within 60 minutes of the end of the aura. Patients can have multiple aura types; most patients with a sensory aura also have a visual aura.⁸⁴

Auras vary in complexity. Simple auras include scotomata, simple flashes (phosphenes), specks, geometrical forms, and shimmering in the visual field. More complicated visual auras include teichopsia or fortification spectra (the characteristic aura of migraine), metamorphopsia, micropsia, macropsia, zoom vision, and mosaic vision. Paresthesias are often cheiro-aural: Numbness starts in the hand, migrates up the arm, and jumps to involve the face, lips, and tongue.^2,⁸⁵ Weakness is rare, occurs in association with sensory symptoms, and is unilateral.⁸⁶ Apraxia, aphasia, agnosia, states of altered consciousness associated with déjà vu or jamais vu, and elaborate dreamy, nightmarish, trancelike, or delirious states can occur.⁸²

Headache Phase

The median migraine attack frequency is 1.5 per month.¹⁴ The typical headache is unilateral, of gradual onset, throbbing (85%),⁸⁷ moderate to marked in severity, and aggravated by movement.³ Pain may be bilateral (40%) or may start on one side and become generalized. It lasts 4 to 72 hours in adults and 2 to 48 hours in children.³

During the headache, anorexia is common. Nausea occurs in almost 90% of patients, and vomiting occurs in about one third.⁸⁸ Sensory hypersensitivity results in patients’ seeking a dark, quiet room.^2,⁸⁸ Blurry vision, nasal stuffiness, hunger, tenesmus, diarrhea, abdominal cramps, polyuria, facial pallor, sensations of heat or cold, and sweating may occur. Depression, fatigue, anxiety, nervousness, irritability, and impairment of concentration are common. Symptom complexes may be generated by linked neuronal modules.⁸⁹

Resolution Phase

After the headache, many patients feel tired, “washed out,” irritable, and listless and may have impaired concentration, scalp tenderness, or mood changes. Some patients feel unusually refreshed or euphoric after an attack; others experience depression and malaise.

FORMAL DIAGNOSTIC CRITERIA

The International Headache Society subdivides the disorder into migraine with aura and migraine without aura.^4,⁹⁰ To diagnose migraine without aura (Table 56-1), five attacks must have occurred. No single feature is mandatory, but recurrent episodic attacks must be documented.³ Migraine persisting for more than 3 days defines “status migrainosus.”^3,⁴

TABLE 56-1 Migraine without Aura: Diagnostic Criteria

Migraine with aura is subdivided into migraine with typical aura, migraine with prolonged aura, hemiplegic migraine, basilar-type migraine, and migraine with acute-onset aura (Table 56-2.) The International Headache Society classification now allows the association of aura with other headache types. Prolonged aura lasts from 1 hour to 1 week; persistent aura lasts for more than 1 week (but resolves). If neuroimaging demonstrates a stroke, a migrainous infarction has occurred.

TABLE 56-2 Migraine with Aura (Classic Migraine): Diagnostic Criteria

At least two attacks

Migraine aura fulfills criteria for typical aura, hemiplegic aura, or basilar-type aura

Not attributed to another disorder

Typical aura:

Fully reversible visual and/or sensory and/or speech symptoms but no motor weakness

Homonymous or bilateral visual symptoms, including positive features (e.g., flickering lights, spots, lines) or negative features (e.g., loss of vision), and/or unilateral sensory symptoms, including positive features (e.g., visual loss, pins and needles) and/or negative features (e.g., numbness)

At least one of the following

At least one symptom develops gradually over ≥5 min and/or different symptoms occur in succession

Each symptom lasts ≥5 minutes and ≤60 minutes

Headache that meets criteria for migraine without aura begins during the aura or follows aura within 60 minutes

Periodic neurological dysfunction (scintillating scotomata and recurrent sensory, motor, and mental phenomena) can occur without headache.⁹¹ Visual phenomena, which are usually benign, occurred in 1.33% of women and in 1.08% of men in a general population sample.⁹² Scintillating scotomata, numbness, aphasia, dysarthria, and motor weakness may occur for the first time after age 45 and be confused with transient ischemic attacks of cerebrovascular origin.⁹³ In general, migrainous symptoms are slower to develop (>5 minutes) and consist of positive and negative phenomena.

MIGRAINE VARIANTS

Basilar-type migraine aura has brainstem symptoms: ataxia, vertigo, tinnitus, diplopia, nausea and vomiting, nystagmus, dysarthria, bilateral paresthesia, and a change in the level of consciousness and cognition.³ The diagnosis should be considered when patients have paroxysmal brainstem disturbances. Some authorities have suggested that hemiplegic migraine should be diagnosed if weakness is present.⁸⁶

Ophthalmoplegic migraine results from an idiopathic inflammatory neuritis.⁹⁴ There is enhancement of the cisternal segment of the oculomotor nerve, followed by resolution over several weeks as symptoms resolve.

Hemiplegic migraine can be sporadic or familial.² Attacks are frequently precipitated by minor head injury.⁸⁶ FHM is an autosomal dominant, genetically heterogeneous disorder with variable penetration. FHM includes attacks of migraine without aura, migraine with typical aura, and episodes of prolonged aura, fever, meningismus, and impaired consciousness.²³ Headache may precede the hemiparesis or be absent. Hemiparesis onset may be abrupt and simulate the effects of a stroke. In 20% of unselected families whose members have FHM, patients have cerebellar symptoms and signs (nystagmus, progressive ataxia). All have mutations within CACNA1A.²²

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain caused by a Notch3 gene mutation on chromosome 19.^95,⁹⁶ CADASIL mutations are highly stereotyped missense mutations within epidermal growth factor–like repeats in the extracellular domain of Notch3. Mutations lead to loss or gain of a cysteine, thereby creating an odd number of cysteines within a given epidermal growth factor domain.⁹⁷ Notch3 expression is restricted to smooth muscle cells, and normal proteolysis of the Notch3 receptor generates a 210-kD extracellular fragment and a 97-kD intracellular fragment. Patients with CADASIL accumulate excess Notch3 ectodomain (i.e., the 210-kD fragment) within the cerebral vasculature, apparently because of impaired clearance of the receptor from the surface of vascular smooth muscle cells and pericytes. Most cases are inherited in an autosomal dominant manner, but a de novo symptomatic mutation, Arg182Cys, has been reported.⁹⁸ Symptoms include recurrent subcortical lacunar infarctions (84%), progressive or stepwise subcortical dementia with pseudobulbar palsy (31%), migraine with aura (22%), and mood disorders with severe depressive episodes (20%).⁹⁹ MRI scans of at-risk individuals are often abnormal, with extensive areas of increased white matter T2 signals. The arteriopathy involves the media of small cerebral arteries and, to a lesser extent, extracerebral arteries, including skin arterioles. In skin biopsy, abnormal patches of agranular osmiophilic material within the basal membranes of vascular smooth muscle cells are diagnostic.⁹⁷ A commercial genetic test is available for the most common CADASIL mutations. It currently has a false-negative rate of at least 20% because it screens only mutational hot spots located in exons 3, 4, 11, and 18. Scanning all 23 exons that encode all 34 epidermal growth factor–like repeat sequences is considered the most accurate test for CADASIL, but it is time-consuming and costly.

TREATMENT

Migraine varies widely in its frequency, severity, and impact on the patient’s quality of life. A treatment plan should account not only for the patient’s diagnosis, symptoms, and any coexistent or comorbid conditions but also for the patient’s expectations, needs, and goals.^100,¹⁰¹ Migraine treatment begins with making a diagnosis,² explaining it to the patient, and developing a treatment plan that considers coincidental or comorbid conditions.¹⁰¹ Headache calendars record headache duration, severity, and treatment response. Comorbidity indicates an association between two disorders that is more than coincidental.

Conditions that occur in migraineurs with a higher prevalence than would be expected include stroke, epilepsy, Raynaud’s disease, and affective disorders, which include depression, mania, anxiety, and panic disorder. Possibly associated disorders include essential tremor, mitral valve prolapse, and irritable bowel syndrome.

The pharmacological treatment of migraine may be acute (abortive) or preventive (prophylactic), and patients with frequent severe headaches often require both approaches. Acute treatment is an attempt to relieve or stop the progression of an attack or the pain and impairment once an attack has begun. It is appropriate for most attacks and should be used a maximum of 2 to 3 days a week. Preventive therapy is given, even in the absence of a headache, in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include improving responsiveness to acute attack treatment, improving function, and reducing disability.

Pharmacotherapy for the Acute Migraine Headache

Acute treatment can be specific (ergots and triptans), or nonspecific (analgesics and opioids) (Table 56-3). Nonspecific medications control the pain of migraine or other pain disorders, whereas specific medications are effective in migraine (and certain other) headache attacks but are not useful for nonheadache pain disorders. Triptans are effective in the range of mild, moderate, and severe migraine attacks.¹⁰²

TABLE 56-3 Acute Medications: Efficacy, Adverse Events, Relative Contraindications, and Indications

	Comorbid Condition
Drug	Relative Contraindication	Relative Indication
Acetaminophen (Paracetamol)	Liver disease	Pregnancy
Aspirin	Kidney disease	CAD
	Ulcer disease	Transient ischemic attack
	PUD
	Gastritis (age <15)
NSAIDs	Kidney disease	Arthritis
	PUD
	Gastritis
Butalbital, caffeine, and analgesics	Use of other sedative	—
Butalbital, caffeine, and analgesics	History of medication overuse	—
Caffeine adjuvant	Sensitivity to caffeine	—
Isometheptene	Uncontrolled HTN, CAD, PVD	—
Opioids	Drug or substance abuse	Pregnancy
Opioids	Drug or substance abuse	Rescue medication
Neuroleptics	Parkinson’s disease	Nausea
	Prolonged QTc	Vomiting
		Pregnancy
		Rescue medication
Dihydroergotamine
Injections	CAD	Orthostatic hypotension
Intranasal instillation	PVD
Intranasal instillation	Uncontrolled HTN	Prominent nausea or vomiting
Ergotamine
Tablets	Prominent nausea or vomiting	—
Suppositories	CAD
	PVD
	Uncontrolled HTN
Triptans
Almotriptan (tablets)	CAD	—
	PVD
	Uncontrolled HTN
Eletriptan (tablets)	CAD	—
	PVD
	Uncontrolled HTN
Frovatriptan (tablets)	CAD	—
	PVD
	Uncontrolled HTN
Naratriptan (tablets)	CAD	—
	PVD
	Uncontrolled HTN
Rizatriptan (tablets)	CAD	—
	PVD
	Uncontrolled HTN
Zolmitriptan (tablets, intranasal)	CAD	Prominent nausea or vomiting
	PVD
	Uncontrolled HTN
Sumatriptan (subcutaneous injection, intranasal instillation, tablets)	CAD	—
	PVD
	Uncontrolled HTN

CAD, coronary artery disease; HTN, hypertension; NSAID, nonsteroidal anti-inflammatory drug; PUD, peptic ulcer disease; PVD, peripheral vascular disease; QTc, corrected QT interval.

Treatment choice depends on attack severity, frequency, associated symptoms, coexistent disorders, prior treatment response, and the medication’s efficacy, its potential for overuse, and adverse events. A nonoral route of administration and an antiemetic should be considered for severe nausea or vomiting.¹¹ Injections provide rapid relief. Headaches can be stratified by severity and disability (on the Migraine Disability Assessment Scale or Headache Impact Test). Analgesics are used for mild to moderate headaches.¹¹ Triptans and dihydroergotamine are first-line drugs for severe attacks and for less severe attacks that do not adequately respond to analgesics.¹¹ Patients with moderate or severe headaches with moderate or severe disability (according to the Migraine Disability Assessment Scale score) who were given a triptan did better than patients given aspirin and metoclopramide.¹⁰³

Early intervention prevents escalation and may increase efficacy.¹⁰⁴ Triptans can prevent the development of cutaneous allodynia, and cutaneous allodynia is predictive of triptans’ effectiveness.⁶⁶ Before the clinician decides that a drug is ineffective, at least two attacks should be treated. It may be necessary to change the dose, formulation, or route of administration or add an adjuvant. When the response is inadequate, the headache recurs, or adverse events are bothersome, a medication change may be needed. Limiting acute treatment to 2 to 3 days a week can prevent medication-overuse headache. When headaches are very frequent, early intervention may not be appropriate.

All treatment occasionally fails; therefore, rescue medications (opioids, neuroleptics, and corticosteroids) are needed. They provide relief but often limit function by causing sedation or other adverse events.

Nonspecific Medication

Analgesics and Nonsteroidal Anti-inflammatory Drugs

Aspirin; ibuprofen; tolfenamic acid; naproxen sodium; acetaminophen; and acetaminophen, aspirin, and caffeine (Excedrin) combination are effective in acute migraine treatment.^11,^105,¹⁰⁶

Barbiturate Hypnotics

No randomized, placebo-controlled studies have established the efficacy of butalbital-containing agents.¹⁰⁷ They are used in the United States but have been withdrawn from the market in many European countries. Because of the potential for medication-overuse headache and withdrawal, their use should be limited and carefully monitored.

Opioids

Opioids are effective.^2,¹¹ However, because of the risk of medication overuse, they should be limited (<2 days a week) to patients who have severe, relatively infrequent headaches.¹⁰⁸ They are used in the United States for patients who do not respond to simple analgesics (or cannot take ergots or a triptan) and as a rescue medication. They are often prescribed for pregnant women in the absence of controlled data.¹⁰⁹

Neuroleptics and Antiemetics

Prochlorperazine is relatively safe and effective for the treatment of migraine and associated nausea and vomiting.^7,^9,^11,^110,¹¹¹ Droperidol, a parenteral neuroleptic, was effective in one placebo-controlled, double-blind trial, at a dose of 2.75 mg intramuscularly. Sedation, akathisia, and other extrapyramidal reactions can be treated with diphenhydramine or benzotropine.¹¹²

Specific Medication

Ergots and triptans are potent 5-HT_1B, 5-HT_1D, and, in some cases, 5-HT_1F receptor agonists. Ergots have much greater receptor affinity at 5-HT_1A, 5-HT₂, adrenergic, and dopaminergic receptors than do triptans, and thus lead to more adverse events. All are indicated for acute migraine treatment. If the initial (appropriate) dose is not effective, it is unlikely that subsequent doses will be effective during the same attack, and rescue medications should be used. Contraindications include documented or suspected ischemic heart disease, Prinzmetal’s angina, uncontrolled hypertension, basilar or hemiplegic migraine, and pregnancy. Patients with sepsis, renal or hepatic failure, and cerebral or peripheral vascular disease should avoid ergots. There is little consensus as to how many risk factors preclude triptan use and what constitutes an appropriate evaluation.¹¹³

Selective 5-HT₁ Agonists (Triptans)

Sumatriptan was the first triptan to be introduced. It was followed by zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan, all of which are more centrally penetrant than is sumatriptan. Eletriptan’s central penetrance is limited, inasmuch as it is a substrate for the P-glycoprotein pump ¹¹⁴: P-glycoprotein pump inhibitors allow higher central penetrance. Data for all formulations of triptans are given in Table 56-4.^11,¹² All are effective, even if given after the onset of migraine, and may be more effective when pain is mild.¹¹⁵ They relieve head pain and nausea and vomiting. Efficacy is measured by 2-hour response rates and therapeutic gain (the difference between active drug and placebo; see Table 56-4). The drug is used to compensate for differences in placebo rates in different trials. Other measures include 2-hour pain-free rates and recurrence rates. Common adverse events include pain, tingling, flushing, and burning sensation at the subcutaneous injection site; warm or hot sensations; dizziness; paresthesias; somnolence; fatigue; sensation of heaviness; neck pain; and dysphoria.^116,¹¹⁷ In the text, mainly nonoral formulations are discussed.

TABLE 56-4 Triptans

Sumatriptan is available in 6-mg subcutaneous injection; 20-mg nasal spray; 25, 50, or 100-mg tablets; and 25-mg suppository.^12,¹¹⁸ Subcutaneous sumatriptan has a rapid onset of action, reaching peak plasma concentrations within 12 minutes. The time of maximal concentration (T_max) for oral sumatriptan is 2 hours. Bioavailability is 97% for subcutaneous injection, 19.2% for suppository, 15.8% for intranasal instillation, and 14.3% for tablet.¹¹⁶ The terminal elimination half-life is 2 hours. Sumatriptan is metabolized principally by the monoamine oxidase (MAO)-A; therefore, the oral, nasal, and suppository formulations are contraindicated in patients using MAO inhibitors.

Subcutaneous sumatriptan (6 mg) produces a 1-hour response rate of 69%, with a therapeutic gain in 50%.¹¹⁹ The 1-hour pain-free rate was 48% to 49%.¹²⁰ Intranasal sumatriptan (20 mg) produced a 2-hour response rate of 61%, with a therapeutic gain in 31%.^119,¹²¹ The 2-hour efficacy for the 25-mg sumatriptan suppository ranges from 64 to 72 (five studies).⁹ The pain-free rate ranged from 34% to 50%. In a comparative study, a combination (ergotamine, 2 mg, and caffeine, 100 mg) suppository was more effective than sumatriptan (73% versus 63%) but produced more adverse events.¹¹⁷ In Ferrari and associates’ metaanalysis of oral triptans, 100-mg sumatriptan was used as the standard.¹²

Zolmitriptan is available in 2.5- and 5-mg regular and orally disintegrating tablets and a 5-mg nasal spray. Zolmitriptan has a 40% oral bioavailability, has a T_max of about 2.5 hours, and is metabolized by the cytochrome P-450 system to an active metabolite that is degraded by MAO-A. Patients taking MAO inhibitors are limited to a total dose of 5 mg/day. The nasal spray is absorbed in the nasopharynx; detectable blood levels appear within 5 minutes, and 40% of maximal concentration is achieved within 10 to 15 minutes.^122,¹²³ First-attack 2-hour headache response rates for 5 mg nasal spray are 69%, with a therapeutic gain in 38%.¹²²^–¹²⁴

Naratriptan is available in 1- and 2.5-mg oral tablets. The recommended dose is 2.5 mg. Bioavailability is 60% to 70%, T_max is 2 hours (outside an attack), and the terminal elimination half-life is 5 hours. Naratriptan is excreted largely as unchanged drug in the urine.¹²⁵

Rizatriptan is available in 5- and 10-mg oral tablets and rapidly dissolving wafers. The recommended dose is 10 mg except for patients taking propranolol, which increases rizatriptan’s plasma concentration; for such patients, the recommended dose is 5 mg. The T_max is 1 hour, bioavailability is 40% to 45%, and the plasma half-life is 2 to 3 hours. Rizatriptan is metabolized principally by MAO-A, metabolites being excreted in the urine. It should not be used by patients taking MAO inhibitors.

Almotriptan is available in 6.25 and 12.5-mg oral tablets. The recommended dose is 12.5 mg, with a two-dose limit in a 24-hour period. Bioavailability is 70%, the T_max is 1 to 3 hours, and mean half-life 3-4 hours. It is partially metabolized in the liver (MAO, 27%; cytochrome P-450 [3A4 and 2D6], 12%) to inactive metabolites. Almotriptan has no significant interaction with propranolol, selective serotonin reuptake inhibitors, or MAO inhibitors.

Frovatriptan is available in 2.5-mg tablets. The daily limit is three tablets. Frovatriptan has a bioavailability of 22% in men and 30% in women. The T_max is 2 to 3 hours. It is metabolized by P4540 (CYP-1A2) and excreted in the urine.¹²⁶ The mean half-life is 26 hours.

Eletriptan is available in 40 and 80-mg oral tablets. It has a 50% bioavailability and a half-life of 5 hours and is rapidly absorbed.¹²⁷ Eletriptan interacts with drugs that are metabolized by cytochrome P-450 (including CYP-3A4). Adverse events are more common with 80-mg eletriptan than with other triptans.

These seven triptans are safe (for patients without cardiovascular risk factors), effective, and appropriate first-line therapy for patients who have a moderate to severe migraine headache or for whom analgesics have failed to provide adequate relief. Although they are safe, no evidence supports their effectiveness during the aura phase of a migraine attack.¹²⁸

Headache severity, rapidity of onset, and duration are important factors for deciding which triptan should be used. When the headache intensifies rapidly (<30 minutes), or when nausea and emesis are early and there are severe associated symptoms, nonoral administration is appropriate. Subcutaneous sumatriptan is the fastest and most effective. Sumatriptan or zolmitriptan nasal spray may provide a faster onset of action than do oral triptans, but sumatriptan nasal spray often has a disagreeable taste.

The oral formulations can be divided into two classes. Almotriptan, eletriptan, rizatriptan, sumatriptan, and zolmitriptan have the highest 2-hour efficacy, can provide headache relief within 30 to 60 minutes, and would be the first choice when patients require efficacy and speed of onset and do not have multiple recurrences. The metaanalysis suggests that almotriptan, eletriptan, and rizatriptan are most effective.¹²

Frovatriptan and naratriptan have lower 2-hour efficacy but produce fewer adverse events (as does almotriptan). Whether headache recurs less often with these drugs is controversial. Almotriptan, frovatriptan, and naratriptan are choices for patients who are prone to adverse events.¹²⁹

All triptans have the same contraindications and safety concerns. None is safer than another; however, the response to triptans is often idiosyncratic. One triptan may work for one patient and cause no adverse events, and a different triptan may work for another patient. The triptan of choice is the one that restores the patient’s ability to function by swiftly and consistently relieving pain and associated symptoms with minimal adverse events and without recurrence of symptoms.

Ergotamine and Dihydroergotamine

The evidence supporting ergotamine’s efficacy is inconsistent.¹³⁰ Some patients respond preferentially to rectal ergotamine.¹³¹ Dihydroergotamine can be administered intramuscularly, subcutaneously, or intravenously. The headache recurrence rate may be low (<20%), there are fewer adverse events, and it may be less likely than ergotamine to produce rebound headache.¹³⁰ Limited efficacy evidence exists for dihydroergotamine nasal spray. No placebo-controlled trials have demonstrated the efficacy and safety of dihydroergotamine subcutaneously, intramuscularly, or intravenously as monotherapy. Repetitive intravenous dihydroergotamine is commonly used in North America to treat intractable headache.^130,¹³²

Corticosteroids

Open-label studies have suggested that corticosteroids are effective. Hydrocortisone, methylprednisolone, and dexamethasone have been used.²

PREVENTIVE TREATMENT

Preventive therapy is given in an attempt to reduce the frequency, duration, or severity of attacks. Additional benefits include improving responsiveness to acute attack treatment, improving function, and reducing disability. Preventive treatment may prevent episodic migraine’s progression to chronic migraine and result in health care cost reductions. Silberstein and colleagues retrospectively analyzed resource utilization information in a large claims database. The addition of migraine preventive drug therapy to therapy that consisted of only an acute medication was effective in reducing resource consumption. During the second 6 months after the initial preventive medication, as compared with the 6 months preceding preventive therapy, office and other outpatient visits with a migraine diagnosis decreased by 51.1%, emergency department visits with a migraine diagnosis decreased 81.8%, computed tomographic scans with a migraine diagnosis decreased 75.0%, MRI scans with a migraine diagnosis decreased 88.2%, and other migraine medication dispensations decreased 14.1%.¹³³

Preventive medications reduce attack frequency, duration, or severity.^2,¹³⁴ According to the U.S. Headache Consortium Guidelines,¹⁰ indications for preventive treatment include the following:

Migraine that significantly interferes with the patient’s daily routine despite acute treatment

Failure of, contraindication to, or troublesome adverse events from acute medications

Acute medication overuse

Very frequent headaches (>2/week) (risk of medication overuse)

Patient preference

Special circumstances, such as hemiplegic migraine or attacks with a risk of permanent neurological injury

Preventive measures are not used to nearly the extent they should be. In the American Migraine Study II, 25% of all people with migraine, or more than 7 million people, experienced more than three attacks per month, and 53% of those surveyed reported either having severe impairment because of their attacks or needing bed rest.¹⁷ However, only 5% of all migraineurs currently use preventive therapy to control their attacks.¹³⁵

Preventive medication groups include β-adrenergic blockers, antidepressants, calcium channel antagonists, serotonin antagonists, anticonvulsants, and NSAIDs. Choice is based on efficacy, adverse events, and coexistent and comorbid conditions (Table 56-5). It is started at a low dose and increased slowly until therapeutic effects develop or the ceiling dose is reached. A full therapeutic trial may take 2 to 6 months. Acute headache medications should not be overused. If headaches are well controlled, medication can be tapered and discontinued. Dose reduction may provide a better risk/benefit ratio. Women of childbearing potential should practice adequate contraception.

TABLE 56-5 Choices of Preventive Treatment in Migraine: Influence of Comorbid Conditions

	Comorbid Condition
Drug	Relative Contraindication	Relative Indication
β Blockers	Asthma, depression	HTN
	CHF	Angina
	Raynaud’s disease
	Diabetes
Antiserotonin Agents
Pizotifen	Obesity	Orthostatic HTN
Methysergide	Angina
Methysergide	PVD
Calcium-Channel Blockers
Verapamil	Constipation	Migraine with aura
	Hypotension	HTN
		Angina
		Asthma
Flunarizine	Parkinson’s disease	Hypertension
Flunarizine	Parkinson’s disease	FHM
Antidepressants
TCAs	Mania	Other pain disorders
	Urinary retention	Depression
	Heart block	Anxiety disorders
	Heart block	Insomnia
SSRIs	Mania	Depression
SSRIs	Mania	OCD
MAOIs	Unreliability of patient	Refractory depression
Anticonvulsants
Divalproex/valproate	Liver disease	Mania
	Bleeding disorders	Epilepsy
	Bleeding disorders	Anxiety disorders
Gabapentin	Liver disease	Mania
	Bleeding disorders	Epilepsy
	Bleeding disorders	Anxiety disorders
Topiramate	Kidney stones	Mania
		Epilepsy
		Anxiety disorders
NSAIDs
Naproxen	Ulcer disease	Arthritis
Naproxen	Gastritis	Other pain disorders

CHF, congestive heart failure; FHM, familial hemiplegic migraine; HTN, hypertension; MAOI, monoamine oxidase inhibitor; NSAID, nonsteroidal anti-inflammatory drug; OCD, obsessive-compulsive disorder; PVD, peripheral vascular disease; SSRI, serotonin-specific reuptake inhibitor; TCA, tricyclic antidepressant.

Behavioral and psychological interventions used for prevention include relaxation training, thermal biofeedback combined with relaxation training, electromyographic biofeedback, and cognitive-behavioral therapy.¹³⁶

Mechanism of Action of Preventive Medications

Most migraine-preventive drugs were designed to treat other disorders. Serotonin antagonists were developed on the basis of the concept that migraine is caused by excess 5-HT. Antidepressants downregulate 5-HT₂ and β-adrenergic receptors. Anticonvulsant medications decrease glutamate and enhance GABA_A. Potential mechanisms of migraine-preventive medications include raising the threshold to migraine activation by stabilizing a more reactive nervous system; enhancing antinociception; inhibiting CSD; inhibiting peripheral and central sensitization; blocking neurogenic inflammation; and modulating sympathetic, parasympathetic or serotonergic tone. Oshinsky showed that descending control from the upper brainstem, through serotonergic and noradrenergic systems, modulates the trigeminal nucleus caudalis and prevents central sensitization (personal communication). Moskowitz has recently shown that preventive medications given chronically, but not acutely, block CSD.¹³⁷

Medication

β Blockers

β-Adrenergic blockers (also called β blockers), the most widely used class of drugs in prophylactic migraine treatment, are approximately 50% effective in producing a greater than 50% reduction in attack frequency. Rabkin and coworkers ¹³⁸ serendipitously discovered propranolol’s effectiveness in headache treatment in patients who were being treated for angina.¹³⁹ Propranolol, nadolol, atenolol, metoprolol, and timolol are effective.⁸ Their relative efficacy has not been established; choice is based on β-adrenergic selectivity, convenience, adverse events, and patients’ reactions.² β Blockers can produce behavioral adverse events, such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depression, memory disturbance, and hallucinations; they should be avoided by patients who are depressed. Decreased exercise tolerance limits their use by athletes. Less common adverse events include impotence, orthostatic hypotension, and bradycardia. β Blockers are useful for patients with angina or hypertension. They are relatively contraindicated in patients with congestive heart failure, asthma, Raynaud’s disease, and insulin-dependent diabetes.

Antidepressants

Antidepressants consist of a number of different classes of drugs with different mechanisms of action. The tricyclic antidepressants (TCAs) most commonly used for headache prophylaxis include amitriptyline, nortriptyline, doxepin, and protriptyline. Imipramine and desipramine have been used at times. With the exception of amitriptyline, the TCAs have not been vigorously evaluated; their use is based on anecdotal or uncontrolled reports. None have been approved for migraine. Antidepressants are especially useful for patients with comorbid depression and anxiety disorders.

Amitriptyline (a TCA) is the only antidepressant whose efficacy has limited support.⁸ Adverse events include increased appetite, weight gain, dry mouth, and sedation; cardiac toxicity and orthostatic hypotension occasionally occur.¹⁴⁰ There has been one trial with positive results for fluoxetine. Sexual dysfunction is a common adverse event.¹⁴¹

Amitriptyline is a tertiary amine TCA that is sedating and has antimuscarinic activity. Patients with coexistent depression are more tolerant and require higher doses of amitriptyline. It should be started at a dosage of 10 to 25 mg at bedtime. The dosage ranges from 10 to 400 mg/day.

Doxepin is a sedating tertiary amine TCA. It should be started at a dosage of 10 mg at bedtime. The dose ranges from 10 to 300 mg a day.

Nortriptyline is a secondary amine that is less sedating than amitriptyline. Nortriptyline is a major metabolite of amitriptyline. If insomnia develops, the drug should be taken earlier in the day or in divided doses. It should be started at a dosage of 10 to 25 mg at bedtime. The dosage ranges from 10 to 150 mg a day.

Protriptyline is a secondary amine similar to nortriptyline. It should be started at a dose of 5 mg/day. The dose ranges from 5 to 60 mg a day.

Calcium-Channel Blockers

The Agency for Healthcare Policy and Research analyzed 45 controlled trials.⁸ Flunarizine was effective, nimodipine produced mixed results, and the results of nifedipine were difficult to interpret. Verapamil was more effective than placebo in two of three trials, but both positive trials had high dropout rates, rendering the findings uncertain.² Its most common adverse event is constipation. Flunarizine is the most effective drug of this class. It also has dopamine-blocking properties.

Verapamil is available as a 40, 80, or 120-mg tablet or as a 120, 180, or 240-mg sustained-release preparation. It should be started at a dosage of 80 mg two to three times a day, with a maximum of 640 mg/day in divided doses. The most common adverse event is constipation; dizziness, nausea, hypotension, headache, and edema are less common. Bioavailability is 20%. The absorbed drug is tightly protein bound. Peak plasma levels occur in 5 hours; the half-life ranges from 2.5 to 7.5 hours.

Flunarizine is not available everywhere. The dose is 5 to 10 mg/day. Adverse events include parkinsonism, depression, weight gain, somnolence, dry mouth, dizziness, and hypotension. The elimination half-life of flunarizine is 19 days.

Anticonvulsant Medications

Anticonvulsant medication is increasingly recommended for migraine prevention because of placebo-controlled, double-blind trials that have proved it to be effective. With the exception of valproic acid, topiramate, and zonisamide, anticonvulsants may interfere substantially with the efficacy of oral contraceptives.^142,¹⁴³ Nine controlled trials of five different anticonvulsants were included in the Agency for Healthcare Policy and Research Technical Report.^145–151,^153,¹⁵⁴

Valproic acid is a simple eight-carbon, two-chain fatty acid with 80% bioavailability after oral administration. It is highly protein bound, with an elimination half-life of between 8 and 17 hours. Valproic acid possesses anticonvulsant activity in a wide variety of experimental epilepsy models. Valproate at high concentrations increases GABA levels in synaptosomes, perhaps by inhibiting its degradation; it enhances the postsynaptic response to GABA, and, at lower concentrations, it increases potassium conductance, producing neuronal hyperpolarization. Valproate turns off the firing of the 5-HT neurons of the dorsal raphe, which are implicated in controlling head pain.

Divalproex sodium (500 to 1000 mg) and sodium valproate are effective, as is the extended-release formulation.⁸ Five studies provided strong and consistent support for the efficacy of divalproex sodium (approved by the U.S. Food and Drug Administration)^146,¹⁴⁷ and sodium valproate.^150,¹⁵¹ Nausea, vomiting, and gastrointestinal distress are the most common adverse events of valproate therapy. These are generally self-limited and are slightly less common with divalproex sodium than with sodium valproate. On rare occasions, valproate administration is associated with severe adverse events, such as hepatitis or pancreatitis. The frequency varies with the number of concomitant medications used, the patient’s age and general state of health, and the presence of genetic and metabolic disorders. Valproate is teratogenic and should not be used by pregnant women or women considering pregnancy.¹⁵² In clinical trials, the most frequent adverse events were nausea (42%), alopecia (31%), tremor (28%), asthenia (25%), dyspepsia (25%), somnolence (25%), and weight gain (19%).¹⁵³ Baseline liver function studies should be obtained, but follow-up studies are probably not needed for adults receiving monotherapy.¹⁵²

Valproic acid is available as 250-mg capsules and as a syrup (250 mg/5 mL). Divalproex sodium is a stable coordination complex composed of sodium valproate and valproic acid in a 1:1 molar ratio. An enteric-coated form of divalproex sodium is available as 125, 250, and 500-mg capsules and a sprinkle formulation. It should be started at a dosage of 250 to 500 mg/day in divided doses, and then the dosage should be slowly increased. Serum levels should be monitored if there is a question of toxicity or compliance. (The usual therapeutic level is from 50 to 100 mg/mL.) The maximum recommended dosage is 60 mg/kg/day. An extended-release form of divalproex sodium demonstrated efficacy comparable with that of the tablet formulation. The adverse event profile in the clinical trial, however, showed almost identical adverse event rates for placebo and active treatment.¹⁵⁴

Gabapentin (1800 to 2400 mg) showed efficacy in a placebo-controlled, double-blind trial only in a modified intent-to-treat analysis. Migraine attack frequency was reduced by 50% in about one third of patients.¹⁵⁵ The most common adverse events were dizziness or giddiness and drowsiness.

Topiramate was originally synthesized as part of a research project to discover structural analogs of fructose-1,6-diphosphate capable of inhibiting the enzyme fructose-1,6- bisphosphatase, thereby blocking gluconeogenesis, but it has no hypoglycemic activity. Topiramate is a derivative of the naturally occurring monosaccharide D-fructose and contains a sulfamate functionality. Topiramate was originally marketed for the treatment of epilepsy ¹⁵⁶; it is now approved by the U.S. Food and Drug Administration for treatment of migraine.

It is associated with weight loss, not weight gain. In two large, double-blind, placebo-controlled, multicenter trials, topiramate, both 100 and 200 mg, was effective in reducing migraine attack frequency by 50% in half of the patients.^157,¹⁵⁸ Withdrawals from the study because of adverse events were common among the topiramate recipients but did not affect statistical significance. The most common adverse event was paresthesia, which was rated as mild to moderate in the majority of patients and limited treatment in only 8% of these subjects. The other most common adverse events were fatigue, decreased appetite, nausea, diarrhea, weight decrease, taste perversion, hypoesthesia and abdominal pain. The most common CNS adverse events were somnolence, insomnia, difficulty with memory, language problems, difficulty with concentration, mood problems, and anxiety. Renal calculi occur with a reported incidence of about 1.5%. A rare syndrome consisting of acute myopia in association with secondary angle-closure glaucoma has been reported.

Topiramate therapy should be started at a dosage of 15 to 25 mg at bedtime and increased by 15 to 25 mg/week. The dosage should not be increased if bothersome adverse events develop; the increase should be delayed until they resolve (they usually do). If they do not resolve, the dosage should be decreased to the last tolerable amount and then increased by a lower increment more slowly. The goal is a dose of 50 to 100 mg/day given twice a day. It is the author’s experience that patients who tolerate the lower dosages with only partial improvement often experience increased benefit with higher doses. The dosage can be increased to 600 mg/day or higher.

Divalproex and topiramate are useful for patients with epilepsy, anxiety disorder, or manic-depressive illness. These drugs can be used by patients with depression, Raynaud’s disease, asthma, and diabetes, circumventing the contraindications to β blockers.

Serotonin Antagonists

The antiserotonin migraine-preventive drugs are potent 5-HT_2B and 5-HT_2C receptor antagonists. Methysergide is a semisynthetic ergot alkaloid that is structurally related to methylergonovine. It is a 5-HT₂ receptor antagonist and 5-HT_1B/5-HT_D agonist. It was probably the first drug developed for migraine prevention,¹⁵⁹ but its usefulness is limited by reports of retroperitoneal and retropleural fibrosis associated with long-term, mostly uninterrupted, administration.¹⁶⁰

Methysergide is effective.^8,¹⁶¹ Adverse events include transient muscle aching, claudication, abdominal distress, nausea, weight gain, and hallucinations. The major complication is rare (1 per 2500) retroperitoneal, pulmonary, or endocardial fibrosis.¹⁶¹ To prevent this, a 4-week medication-free interval is recommended after 6 months of continuous treatment.^2,¹⁶¹

Methysergide is indicated for the treatment of migraine and cluster headache. The dosage ranges from 2 to 8 mg/day, the higher doses being given two or three times a day. Clinicians find that some patients can take higher doses, up to 14 mg a day, without adverse events and with higher efficacy.¹⁶² To minimize early adverse events, patients can start with a dose of 1 mg/day and increase the dose gradually by 1 mg every 2 to 3 days. Methysergide, in general, should not be taken continuously for long periods, because this may produce retroperitoneal fibrosis.^160,^163,¹⁶⁴ Instead, the drug should be given for 6 months, stopped for 1 month, and then restarted. To avoid an increase in headache when methysergide is stopped, the patient should be weaned off the drug over a 1-week period. Some authorities use methysergide on a continuous basis with careful monitoring,¹⁶² which includes auscultation of the heart and yearly echocardiography, chest radiography, and abdominal MRI. The drug should be discontinued immediately on suspicion of pulmonary or cardiac retroperitoneal fibrosis.¹⁶²

Cyproheptadine, an antagonist at the 5-HT₂, histamine H₁, and muscarinic cholinergic receptors, is widely used in the prophylactic treatment of migraine in children.^162,^165,¹⁶⁶ Cyproheptadine is available as 4-mg tablets. The total dosage ranges from 12 to 36 mg/day (given two to three times a day or at bedtime). Common adverse events are sedation and weight gain; dry mouth, nausea, lightheadedness, ankle edema, aching legs, and diarrhea are less common. Cyproheptadine may inhibit growth in children¹⁶⁷ and reverse the effects of selective serotonin reuptake inhibitors.

Pizotifen, a benzocycloheptathiophene derivative, is a 5-HT₂ receptor antagonist structurally similar to cyproheptadine.¹⁰ It is not available everywhere. According to the United States Headache Consortium guidelines,¹¹⁸ evidence was inconsistent for its efficacy. Analysis of the placebo-controlled trials suggested a large clinical effect that was statistically significant. Pizotifen was generally poorly tolerated.⁸ Substantial weight gain, tiredness, drowsiness, or a combination of these was frequently reported. Pizotifen was associated with a high rate of withdrawals from the study because of adverse events. Controlled and uncontrolled studies in Europe¹⁶⁸ have shown this drug to be of benefit in 40% to 79% of patients. The dosage recommendation is 0.5 to 1 mg, one three times daily by titration. Adverse events include drowsiness, increased appetite, and weight gain.¹⁶⁹

Natural Products

Feverfew (Tanacetum parthenium) is a medicinal herb whose effectiveness has not been totally established.¹⁷⁰ Riboflavin (400 mg) was effective in one placebo-controlled, double-blind trial; more than half the patients responded.¹⁷¹ A standardized extract (75 mg bid) of Petasites hybridus root (butterbur), a perennial shrub,¹⁶ was effective in a double-blind, placebo-controlled study.¹⁷² The most common adverse event was belching. Coenzyme Q10 was effective in one double-blind, placebo-controlled trial.¹⁷³

Newer Treatments

Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

Schrader and associates ¹⁷⁴ conducted a double-blind, placebo-controlled, crossover study of lisinopril, an angiotensin-converting enzyme inhibitor. The treatment period was 12 weeks, with one 10-mg lisinopril tablet taken once daily for 1 week and then two 10-mg lisinopril tablets taken once daily for 11 weeks, followed by a 2-week washout period. Hours with headache, days with headache, days with migraine, and headache severity index were significantly reduced by 20% (95% confidence interval, 5% to 36%), 17% (5% to 30%), 21% (9% to 34%), and 20% (3% to 37%), respectively, with lisinopril, in comparison with placebo. Tronvik and colleagues¹⁷⁵ performed a randomized, double-blind, placebo-controlled crossover study of candesartan (16-mg), an angiotensin II receptor blocker. The number of candesartan responders (reduction of 50% or more in comparison with placebo) was 18 (31.6%) of 57 for days with headache and 23 (40.4%) of 57 for days with migraine. Adverse events were similar in the two periods. In this study, candesartan was effective, with a tolerability profile comparable with that of placebo.

Botulinum toxin type A (Botox) in dosages of 0, 25, or 75 U showed promising results in one placebo-controlled, double-blind trial. It was injected into glabellar, frontalis, and temporalis muscles. The 25-U treatment was significantly better than placebo in reducing mean frequency of moderate to severe migraines during days 31 to 60, 50% reduction of incidence of all migraine at days 61 to 90, and reduction in all migraine at days 61 to 90.¹⁷⁶

Setting Treatment Priorities

The goals of preventive treatment are to reduce the frequency, duration, or severity of attacks, improve responsiveness to acute attack treatment, improve function, and reduce disability. Preventive treatment may also prevent episodic migraine’s progression to chronic migraine and result in health care cost reductions. The preventive medications with the best documented efficacy are the β blockers, divalproex, and topiramate. The choice of drug is based on a drug’s proven efficacy, the physician’s informed belief about medications not yet evaluated in controlled trials, the drug’s adverse events, the patient’s preferences and headache profile, and the presence or absence of coexisting disorders.² The drug chosen should be the one that has the best risk/benefit ratio for the individual patient and takes advantage of the drug’s side effect profile.^177,¹⁷⁸

Comorbid and coexistent diseases have important implications for treatment. The presence of a second illness provides therapeutic opportunities but also imposes certain therapeutic limitations. An underweight patient would be a candidate for one of the medications that commonly produce weight gain, such as a TCA; in contrast, these drugs should be avoided by an overweight patient and the use of topiramate considered instead. Tertiary TCAs that have a sedating effect would be useful at bedtime for patients with insomnia. Older patients with cardiac disease or patients with significant hypotension may not be able to use TCAs or calcium channel or β blockers, but they could use divalproex or topiramate. In the athletic patient, β blockers should be used with caution. Medication that can impair cognitive functioning should be avoided when patients are dependent on their wits.^177,¹⁷⁸

In some instances, two or more conditions may be treated with a single drug. When migraine occurs with hypertension and/or angina, β blockers or calcium channel blockers may be effective for all conditions.¹⁷⁹ For the patient with migraine and depression, TCAs or selective serotonin reuptake inhibitors may be especially useful.¹⁸⁰ For the patient with migraine and epilepsy¹⁸¹ or migraine and bipolar illness,^152,¹⁸² divalproex and topiramate are the drugs of choice. The pregnant migraineur who has a comorbid condition that necessitates treatment should be given a medication that is effective for both conditions and has the lowest potential for adverse events on the fetus. When individuals have more than one disease, certain categories of treatment may be relatively contraindicated. For example, β blockers should be used with caution in depressed migraineurs, whereas TCAs, neuroleptics, or sumatriptan may lower the seizure threshold and should be used with caution in the epileptic migraineur.

Although monotherapy is preferred, it is sometimes necessary to combine preventive medications. Antidepressants are often used with β blockers or calciums-channel blockers, and topiramate or divalproex sodium may be used in combination with any of these medications. Pascual and colleagues ¹⁸³ found that combining a β blocker and sodium valproate could lead to an increased benefit for patients with migraine that had previously been resistant to either drug alone. Fifty-two patients (43 women) with a history of episodic migraine with or without aura and previously unresponsive to β blockers or sodium valproate monotherapy were treated with a combination of propranolol (or nadolol) and sodium valproate in an open-label manner. Fifty-six percent had a greater than 50% reduction in days with migraine. This open-label trial supports the practice of combination therapy. Controlled trials are needed to determine the true advantage of this combination treatment in episodic and chronic migraine.