Background

Migraine headache is a complex, recurrent headache disorder that is one of the most common complaints in medicine. In the United States, more than 30 million people have 1 or more migraine headaches per year. Approximately 75% of all persons who experience migraines are women (see Epidemiology). The term migraine is derived from the Greek word hemikrania. This term was corrupted into low Latin as hemigranea, which eventually was accepted by the French translation as migraine. Migraine was previously considered a vascular phenomenon that resulted from intracranial vasoconstriction followed by rebound vasodilation. Currently, however, the neurovascular theory describes migraine as primarily a neurogenic process with secondary changes in cerebral perfusion (see Pathophysiology). Approximately 70% of patients have a first-degree relative with a history of migraine. In addition, a variety of environmental and behavioral factors may precipitate migraine attacks in persons with a predisposition to migraine (see Etiology). The classic migraine episode is characterized by unilateral head pain preceded by various visual, sensory, motor symptoms, collectively known as an aura. Most commonly, the aura consists of visual manifestations such as scotomas, photophobia, or visual scintillations (eg, bright zigzag lines) (see Clinical Presentation). In practice, however, migraine headaches may be unilateral or bilateral and may occur with or without an aura. In the current International Headache Society (IHS) categorization, the headache previously described as classic migraine is now known as migraine with aura, and that described as common migraine is now termed migraine without aura. Migraines without aura are the most common, accounting for more than 80% of all migraines. The diagnosis of migraine is clinical in nature, based on criteria established by the International Headache Society. A full neurologic examination should be performed during the first visit; the findings are usually normal. Neuroimaging is not necessary in a typical case (see Workup). Migraine treatment involves acute (abortive) and preventive (prophylactic) therapy. Patients with frequent attacks usually require both. Measures directed toward reducing migraine triggers are also generally advisable. Acute treatment aims to stop or prevent the progression of a headache or reverse a headache that has started. Preventive treatment, which is given even in the absence of a headache, aims to reduce the frequency and severity of the migraine attack, make acute attacks more responsive to abortive therapy, and perhaps also improve the patient's quality of life (see Treatment and Management). See Migraine in Children for a pediatric perspective on migraine. Also see Migraine Variants.

Migraine classification
The second edition of the International Classification of Headache Disorders[1] lists the following types of migraine:

Migraine without aura (formerly common migraine) Probable migraine without aura Migraine with aura (formerly classic migraine) Probable migraine with aura Chronic migraine Chronic migraine associated with analgesic overuse Childhood periodic syndromes that may not be precursors to or associated with migraine Complications of migraine Migrainous disorder not fulfilling above criteria Hemicrania continua

Migraine guidelines
In April 2000, the US Headache Consortium, a multispecialty group that includes the American College of Emergency Physicians, released evidence-based guidelines for the diagnosis, treatment, and prevention of migraine headaches. Guidelines are also available from the American Academy of Neurology, the National Headache Foundation, and the Canadian Association of Emergency Physicians.[2, 3, 4]

Pathophysiology
The mechanisms of migraine remain incompletely understood. However, new technologies have allowed formulation of current concepts that may explain parts of the migraine syndrome.

Vascular theory
In the 1940s and 1950s, the vascular theory was proposed to explain the pathophysiology of migraine headache. Wolff et al believed that ischemia induced by intracranial vasoconstriction is responsible for the aura of migraine and that the subsequent rebound vasodilation and activation of perivascular nociceptive nerves resulted in headache. This theory was based on the following 3 observations:

Extracranial vessels become distended and pulsatile during a migraine attack Stimulation of intracranial vessels in an awake person induces headache Vasoconstrictors (eg, ergots) improve the headache, whereas vasodilators (eg, nitroglycerin) provoke an attack

However, this theory did not explain the prodrome and associated features, the efficacy of some drugs used to treat migraines that have no effect on blood vessels, and the fact that most patients do not have an aura. Moreover, with the advent of newer imaging technologies, researchers found that intracranial blood flow patterns were inconsistent with the vascular theory. Intracarotid and single-photon emission computed tomography (SPECT) studies revealed that the headache is dissociated from hyperperfusion at its onset and termination in patients suffering from migraine headache with aura. SPECT studies also revealed that regional cerebral blood flow (rCBF) decreases in the posterior area of the relevant cerebral hemisphere even before the aura is noted and that headache occurred while rCBF remained decreased; rCBF gradually increased throughout the remainder of the headache phase. No consistent flow changes have been identified in patients suffering from migraine headache without aura, but rCBF remains normal in the majority. However, bilateral decrease in rCBF beginning at the occipital cortex and spreading anteriorly has been reported. More recently, Perciaccante has shown that migraine is characterized by a cardiac autonomic dysfunction.[5] As a result of these anomalous findings, the vascular theory was supplanted by the neurovascular theory.

Neurovascular theory
The neurovascular theory holds that a complex series of neural and vascular events initiates migraine.[6] According to this theory, migraine is primarily a neurogenic process with secondary changes in cerebral perfusion.[7] At baseline, a migraineur who is not having any headache has a state of neuronal hyperexcitability in the cerebral cortex, especially in the occipital cortex.[8] This finding has been demonstrated in studies of transcranial magnetic stimulation and with functional MRI. This observation explains the special susceptibility of the migrainous brain to headaches.[9] One can draw a parallel with the patient with epilepsy who similarly has interictal neuronal irritability.

Cortical spreading depression

In 1944, Leao proposed the theory of cortical spreading depression (CSD) to explain the mechanism of migraine with aura. CSD is a well-defined wave of neuronal excitation in the cortical gray matter that spreads from its site of origin at the rate of 2-6 mm/min. This cellular depolarization causes the primary cortical phenomenon or aura phase; in turn, it activates trigeminal fibers causing the headache phase. The neurochemical basis of the CSD is the release of potassium or the excitatory amino acid glutamate from neural tissue. This release

depolarizes the adjacent tissue, which, in turn, releases more neurotransmitters, propagating the spreading depression. Positron emission tomography (PET) scanning demonstrates that blood flow is moderately reduced during a migrainous aura, but the spreading oligemia does not correspond to vascular territories. The oligemia itself is insufficient to impair function. Instead, the flow is reduced because the spreading depression reduces metabolism. Although CSD is the disturbance that presumably results in the clinical manifestation of migraine aura, this spreading oligemia can be clinically silent (ie, migraine without aura). Perhaps a certain threshold is required to produce symptoms in patients having aura but not in those without aura. A study of the novel agent tonabersat, which inhibits CSD, found that the agent helped prevent migraine attacks with aura only, suggesting that CSD may but not be involved in attacks without aura.[10] Activation of the trigeminovascular system from CSD stimulates nociceptive neurons on dural blood vessels to release plasma proteins and pain-generating substances such as calcitonin generelated peptide, substance P, vasoactive intestinal peptide, and neurokinin A. The resultant state of sterile inflammation is accompanied by further vasodilation, producing pain. The initial cortical hyperperfusion in CSD is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibers, whereas delayed meningeal blood flow increase is mediated by a trigeminal-parasympathetic brainstem connection. According to Moulton et al, altered descending modulation in the brainstem has been postulated to contribute to the headache phase of migraine; this leads to loss of inhibition or enhanced facilitation, resulting in trigeminovascular neuron hyperexcitability.[11] In addition, through a variety of molecular mechanisms, cortical spreading depression upregulates genes, such as those encoding cyclo-oxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta, galanin, and metalloproteinases. The activation of metalloproteinases leads to leakage of the blood-brain barrier, allowing potassium, nitric oxide, adenosine, and other products released by cortical spreading depression to reach and sensitize the dural perivascular trigeminal afferent endings.[12] Increased net activity of matrix metalloproteinase2 (MMP-2) has been demonstrated in migraineurs. Patients who have migraine without aura seem to have an increased ratio of matrix metalloproteinase9 (MMP-9) to tissue inhibitors of metalloproteinase1 (TIMP-1), in contrast to a lower MMP-9/TIMP-1 ratio in migraine with aura patients.[13] MMP-9 when measured alone is the same for migraine patients with or without aura.[14] . In an experimental study, acute hypoxia was induced by a single episode of CSD. This was accompanied by dramatic failure of brain ion homeostasis and prolonged impairment of neurovascular and neurometabolic coupling.[15]

Vasoactive substances and neurotransmitters

Perivascular nerve activity also results in release of substances such as substance P (SP), neurokinin A (NKA), calcitonin gene-related peptide (CGRP), and nitric oxide (NO), which interact with the blood vessel wall to produce dilatation, protein extravasation, and sterile inflammation, stimulating the trigeminocervical complex as shown by induction of c-fos antigen by PET scan. Information then is relayed to the thalamus and cortex for registering of pain. Involvement of other centers may explain the associated autonomic symptoms and affective aspects of this pain. Is the neurologically mediated sterile plasma extravasation the cause of this pain? Neurogenic plasma extravasation is inhibited by 5-HT1 agonists, gamma aminobutyric acid (GABA) agonists, neurosteroids, prostaglandin inhibitors, SP antagonists, and the endothelin antagonist bosentan; the latter 2 are ineffective as antimigraine drugs, showing that blockade of neurogenic plasma extravasation is not completely predictive of antimigraine efficacy in humans. Neurogenically induced plasma extravasation may play a role in expression of pain in migraine, but whether this in itself is sufficient to cause pain is not clear; the presence of other stimulators may be required. Also, the pain process requires not only the activation of nociceptors of painproducing intracranial structures but also reduction in the normal functioning of endogenous pain control pathways that gate the pain.

Migraine center
What generates a migraine episode? A potential "migraine center" in the brain stem has been proposed, based on findings on PET of persistently elevated rCBF in the brain stem (ie, periaqueductal gray, midbrain reticular formation, locus ceruleus) even after sumatriptanproduced resolution of headache and related symptoms in 9 patients who had experienced spontaneous attack of migraine without aura. This increased rCBF was not observed outside of the attack, suggesting that this activation is not due to pain perception or increased activity of the endogenous antinociceptive system. The fact that sumatriptan reversed the concomitant increased rCBF in the cerebral cortex but not the brainstem centers suggests dysfunction in the regulation involved in antinociception and vascular control of these centers. Thalamic processing of pain is known to be gated by ascending serotonergic fibers from the dorsal raphe nucleus and from aminergic nuclei in the pontine tegmentum and locus ceruleus; the latter can alter brain flow and blood-brain barrier permeability. Because of the set periodicity of migraine, linkage to the suprachiasmatic nucleus of the hypothalamus that governs circadian rhythm has been proposed. Discovering the central trigger for migraine would help identify better prophylactic agents.

Brainstem activation
PET scanning in patients having an acute migraine headache demonstrates activation of the contralateral pons, even after medications abort the pain. Weiler et al proposed that brainstem activation may be the initiating factor of migraine.

Once the CSD occurs on the surface of the brain, H+ and K+ ions diffuse to the pia mater and activate C-fiber meningeal nociceptors, which releases a proinflammatory soup of neurochemicals (eg, calcitonin generelated peptide), and plasma extravasation occurs. Therefore, a sterile, neurogenic inflammation of the trigeminovascular complex is present. Once the trigeminal system is activated, it stimulates the cranial vessels to dilate. The final common pathway to the throbbing headache is the dilatation of blood vessels.

Cutaneous allodynia
Burstein et al described the phenomenon of cutaneous allodynia, in which secondary pain pathways of the trigeminothalamic system become sensitized during a migrainous episode.[16] This observation further demonstrates that sensitization of central pathways in the brain mediates the pain of migraine, in addition to the previously described neurovascular events.

Dopamine pathway
Some authors have proposed a dopaminergic basis for migraine.[17] In 1977, Sicuteri postulated that a state of dopaminergic hypersensitivity is present in patients with migraine. Interest in this theory has recently been renewed. Some of the symptoms associated with migraine headaches, such as nausea, vomiting, yawning, irritability, hypotension, and hyperactivity, can be attributed to relative dopaminergic stimulation. Dopamine receptor hypersensitivity has been shown experimentally with dopamine agonists (eg, apomorphine). Dopamine antagonists (eg, prochlorperazine) completely relieve almost 75% of acute migraine attacks.

Magnesium deficiency
Another theory proposes that deficiency of magnesium in the brain triggers a chain of events, starting with platelet aggregation and glutamate release and finally resulting in the release of 5hydroxytryptamine, which is a vasoconstrictor.

Endothelial dysfunction
Vascular smooth muscle cell dysfunction may involve impaired cyclic guanosine monophosphate and hemodynamic response to nitric oxide.[18] Nitric oxide released by microglia is a potentially cytotoxic proinflammatory mediator, initiating and maintaining brain inflammation through activation of the trigeminal neuron system, and nitric oxide continues to be increased even in the headache-free period in migraineurs.[19] In premenopausal women with migraine, particularly in those with migraine aura, increased endothelial activation, which is a component of endothelial dysfunction, is evident.[20]

Endothelial function is only one aspect of vascular reactivity, which, in turn, may be affected by many different factors: The most important measurable factors of vascular reactivity in conduit artery function are flow-mediated dilation (FMD), pulse wave velocity (PWV), and the following 4 measures of resistance or microvascular function:

Forearm reactive hyperemia Reactive hyperemia index by finger plethysmography (RHI) Skin reactive hyperemia Fingertip temperature rebound

These may all provide additional prognostic information in the assessment of cardiovascular risk in postmenopausal women.[21]

Serotonin and migraine

The serotonin receptor (5-hydroxytryptamine [5-HT]) is believed to be the most important receptor in the headache pathway. To facilitate understanding of the mechanisms of action of the various medications, the relationship between serotonin and migraine is reviewed here briefly, as some of these studies partly define the current understanding of migraine. Stimulation of the trigeminal nerve releases substance P (SP), calcitonin gene-related peptide (CGRP), and neurokinin A (NKA) from the sensory C-fibers. These substances produce neurogenic inflammation that then interacts with the blood vessel wall, producing dilatation, plasma extravasation, and sterile inflammation. Plasma extravasation is blocked by ergots, sumatriptan, the newer 5-HT1B/D agonists, indomethacin, acetylsalicylic acid, gamma aminobutyric acid (GABA) agonists such as valproic acid and benzodiazepines, neurosteroids, SP antagonists, and the endothelin antagonist bosentan. Immunohistochemical studies have detected 5-HT1D receptors in trigeminal sensory neurons, including peripheral projections to the dura and within the trigeminal nucleus caudalis (TNC) and solitary tract, while 5-HT1B receptors are present on smooth muscle cells in meningeal vessels; however, both can be found in both tissues to some extent and even in coronary vessels. These findings suggest that sumatriptan and other selective 5-HT1 agonists decrease headache by abolishing neuropeptide release in the periphery and blocking neurotransmission by acting on second-order neurons in the trigeminocervical complex. All the currently available triptans are selective 5-HT1B/D full agonists. The major differences among these agents lie in their pharmacokinetic properties, which may affect onset of action (eg, rizatriptan has a shorter time to maximum plasma concentration [tmax], leading to faster onset), duration of action (eg, naratriptan has a longer half-life, leading to lower recurrence rate), bioavailability (eg, naratriptan has higher oral bioavailability, leading to more consistent response), and CNS penetration (eg, sumatriptan not shown to cross the intact blood-brain barrier).

The GABA-A receptor is suggested to reside on the parasympathetic fibers emanating from the sphenopalatine ganglia, as the effects of valproic acid, benzodiazepines, and steroids are abolished when these projections are sectioned. The possible relationship of dopamine and migraine has been shown by a direct relationship between dopamine concentration and migraine symptomatology and the demonstrated efficacy of dopamine antagonists in the acute treatment of migraine.

Migraine risk factors

Predisposing vascular risk factors include the following:

Increased levels of C-reactive protein Interleukins Tumor necrosis factor (TNF)-alpha and adhesion molecules, which are markers of systemic inflammation Oxidative stress and thrombosis Increased body weight, high blood pressure, hypercholesterolemia Impaired insulin sensitivity High homocysteine levels, stroke, and coronary heart disease[22]

Progression to chronic migraine

In some patients, migraine progresses to chronic migraine. Acute overuse of symptomatic medication is considered one of the most important risk factors for migraine progression. Bigal and Lipton identified the following associations of medication with progression to chronic migraine[23] :

Opiates - Critical dose of exposure is around 8 days per month; the effect is more pronounced in men Barbiturates - Critical dose of exposure is around 5 days per month; the effect is more pronounced in women Triptans - Migraine progression is seen only in patients with high frequency of migraine at baseline (10-14 d/mo)

The effect of anti-inflammatory medications varied with headache frequency. These agents were protective in patients with fewer than 10 days of headache at baseline, but induced migraine progression in patients with a high frequency of headaches at baseline.

Etiology
Approximately 70% of patients have a first-degree relative with a history of migraine. The risk of migraine is increased 4-fold in relatives of people who have migraine with aura.[24] Although no genetic basis has been identified for common migraine, it generally demonstrates a maternal inheritance pattern.

Familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a type of migraine with aura that is preceded or followed by hemiplegia, which typically resolves. Three loci have been identified in FHM. FHM type 1, which occurs in approximately 50% of affected families, is linked to band 19p13 or a mutation in the calcium channel gene (CACNA1A4) at the 1q locus. FHM may be associated with cerebellar ataxia, which is also linked to the 19p locus. Evidence suggests that the 19p locus for FHM may also be involved in patients with nonhemiplegic migraine. FHM type 2 is due to mutation in the sodium channel gene ATP1A2 on chromosome 1.[25] FHM3 is a rare subtype of FHM and is caused by mutations in a sodium channel -subunit coding gene, SCNA1.[26]

Migraine in other inherited disorders

Migraine occurs with increased frequency in patients with mitochondrial disorders, such as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a genetic disorder of the notch 3 gene on chromosome 19 that causes migraine with aura. Migraine is also a common symptom in other genetic vasculopathies, including RVCL (retinal vasculopathy with cerebral leukodystrophy) and HIHRATL (hereditary infantile hemiparesis; retinal arteriolar tortuosity; and leukoencephalopathy). The mechanisms by which these genetic vasculopathies give rise to migraine is still unclear.[27]

Migraine precipitants
Various precipitants of migraine events have been identified, as follows:

Stress Excessive or insufficient sleep Medications (eg, vasodilators, oral contraceptives[28] ) Smoking Exposure to bright or fluorescent lighting Strong odors (eg, perfumes, colognes, petroleum distillates) Hormonal changes, such as menstruation (common),[29] pregnancy, and ovulation Head trauma Weather changes Metabolic or infectious diseases Physical exertion or fatigue Motion sickness Cold stimulus (eg, ice cream headaches)

Certain foods and food additives can precipitate migraine. These include alcohol, caffeine, chocolates, artificial sweeteners (eg, aspartame, saccharin), monosodium glutamate (MSG), citrus fruits, and meats with nitrites. Foods containing tyramine may provoke migraine. Such foods include the following:

Aged cheese Yogurt Sour cream Chicken livers Sausages Bananas Avocados Canned figs Raisins Peanuts Soy sauce Pickled fish Fresh-baked breads Pork Vinegars Beans

Migraine and other vascular disease

People who suffer from migraine headaches are more likely to also have cardiovascular or cerebrovascular disease (ie, stroke and heart attacks).[30] The physiopathology of the mechanism is still unknown. Reliable evidence comes from the Women's Health Study, which found that migraine with aura raised the risk of myocardial infarction by 91% and ischemic stroke by 108% and that migraine without aura raised both risks by approximately 25%.[31] Migraines during pregnancy are also linked to stroke and vascular diseases.[32] Migraine with aura for women in midlife has a statistical significant association with late-life vascular disease (infarcts) in the cerebellum. This association is not seen in migraine without aura.[33]

Other related factors

In a population-based magnetic resonance imaging study by Kruit et al, migraineurs had increased local iron deposits in the putamen, globus pallidus, and red nucleus, compared with controls.[34] This increase in iron deposits may be explained as a physiological response induced by repeated activation of nuclei involved in central pain processing or by the damage of these structures secondary to formation of free radicals in oxidative stress, possibly the cause of chronification of the disease.[35]

Epidemiology
In the United States, more than 30 million people have 1 or more migraine headaches per year. This roughly corresponds to approximately 18% of females and 6% of males.[36] Migraine accounts for 64% of severe headaches in females and 43% of severe headaches in males. Approximately 75% of all persons who experience migraines are women. Currently, 1 in 6 American women has migraine headaches. The incidence of migraine with aura peaks in boys at around age 5 years and in girls at around age 12-13 years. The incidence of migraine without aura peaks in boys at age 10-11 years and in girls at age 14-17 years.[37] Before puberty, both the prevalence and incidence of migraine are higher in boys than in girls. In individuals older than 12 years, the prevalence increases in both males and females, reaching a peak at age 30-40 years. The female-to-male ratio increases from 2.5:1 at puberty to 3.5:1 at age 40 years. Attacks usually decrease in severity and frequency in individuals older than 40 years, except for women in perimenopause. Onset of migraine after age 50 years is rare. A study by Hsu et al suggests that women in aged 40-50 years are also more susceptible to migrainous vertigo.[38] Onset of migraine after age 50 years is rare. The reported incidence of migraine in females of reproductive age has increased over the last 20 years. This increase probably reflects greater awareness of the condition. The prevalence of migraine appears to be lower among African Americans and Asian Americans than among whites. One study showed that among women, 20.4% of whites, 16.2% of African Americans, and only 9.2% of Asian Americans met International Classification of Headache Disorders (ICHD) criteria for migraine. Similarly, in males, 8.6% of whites, 7.2% of African Americans, and 4.8% of Asian Americans were considered to have migraine. A study by Wilper et al found that insurance status affects migraine care in the United States. After controlling for age, gender, race, and geographic location, patients with migraines with no insurance or with Medicaid were less likely than the privately insured to receive abortive therapy. Thus, uninsured and those with Medicaid receive substandard therapy for migraine because they receive more care in emergency departments and less in the outpatient settings.[39]

Economic impact of migraine

In the American Migraine Study, more than 85% of women and 82% of men with severe migraine had some headache-related disability. Migraineur males required 3.8 bed-rest days per year, whereas women required 5.6 bed-rest days per year. The loss of productive time from migraine in the US workforce is more than $13 billion per year, most of which is in the form of reduced productivity while at work.[40]

International statistics

The World Health Organization (WHO) estimates a worldwide prevalence of current migraine of 10% and a lifetime prevalence of 14%. The adjusted prevalence of migraine is highest in North America, followed by South and Central America, Europe, Asia and Africa. Approximately 3000 migraine attacks occur every day for each million of the general population worldwide. According to the WHO, migraine is 19th among all causes of years lived with disability. In the United States, migraine prevalence is inversely correlated with household income and level of education. However, this relationship between migraine and socioeconomic status is not present internationally.

Prognosis
Migraine is a chronic condition, but prolonged remissions are common. One study showed that 62% of young adults were migraine free for more than 2 years, but only 40% continued to be migraine free after 30 years. The severity and frequency of attacks tend to diminish with increasing age. After 15 years, approximately 30% of men and 40% of women no longer have migraine attacks.

Migraine and vascular disorders

Migraine and ischemic strokes reportedly occur in 1.4-3.3 per 100,000 population and account for 0.8% of total strokes. Milhaud et al showed that in young patients (< 45 y) with active migraine who had ischemic stroke, certain risk factors, such as patent foramen ovale, female gender, oral contraceptive use, and posterior circulation stroke, were much more likely to be present.[41] Even in patients older than 45 years, women with migraine were more likely to suffer from ischemic stroke. Migraineurs have a 2.5-fold increased risk of subclinical cerebellar stroke and those with migraines with aura and increased headache frequency are at the highest risk.[42] Migraineurs also have a higher incidence of adverse cardiovascular profile (including diabetes and hypertension), and they are more likely to be smokers, have a family history of early heart attacks, and have an unfavorable cholesterol profile. The odds of an elevated Framingham risk score of coronary artery disease are doubled with migraine with aura, and females with aura are more likely to be using oral contraceptives.[43, 44] The Women's Health Study, which included professional women older than 45 years showed that any history of migraine is associated with a higher incidence of major cardiovascular disease and that the highest risk is associated with migraine with aura, with a 2.3-fold risk of cardiovascular death and a 1.3-fold increased risk of coronary vascularization.[45] However, those with migraine without aura have the same risks as the general population.

These findings have been confirmed in a population-based study by Bigal et al.[46] According to Gudmundsson et al, both men and women who have migraine with aura are at a higher risk for cardiovascular and all-cause mortality than those without headache.[47]

Patient Education
Patient education is key to successful long-term management. Migraine is a chronic neurologic disorder that requires a lifestyle change at some level

History
Migraine attacks commonly occur when the person is awake, although it may have already started upon awakening. Less commonly, it may awaken the patient at night. The typical headache of migraine is throbbing or pulsatile. (However, more than 50% of people who suffer from migraines report nonthrobbing pain at some time during the attack.) The headache is initially unilateral and localized in the frontotemporal and ocular area, but pain can be felt anywhere around the head or neck. The pain typically builds up over a period of 1-2 hours, progressing posteriorly and becoming diffuse. The headache typically lasts from 4-72 hours. Among females, more than two thirds of patients report attacks lasting longer than 24 hours. Pain intensity is moderate to severe and intensifies with movement or physical activity. Many patients prefer to lie quietly in a dark room. The pain usually subsides gradually within a day and after a period of sleep; a majority of patients report feeling tired and weak afterwards.

Other symptoms
Nausea and vomiting usually occur later in the attack in about 80% and 50% of patients, respectively, along with anorexia and food intolerance. Some patients have been noted to be pale and clammy, especially if nausea develops. Photophobia and/or phonophobia also commonly are associated with the headache. Light-headedness is frequent. See Migraine-Associated Vertigo for more information on migraine-related vestibulopathy. Other neurological symptoms that may be observed include hemiparesis (this symptom defines hemiplegic migraine), aphasia, confusion, and paresthesias or true numbness.

Prodrome
About 60% of people who experience migraines report premonitory symptoms that occur hours to days before headache onset. Although the prodromal features vary, they tend to be consistent for a given individual and may include the following:

Heightened sensitivity to light, sound, and odors Lethargy or uncontrollable yawning Food cravings Mental and mood changes (eg, depression, anger, euphoria) Excessive thirst and polyuria Fluid retention Anorexia Constipation or diarrhea

These symptoms may be difficult to diagnose as part of the migraine complex if they occur in isolation from the headache or if they are mild. The prodrome of migraine has yet to receive significant investigational attention.

Aura
The migraine aura is a complex of neurologic symptoms that may precede or accompany the headache phase or may occur in isolation. It usually develops over 5-20 minutes and lasts less than 60 minutes. The aura can be visual, sensory, motor, or any combination of these. Auras most commonly consist of visual symptoms, which may be negative or positive. Negative symptoms include negative scotomata or negative visual phenomena, such as homonymous hemianopic or quadrantic field defects, central scotomas, tunnel vision, altitudinal visual defects, or even complete blindness (see the image below).

Migraine headache. Frank visual field loss can also occur associated with migraine. This example shows loss of the entire right visual field as described by a person who experiences migraines. The most common positive visual phenomenon is the scintillating scotoma. This consists of an arc or band of absent vision with a shimmering or glittering zigzag border. The disturbance begins in the paracentral area, and gradually enlarges and moves across the hemifield, eventually breaking up and resolving. It is often combined with photopsias or visual hallucinations, which may take various shapes (see the images below).

Migraine headache. Example of a visual migraine aura as described by a person who experiences migraines. This patient reported that these visual auras

preceded her headache by 20-30 minutes. Migraine headache. Example of a central scotoma as described by a person who experiences migraines. Note the visual loss in

the center of vision. Migraine headache. Example of a central scotoma as described by a person who experiences migraine headaches. Again note the visual

loss in the center of vision. Migraine headache. Example of visual changes during migraine. Multiple spotty scotomata are described by a person who experiences migraines. Scintillating scotoma is a highly characteristic syndrome that always occurs prior to the headache phase of an attack and is pathognomonic of a classic migraine. It is sometimes called a "fortification spectrum" because the serrated edges of the hallucinated "C" resemble a "fortified town with bastions around it."

Other positive visual phenomena include photopsia (uniform flashes of light) or simple forms of visual hallucinations. Heat waves, fractured vision, macropsia, micropsia, and achromatopsia may also occur. Paresthesias, occurring in 40% of cases, constitute the next most common aura; they are often cheiro-oral with numbness starting in the hand, migrating to the arm, and then jumping to involve the face, lips, and tongue. As with visual auras, positive symptoms typically are followed by negative symptoms; paresthesias may be followed by numbness. Sensory aura rarely occurs in isolation and usually follows visual aura. The rate of spread of sensory aura is helpful in distinguishing it from transient ischemic attack (TIA) or a sensory seizure. Just as a visual aura spreads across the visual field slowly, paresthesias may take 10-20 minutes to spread, which is slower than the spread of sensory symptoms of TIA. Motor symptoms may occur in 18% of patients and usually are associated with sensory symptoms. Motor symptoms often are described as a sense of heaviness of the limbs before a headache but without any true weakness. Speech and language disturbances have been reported in 17-20% of patients. These disturbances are commonly associated with upper extremity heaviness or weakness. The migrainous aura generally resolves within a few minutes and then is followed by a latent period before the onset of headache, although merging of the 2 also is reported. Whether migraine with and without aura (prevalences, 36% and 55%, respectively) represent 2 distinct processes remains debatable; however, the similarities of the prodrome, headache, and resolution phases of the attacks, as well as the similarity in therapeutic response and the fact that 9% of patients experience both, suggest that they are the same entity. When an aura is not followed by a headache, it is called a migraine equivalent or acephalic migraine. This is reported most commonly in patients older than 40 years who have a history of recurrent headache. Scintillating scotoma has been considered to be diagnostic of migraine even in the absence of a headache; however, paresthesias, weakness, and other transient neurologic symptoms are not. In the absence of a prior history of recurrent headache and first occurrence after age 45 years, TIA should be considered and must be investigated fully.

Postdromal symptoms
Postdromal symptoms may persist for 24 hours after the headache. They may include the following:

Feeling tired, washed out, or irritable Feeling unusually refreshed or euphoric Muscle weakness or myalgias

Anorexia or food cravings

Migraine triggers
A history of migraine triggers may be elicited. Common triggers include the following:

Certain foods (eg, chocolate, cheese, oranges, tomatoes, onions, monosodium glutamate [MSG], aspartame, red wine, alcohol) Hormonal changes (eg, menstruation, ovulation, oral contraceptives, hormone replacement) Head trauma Physical exertion Fatigue Medications (eg, nitroglycerin, histamine, reserpine, hydralazine, ranitidine, estrogen) Stress

Family history
Approximately 70% of patients have a first-degree relative with a history of migraine. The risk of migraine is increased 4-fold in relatives of people who have migraine with aura.[24] Although no genetic basis has been identified for common migraine, it generally demonstrates a maternal inheritance pattern.

Disability assessment
Simple questionnaires, such as the Migraine Disability Assessment Scale (MIDAS), can be used to quantify the extent of disability on the first visit. These questionnaires can also be used for follow-up evaluations.

Physical Examination
Although a thorough screening neurologic examination is essential, the results will be normal in most patients with headache. Evidence of autonomic nervous system involvement can be helpful, although most patients with migraine exhibit few or no findings. Serial neurologic examinations are recommended. Possible findings during a migraine include the following:

Cranial/cervical muscle tenderness Horner syndrome (ie, relative miosis with 1-2 mm of ptosis on the same side as the headache) Conjunctival injection Tachycardia/bradycardia Hypertension/hypotension

Hemisensory or hemiparetic neurological deficits (ie, complicated migraine) Adie type pupil (ie, poor light reactivity with light-near dissociation)

Pertinent physical examination findings that suggest a headache diagnosis other than migraine include the following:

Dim scotoma lasting a few seconds to several minutes (ie, amaurosis) Temporal artery tenderness in the elderly Meningismus Increased lethargy (unrelated to medication use) Mental status changes

Physical examination findings suggesting a more serious cause of headache include systemic symptoms (eg, myalgia, fever, malaise, weight loss, scalp tenderness, jaw claudication) and focal neurologic abnormalities or confusion, seizures, or any impairment of level of consciousness. On the other hand, focal neurologic findings that occur with the headache and persist temporarily after the pain resolves suggest a migraine variant, as follows:

Unilateral paralysis or weakness: hemiplegic migraine Aphasia, syncope, and balance problems: basilar migraines Third nerve palsy, with ocular muscle paralysis and ptosis, including or sparing the pupillary response: ophthalmoplegic migraine

Ophthalmic migraines cause a visual disturbance (usually lateral field deficit). This diagnosis is more common in children, with the abnormal motor findings lasting hours to days after the headache.

Diagnostic Criteria
The diagnosis of migraine is based on the history. Diagnostic criteria have been established by the International Headache Society (IHS). (See the image below.)

Overview of migraine treatment. Five steps.

Migraine Variants
Migraine variants include the following:

Childhood periodic syndromes Late-life migrainous accompaniments Vertebrobasilar migraine Hemiplegic migraine Status migrainosus

Ophthalmoplegic migraine Retinal migraine

See Migraine Variants for more information on these topics.

Childhood periodic syndromes

Childhood periodic syndromes evolve into migraine in adulthood. These syndromes include cyclic vomiting, abdominal migraine, and benign paroxysmal vertigo of childhood. In cyclic vomiting, the child has at least 5 attacks of intense nausea and vomiting ranging from 1 hour to 5 days. Abdominal migraine consists of episodic midline abdominal pain lasting 1-72 hours with at least 2 of 4 other symptoms (ie, nausea, vomiting, anorexia, and/or pallor). Benign paroxysmal vertigo of childhood involves recurrent attacks of vertigo, often associated with vomiting or nystagmus. See Migraine in Children for more information on these topics.

Late-life migrainous accompaniments

In elderly persons, a stereotypical series of prodromelike symptoms may entirely replace the migrainous episode; this is termed late-life migrainous accompaniments. If the headache is always on one side, a structural lesion needs to be excluded using imaging studies. Eliciting a history of recurrent typical attacks and determining the provoking agent are important because a secondary headache can mimic migraine. A new headache, even if it appears typical on the basis of its history, should always suggest a broad differential diagnosis and the possibility of a secondary headache.

Vertebrobasilar migraine
Patients with vertebrobasilar migraine can present without headaches but with vertebrobasilar symptoms such as vertigo, dizziness, confusion, dysarthria, tingling of extremities, and incoordination.

Hemiplegic migraine
Hemiplegic migraine is a very rare migraine variant in which headaches are associated with temporary unilateral hemiparesis or hemiplegia, at times accompanied by ipsilateral numbness or tingling, with or without a speech disturbance. The focal neurologic deficit may precede or accompany the headache, which is usually less dramatic than the motor deficit. Other migraine symptoms may variably be present. Patients may also experience disturbance of consciousness, and rarely coma

Ophthalmoplegic migraine

This variant has recently been reclassified by the IHS as a neuralgia. It is associated with transient palsies of the extraocular muscle with dilated pupils and eye pain. It is thought to be due to idiopathic inflammatory neuritis. In the acute phase, enhancement of the cisternal segment of the third cranial nerve occurs.

Retinal migraine
Occasionally, patients develop retinal and optic nerve ischemia and present with monocular blindness, papilledema, and retinal hemorrhages; this variant is called retinal migraine or ocular migraine.

Status migrainosus
This occurs when the migraine attack persists for more than 72 hours. Status migrainosus may result in complications such as dehydration.

Chronic migraine
Chronic migraine is defined as migraine headache that occurs for more than 15 days a month for greater than 3 months. Most of these patients have a history of migraine headaches since a young age. Associated symptoms of nausea, vomiting, photophobia, and phonophobia may be less frequent.

Comorbidities of Migraine
Migraine is associated with the following:

Epilepsy (eg, benign rolandic epilepsy, benign childhood epilepsy) Familial dyslipoproteinemias Hereditary hemorrhagic telangiectasia Tourette syndrome Hereditary essential tremor Hereditary cerebral amyloid angiopathy Ischemic stroke (migraine with aura is a risk factor, with an odds ratio of 6) Depression and anxiety Asthma Patent foramen ovale

Epilepsy increases the relative risk of migraine by 2.4. A Danish study found that migraine occurs in 20-30% of patients with several medical conditions, including kidney stone, psoriasis, rheumatoid arthritis, and fibromyalgia.[48] Migraine with aura had more comorbidities than migraine without aura.

Complications of Migraine

Complications of migraine include chronic migraine, migraine-triggered seizures, migrainous infarction (stroke with migraine), and persistent aura (eg, 30-60 minutes) without infarction. Ischemic stroke may occur as a rare but serious complication of migraine.[49] In migraines with aura, the risk for hemorrhagic stroke may be possible, but rare.[50] Risk factors for stroke include migraine with aura, female sex, cigarette smoking, and estrogen use.

Diagnostic Considerations
When headache is episodic and recurrent and follows a well-established pattern, the patient likely has a primary headache disorder (ie, headaches with no organic or structural etiology). Differentiating migraine from other primary headaches (eg, muscle contraction tension headache, cluster headache) is important, as optimal treatment may differ. Migraine may also may simulate or be simulated by secondary headache disorders or coexist with a secondary headache disorder. Any of the following features suggest a secondary headache disorder and warrant further investigation:

The first or worst headache of the patient's life, especially if rapid in onset A change in frequency, severity, or clinical features of the attack from what the patient usually experiences New progressive headache that persists for days Precipitation of headache with Valsalva maneuvers (ie, coughing, sneezing, bearing down) The presence of associated neurological signs or symptoms (eg, diplopia, loss of sensation, weakness, ataxia) Onset of headaches after the age of 55 years Headache developing after head injury or major trauma Persistent one-sided throbbing headaches Headaches that are associated with stiff neck or fever Atypical history or unusual character that does not fulfill the criteria for migraine Inadequate response to optimal therapy

Crash migraine Severe headache of sudden onset is a concern despite its occurrence in primary headache disorders. Migraine headaches may have an abrupt onset; these are termed "crash" migraine and are similar to a "thunderclap" headache. Cluster headache also may be sudden and excruciating, but it lasts only 15-180 minutes and is recognized easily if the patient has had previous attacks. Exertional headache Exertional headache builds in intensity over minutes and occurs with sustained physical exertion. Coital headache can develop at the height of orgasm or it may build up through intercourse. Intracranial aneurysm

Despite these possibilities, a ruptured intracranial aneurysm is the primary consideration if the headache is severe with sudden onset and reaches maximum intensity in minutes. The classical presentation of an aneurysmal subarachnoid hemorrhage (SAH) is a severe headache with sudden, explosive onset, stiff neck, photophobia, nausea and vomiting, and possibly alteration of consciousness. An extensive evaluation is indicated in such cases, including initial CT scan of the head without contrast. Lumbar puncture (LP) should be considered if CT scan is negative, as 25% of cases are missed by CT. Questions remain over whether an angiogram should be performed if the patient has normal findings on neurologic examination, cerebrospinal fluid (CSF) examination, and CT or MRI. In one study, acute severe thunderclap headache comparable to that of SAH without the nuchal rigidity occurred in 6.3% of patients with unruptured aneurysm. Other studies have revealed that in patients with severe thunderclap headache with normal CT and CSF findings, none developed SAH.[51] If the CT scan and LP are performed late after symptom onset, so that negative results are unreliable, and if clinical features such as family history or past medical history, classic SAHlike symptoms, or the presence of neurological signs (in particular a third cranial nerve palsy affecting the pupil) suggest that the patient is at risk, angiography should probably be performed if an experienced angiographer is available. In patients with unrevealing studies in whom the diagnosis of aneurysmal SAH is possible but very unlikely, MRI and magnetic resonance angiography (MRA) are screening tests, and close follow-up is appropriate if the findings of these tests are negative. Space-occupying lesion Another concern is the possibility of a space-occupying lesion mimicking migraine. In a series of 111 patients with primary (34%) or metastatic (66%) brain tumor, headache was reported in 48%; the headache had characteristics similar to migraine in 9% and to tension-type headache in 77%, while the so-called classic brain tumor headache occurred in only 17%. Headache was intermittent in 62%, usually lasting a few hours. All patients with headaches similar to migraine had other neurological symptoms or abnormal signs. Of note is that 32% had history of headache; in 36% of those, the headache was of identical character to prior headaches but was more severe or frequent and was associated with other symptoms such as seizures, confusion, prolonged nausea, and hemiparesis.[52] These data indicate that patients with a history of headache should have further diagnostic workup if the headache is accompanied by new symptoms or abnormal signs or differs in any way from their usual headache. With new-onset headache, imaging should be obtained if headache is severe or occurs with nausea, vomiting, or abnormal signs.

Other space-occupying lesions must be considered in the appropriate clinical setting. Large intraparenchymal hemorrhage presents dramatically with headache and neurological symptoms or signs shortly after onset. Of patients with chronic, subacute, or acute subdural hematoma, 81%, 53%, and 11%, respectively, have headaches. In brain abscesses, a progressive, severe, intractable headache is common, and headache is reported in 70-90% of patients. Cerebral venous thrombosis Cerebral venous thrombosis involves the sagittal sinus in about 70% of cases; these patients present with signs and symptoms of increased intracranial pressure (ICP), such as headache and papilledema. Should the thrombus extend to the superficial cortical veins, then focal findings may be noted. In the appropriate setting with known risk factors, cerebral venous thrombosis must be considered and evaluated with MRI, MRA, or magnetic resonance venography (MRV). Spontaneous internal carotid artery dissection Spontaneous internal carotid artery dissection is an uncommon cause of headache and acute neurological deficit, but it must be considered in the younger individuals who have unilateral, severe, persistent head pain of sudden onset preceding neurological signs, most commonly Horner syndrome, differentiating it from traumatic causes, in which cerebral ischemic symptoms are more common. Other secondary causes Other secondary causes of alarming headaches should be sought in the presence of the "red flags" mentioned above and must be sought in the appropriate clinical setting. Other features needing further diagnostic workup include positional headaches, which may occur in colloid cysts or other ventricular tumors such as ependymomas, Chiari malformations, and low CSF pressure headache. Headaches after age 50 years must be investigated to consider temporal or giant cell arteritis. Headaches associated with systemic disease require consideration of infectious and noninfectious inflammatory processes. Bear in mind that sumatriptan and related compounds, by virtue of being able to block expression of c-fos by their action on 5-HT1 receptors, decrease headaches with diverse pathogenesis. These agents may be effective in decreasing headache pain associated with meningovascular irritation, such as viral and bacterial infections and subarachnoid hemorrhage. Hence, response to 5-HT1 agonists is not diagnostic of a migraine headache.

Differentials

Cerebral Aneurysms Chronic Paroxysmal Hemicrania Cluster Headache Dissection Syndromes

Herpes Simplex Encephalitis Intracranial Hemorrhage Muscle Contraction Tension Headache Temporal/Giant Cell Arteritis Tolosa-Hunt Syndrome Viral Meningitis

Approach Considerations
Migraine is a clinical diagnosis. Diagnostic investigations are performed for the following reasons:

Exclude structural, metabolic, and other causes of headache that can mimic or coexist with migraine Rule out comorbid diseases that could complicate headache and its treatment Establish a baseline for treatment and exclude contraindications to drug administration Measure drug levels to determine compliance, absorption, or medication overdose

Laboratory Studies
The choice of laboratory and/or imaging studies is determined by the individual presentation. For example, in an older person with compatible findings (eg, scalp tenderness), measurement of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be appropriate to rule out temporal/giant cell arteritis.

Neuroimaging
Neuroimaging is not necessary in patients with a history of recurrent migraine headaches and a normal neurologic examination. Neuroimaging is indicated for any of the following[53] :

Onset of migraine after age 50 years Change in the pattern of previous migraine First or worst severe headache New onset of headache in a patient with cancer or HIV infection Headache with an abnormal neurologic examination Headache with fever Migraine and epilepsy New daily persistent headache Escalation of headache frequency/intensity in the absence of medication overuse headache Posteriorly located headaches in children

CT scan of the head is indicated to rule out intracranial mass or hemorrhage in selected or atypical cases. A negative CT scan may miss some small subarachnoid hemorrhages, tumors, and strokes, particularly those in the posterior fossa. A CT scan without intravenous contrast also

may miss some aneurysms. MRI and magnetic resonance angiography are more sensitive for detection of aneurysm or arteriovenous malformation.

Visual Field Testing

Visual field testing should be performed in patients with persistent visual phenomena.

Lumbar Puncture
Indications for LP include the following:

First or worst headache of a patient's life Severe, rapid-onset, recurrent headache Progressive headache Atypical chronic intractable headache

Neuroimaging (CT scan or MRI) should precede LP to rule out a mass lesion and/or increased intracranial pressure.

Approach Considerations
Migraine treatment involves acute (abortive) and preventive (prophylactic) therapy. Patients with frequent attacks usually require both. Measures directed toward reducing migraine triggers are also generally advisable. Acute treatment aims to stop or prevent the progression of a headache or reverse a headache that has started. Preventive treatment, which is given even in the absence of a headache, aims to reduce the frequency and severity of the migraine attack, make acute attacks more responsive to abortive therapy, and perhaps also improve the patient's quality of life. An overview of migraine treatment is shown in the image below.

Overview of migraine treatment. Five steps.

Emergency Department Considerations

Patients should be transported in a way that minimizes visual and auditory stimulation. Most patients should not receive opiate analgesics until a thorough neurologic examination can be completed by the responsible physician. While the emergency physician must be able to identify patients with serious headache etiology, note that more than 90% of patients in the ED have migraine, tension, or mixed-type benign

headache. Therefore, providing symptomatic relief should be a priority. Rest in a darkened, quiet room is helpful. Some patients find cool compresses to painful areas helpful. Migraine-specific medications and analgesia are the keys of ED care. Despite contrary evidence, narcotics remain the most frequently administered medication for patients with migraine and for ED patients with headache.[54] Friedman et al reported that nearly three quarters of ED patients with migraine or other primary headache reported headache recurrence within 48 hours of ED discharge; in this study, naproxen 500 mg and oral sumatriptan 100 mg provided comparable relief of post-ED recurrent migraine.[55] Hospital admission for migraine may be indicated for the following:

Treatment of severe nausea, vomiting, and subsequent dehydration Treatment of severe refractory migraine pain (ie, status migrainosus) Detoxification from overuse of combination analgesics, ergots, or opioids

Reduction of Migraine Triggers

Patients should avoid factors that precipitate a migraine attack (eg, lack of sleep, fatigue, stress, certain foods, use of vasodilators). Encourage patients to use a daily diary to document the headaches. This is an effective and inexpensive tool to follow the course of the disease. Patients may need to discontinue any medications that exacerbate their headaches. If an oral contraceptive is suspected to be a trigger, the patient may be advised to modify, change, or discontinue its use for a trial period.[56] Similarly, when hormone replacement therapy is a suspected trigger, patients should reduce dosages, if possible. If headaches persist, consider discontinuing hormone therapy.

Nonpharmacologic Therapy
Biofeedback, cognitive-behavioral therapy and relaxation therapy are frequently effective and may be used adjunctively with pharmacologic treatments. Occipital nerve stimulators may be helpful in patients who are refractory to other forms of treatment.

Abortive Therapy
Numerous abortive medications are used for migraine, and the choice for each patient depends on the severity of the attacks, associated symptoms such as nausea and vomiting, comorbid problems, and the patient's treatment response. A stratified approach based on the patient's therapeutic needs has been advanced (see Table 1 below), as has a step-care approach. Table 1. Abortive Medication Stratification by Headache Severity (Open Table in a new window)

Moderate Severe Extremely Severe NSAIDs Naratriptan DHE (IV) Isometheptene Rizatriptan Opioids Ergotamine Sumatriptan (SC,NS) Dopamine antagonists Naratriptan Zolmitriptan Rizatriptan Almotriptan Sumatriptan Frovatriptan Zolmitriptan Eletriptan Almotriptan DHE (NS/IM) Frovatriptan Ergotamine Eletriptan Dopamine antagonists Dopamine antagonists Simple analgesics alone or in combination with other compounds have provided relief for mild to moderately severe and even at times severe headaches.[57] Acute treatment is most effective when given within 15 minutes of pain onset and when pain is mild.[58] Analgesics used in migraine include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and narcotic analgesics (eg, oxycodone, morphine sulfate). Propoxyphene (Darvon) was formerly used; however, propoxyphene products were withdrawn from the United States market on November 19th, 2010. The withdrawal was based on new data showing QT prolongation at therapeutic doses. For more information, see the FDA MedWatch safety information. 5-Hydroxytryptamine1 (5-HT1) agonists (triptans) and/or opioid analgesics, alone or in combination with dopamine antagonists (eg, prochlorperazine [Compazine]), are used for more severe pain. The use of abortive medications must be limited to 2-3 days a week to prevent development of a rebound headache phenomenon. Intravenous metoclopramide is recognized as an effective therapy for acute migraine, but the optimal dosing has not been established. A study by Friedman et al determined that 20 mg or 40 mg of metoclopramide is no better in the treatment of acute migraine when compared with 10 mg of metoclopramide.[59]

Triptans and ergot alkaloids

The 2 categories of migraine-specific oral medications are triptans and ergot alkaloids. The specific triptans are as follows[60] :

Sumatriptan Rizatriptan Zolmitriptan Naratriptan Almotriptan

Eletriptan Frovatriptan

Although the triptans share a common mechanism of action, they differ in the available routes of administration, onset of action, and duration of action. Routes of administration include oral, intranasal, subcutaneous, and intramuscular. Transdermal patches have proved effective for delivery of sumatriptan, and one such product is currently under FDA review.[61] All the triptans are most effective when taken early during a migraine and all may be repeated in 2 hours as needed, with a maximum of 2 doses daily. While different formulations of a specific triptan may be used in the same 24-hour period, only 1 triptan may be used during this timeframe. The longer-acting triptans (eg, frovatriptan, naratriptan) may be used continuously for several days (mini-prophylaxis) to treat menstrual migraine. Triptans should not be used more than 3 days weekly to avoid transformed migraine and medication overuse headache. The effectiveness and tolerability of triptans varies among patients. Lack of response or side effects experienced with 1 triptan does not predict the response to another. The safety of triptans is well established and the risk of de novo coronary vasospasm from triptan use is exceedingly rare. However, triptans should not be taken by patients with known or suspected coronary artery disease, as they may increase risk of myocardial ischemia, infarction, or other cardiac or cerebrovascular events (5-HT1 agonists may cause coronary vasospasm). The dose of rizatriptan must be reduced to 5 mg in patients taking propranolol. Sumatriptan, zolmitriptan, and rizatriptan are primarily metabolized by monoamine oxidase (MAO), and should be avoided in patients taking MAO-A inhibitors. The first combination product of a triptan and an NSAID, Treximet, was approved by the US Food and Drug Administration in April 2008. Treximet contains sumatriptan and naproxen sodium. In 2 randomized, double-blind, multicenter, parallel-group trials, a significantly greater percentage of patients remained pain free for 24 hours postdose after a single dose of Treximet (25% and 23%) compared with placebo (8% and 7%) or either sumatriptan (16% and 14%) or naproxen sodium (10%) alone.[62] The specific ergot alkaloids are ergotamine and dihydroergotamine (DHE).[63] Do not administer vasoconstrictors, such as ergots or triptans, to patients with known complicated migraine; treat their acute attacks with one of the other available agents, such as NSAIDs or prochlorperazine. Patients with severe headaches need subcutaneous, intravenous, or oral formulations of an ergot alkaloid or triptan. Patients with severe nausea and vomiting at the onset of an attack may respond best to intravenous prochlorperazine. These patients may be dehydrated, and adequate hydration is necessary.

Treatment of nausea and vomiting

Antiemetics (eg, chlorperazine, promethazine) are used to treat the emesis associated with acute migraine attacks. Drugs in this category are commonly combined with diphenhydramine to minimize the risk of akathisia. This combination of drugs has been found to be superior to subcutaneous sumatriptan when given intravenously in emergency patients.[64]

Prophylactic Therapy
The following may be considered indications for prophylactic migraine therapy:

Frequency of migraine attacks is greater than 2 per month Duration of individual attacks is longer than 24 hours The headaches cause major disruptions in the patients lifestyle, with significant disability that lasts 3 or more days Abortive therapy fails or is overused Symptomatic medications are contraindicated or ineffective Use of abortive medications more than twice a week Migraine variants such as hemiplegic migraine or rare headache attacks producing profound disruption or risk of permanent neurological injury[65]

The goals of preventive therapy are as follows:

Reduce attack frequency, severity, and/or duration Improve responsiveness to acute attacks Reduce disability

Currently, the major prophylactic medications for migraine work via one of the following mechanisms:

5-HT2 antagonism - Methysergide Regulation of voltage-gated ion channels - Calcium channel blockers Modulation of central neurotransmitters - Beta-blockers, tricyclic antidepressants Enhancing GABAergic inhibition - Valproic acid, gabapentin

Another notable mechanism is alteration of neuronal oxidative metabolism by riboflavin and reducing neuronal hyperexcitability by magnesium replacement. As with abortive medications, the selection of a preventive medication must take into consideration comorbid conditions and side effect profile (see Table 2 and Table 3 below). Most preventive medications have modest efficacies and have therapeutic gains of less than 50% when compared to placebo. The latency between initiation of therapy and onset of positive treatment response can be quite prolonged. Furthermore, the scientific basis for using most of these medications is wanting. Propranolol, timolol, methysergide, valproic acid, and topiramate (Topamax) have been approved by the FDA for migraine prophylaxis. However, a 2009 report suggested that long-

term topiramate use in pediatric patients can cause metabolic acidosis and hypokalemia; the risk was deemed mild but statistically significant.[66] The nonsteroidal anti-inflammatory drug naproxen sodium has also been used for prophylaxis. In controlled clinical trials, naproxen sodium demonstrated better efficacy than placebo and efficacy similar to propranolol. Tolfenamic acid has also been tried for migraine prophylaxis, but the clinical efficacy is not as good as that of beta-blockers, valproate, or methysergide. Table 2. Preventive Drugs (Open Table in a new window) First line High efficacy Beta-blockers Tricyclic antidepressants Divalproex Topiramate Low efficacy Verapamil NSAIDs SSRIs Second line High efficacy Methysergide Flunarizine MAOIs Unproven efficacy Cyproheptadine Gabapentin Lamotrigine

Table 3. Preventive Medication for Comorbid Conditions (Open Table in a new window) Comorbid Condition Medication Hypertension Beta-blockers Angina Beta-blockers Stress Beta-blockers Depression Tricyclic antidepressants, SSRIs Underweight Tricyclic antidepressants

Epilepsy Mania

Valproic acid, Topiramate Valproic acid

Of note, an open pilot study reports that quetiapine is effective for migraine prophylaxis in patients with migraine refractory to treatment with standard therapies (eg, atenolol, nortriptyline, flunarizine). The authors stated that controlled studies are necessary to confirm their observations.[67]

Classes of prophylactic drugs

The 3 principal classes of medications that are effective for migraine prevention are antiepileptics, antidepressants, and antihypertensives. Antiepileptics are generally well tolerated. The main adverse effects of topiramate are weight loss and dysesthesia.[68] Valproic acid (Depakote) is useful as a first-line agent. It is a good mood stabilizer and can benefit patients with concomitant mood swings. However, it can cause weight gain, hair loss, and polycystic ovary disease; therefore, it may not be ideal for young female patients who have a tendency to gain weight. Valproic acid also carries substantial risks in pregnancy; it may be best suited for women who have had tubal ligation and who cannot tolerate calcium channel blockers because of dizziness. Data for other antiepileptics (eg, gabapentin,[69] lamotrigine, oxcarbazepine) are limited in migraine. Tricyclic antidepressants are good second-line alternatives because of their adverse-effect profile and efficacy. Amitriptyline and nortriptyline are most effective. Although serotonin-selective reuptake inhibitors are widely used, data regarding their efficacy in migraine prevention are lacking. Antihypertensives such as beta-blockers should be tailored if the patient is young and anxious. They may not be the ideal choice for elderly patients or patients with depression, thyroid problems, or diabetes. Calcium channel blockers are another possible choice of treatment. ACE inhibitors (eg, lisinopril) and angiotensin-receptor blockers (eg, candesartan)[70] have also been shown to be effective for migraine prevention.[71] For any of these prophylactic agents, prophylaxis should not be considered a failure until it has been given at the maximum tolerable dose for at least 30 days.

Botulinum toxin
Botulinum toxin A (onabotulinumtoxinA; BOTOX) may be beneficial in patients with intractable migraine headaches that fail to respond to at least 3 conventional preventive medication. The injections are administered to the scalp and temple. They may reduce the frequency and severity of migraine attacks after 2-3 months of injections.

The injections are expensive and must be administered every 2-3 months to maintain their effectiveness. The most appropriate duration of prophylactic therapy has not been determined. In most patients who are receiving prophylaxis, therapy must be continued for at least 3-6 months. Multiple trials of onabotulinumtoxinA for migraine prevention have been conducted, with mixed results.[72] A review by Schulte-Mattler and Martinez-Castrillo found no evidence for a beneficial effect of botulinum toxin. These authors do not recommend the widespread use of botulinum toxin therapy in headaches.[73] More recently, however, 2 multicenter, placebo-controlled trials included in the Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program found onabotulinumtoxinA to be effective for headache prophylaxis in adults with chronic migraine. Nearly 1400 patients were included in the results. Secondary benefits included significantly reduced headache-related disability and improved functioning, vitality, and overall health-related quality of life.[74]

Status Migrainosus Treatment

Approximately 40% of all migraine attacks do not respond to a given triptan or any other substance. If all else fails, an intractable migraine attack (status migrainosus), or an attack lasting longer than 72 hours, should be addressed in an urgent care or emergency department. In rare cases, patients may need to be hospitalized for a short period and may need to be treated with intravenous valproate or dihydroergotamine (intravenously/subcutaneously/intramuscularly) for a few days.[75]

Complementary and Alternative Treatments

Interest in the use of complementary and alternative medicine (CAM) by headache patients is widespread. A 2002 survey showed that more than 85% of headache patients use CAM therapies and 60% felt they provided some relief.[76] Overall, more than 70% of patients who use CAM do not tell their doctors about it. Some CAM techniques have good scientific evidence of benefit and have been proven by studies to be effective in preventing migraine. Biofeedback and behavioral therapy should be part of the standard of care for a difficult migraine patient. Recently, some good studies have demonstrated the effectiveness of the herb Butterbur (Petasites hybridus) in preventing migraines.[77] Another herb, feverfew, is also widely used and some studies have shown it to be safe and possibly effective for migraine prevention. Riboflavin (vitamin B2), when used in higher doses (200-400 mg) for 3-4 months, can significantly decrease the frequency and intensity of migraines.[78] A variety of other CAM techniques are not bolstered by solid scientific data, but they may be perceived to be of benefit to patients.[79] Techniques commonly practiced for headache relief include the following:

Body work (eg, chiropractic, massage) Creative arts (eg, dance, music) Nutritional/herbal supplements (eg, vitamins, herbs) Yoga Acupressure and acupuncture[80] Ayurveda

Overall, scientific evidence on the efficacy of these modalities is lacking, partly due to the poor design and/or poor quality of the studies performed to date. Mindfulness-based stress reduction and home meditation have been studied as a method to reduce the pain and improve health-related quality of life in patients with chronic pain syndromes. While this method proved effective for chronic arthritis patients, it was not deemed effective in patients with chronic headache/migraine or fibromyalgia.[81] The advantages of CAM therapies are that many of these remedies have no adverse effects, they advocate a self-help technique that is attractive to patients, and they offer a holistic approach. The practitioners often spend significant time with their patients, and that in itself makes the patient feel as if he or she has been given careful attention. The disadvantages of CAM therapies are that the method to either the practice or the dispensing of the therapies and techniques is not standardized. In addition, for many of these modalities, no standard format exists to ensure the practitioners are adequately trained in the techniques they use.

Migraine and Vascular Disease

Migraineurs should be screened for cardiovascular risk factors, which, if present, should be aggressively treated. Migraineurs with aura should also be counseled on the increased risk of stroke with smoking and oral contraceptive use.

Surgical Care
Guyuron and colleagues have shown that surgical deactivation of migraine headache trigger sites can help eliminate or significantly reduce migraine.[82] In this study, patients who experienced complete elimination of migraine headaches with botulinum toxin injection underwent resection of the corrugator supercilii muscles; those who experienced only significant improvement with botulinum toxin also underwent transection of the zygomaticotemporal branch of the trigeminal nerve with repositioning of the temple soft tissues. Dirnberger and Becker reported that corrugators muscle resection produced improvement or total elimination of migraine in almost 90% of patients with up to 4 days of migraine per month and in 75% of patients with 5 to 14 days of migraine per month; those with more than 15 days of migraine per month did less well.[83]

Diet
Many patients can identify dietary triggers of migraine. Common dietary triggers include the following:

Alcohol, particularly wine and beer Caffeine overuse or caffeine withdrawal Chocolate Aspartame (NutraSweet) Monosodium glutamate (MSG) - May be found in Asian food, canned soup, frozen or processed foods, Accent seasoning Fruits (citrus fruits, bananas, avocados, dried fruit) Nuts (peanuts, soy nuts, soy sauce)

Tyramine, a biogenic amine that accumulates in food as it ages, may provoke migraine. Sources include the following:

Dairy - Aged cheese, yogurt, sour cream Meat - Bacon, sausage, luncheon meat, deli meat, pepperoni, smoked or cured meat Pickled foods Heavily yeasted breads (eg, sourdough) Vinegars (especially wine vinegar) Some types of beans

Nutraceuticals shown to be effective in randomized clinical trials include vitamin B2, coenzyme Q-10, magnesium, and butterbur (Petadolex).[84]

Activity
Most studies of aerobic exercise in migraine patients have not found a significant reduction of headache attacks or headache duration. However, regular exercise has been shown to reduce pain intensity in many patients.[85]

Novel Treatments and Future Drugs

Tonabersat is a novel benzopyran compound that markedly reduces cortical spreading depression (CSD) and CSD-associated events by inhibiting gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion.[86] In a randomized, double-blind, placebocontrolled crossover trial, preventive therapy with tonabersat reduced the frequency of aura attacks with or without headache, but had no efficacy on non-aura attacks.[10] Calcitonin generelated protein (CGRP) receptor antagonism is a new approach to the treatment of migraine attacks. In a phase III trial, telcagepant, an orally active CGRP receptor antagonist, proved as effective as zolmitriptan for acute migraine, and caused fewer adverse effects.[87]

The pipeline of future compounds for the treatment of acute migraine headaches also includes transient receptor potential vanilloid type 1 (TRPV1) antagonists, prostaglandin E receptor 4 (EP(4)) receptor antagonists, serotonin 5HT1(F) receptor agonists, and nitric oxide synthase inhibitors. The immediate future of a preventive treatment for migraine headaches will likely involve glutamate N-Methyl-D-aspartic acid (NMDA) receptor antagonists and gap-junction blockers.[88]

Consultations
A neurologist, neuro-ophthalmologist, and/or neurosurgeon should be consulted as deemed clinically appropriate.

Medication Summary
Pharmacologic agents used for the treatment of migraine can be classified as abortive (ie, for alleviating the acute phase) or prophylactic (ie, preventive). Abortive medications include the following:

Selective serotonin receptor (5-HT1) agonists (triptans) Ergot alkaloids Analgesics Nonsteroidal anti-inflammatory drugs (NSAIDs) Combination products Antiemetics

Prophylactic medications include the following:

Antiepileptic drugs Beta-blockers Tricyclic antidepressants Calcium channel blockers Selective serotonin reuptake inhibitors (SSRIs) NSAIDs Serotonin antagonists Botulinum toxin

Selective Serotonin Receptor (5-HT1) Agonists

Class Summary
Triptans are selective serotonin agonists, specifically acting at 5-hydroxytryptamine 1B/1D/1F (5-HT1B/1D/1F) receptors on intracranial blood vessels and sensory nerve endings. Triptans are used as abortive medications for moderately severe to severe migraine headaches.

The most common side effects are asthenia; nausea/vomiting; dizziness; somnolence; chest, throat, or jaw tightness/discomfort; and worsening of head pain (often transient). Drug interactions include potent CYP450 3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir), which may increase toxicity, and concurrent administration with ergot-containing drugs, which may increase vasospastic reactions. Zolmitriptan, eletriptan, and naratriptan are primarily metabolized by CYP450 3A4. View full drug information

Sumatriptan (Imitrex, Sumavel DosePro)

The efficacy of sumatriptan is 82% at 20 min when administered by injection, 52-62% at 2 h when administered intranasally, and 67-79% at 4 h when administered orally.[89, 90, 91] View full drug information

Naratriptan (Amerge)

A selective agonist for serotonin 5-HT1 receptors, naratriptan has higher bioavailability and longer half-life than sumatriptan, which may contribute to lower rate of headache recurrences. It has a duration of action of up to 24 hours with low headache recurrence rate. It is useful for patients with slow onset, prolonged migraine, such as menstrual migraine. Pain relief is experienced by 60-68% of patients within 4 h of treatment and maintained up to 24 h in 49-67% of patients. View full drug information

Zolmitriptan (Zomig, Zomig-ZMT)

A selective agonist for serotonin 5-HT1 receptors in cranial arteries, zolmitriptan suppresses the inflammation associated with migraine headaches. It has efficacy of 62% at 2 h and 75-78% within 4 h. View full drug information

Rizatriptan (Maxalt, Maxalt-MLT)

A selective agonist for serotonin 5-HT1 receptors in cranial arteries, rizatriptan suppresses the inflammation associated with migraine headaches. It has reported early onset of action (30 min) and efficacy of 71% at 2 h. View full drug information

Almotriptan (Axert)

A selective 5-HT1B/1D receptor agonist, almotriptan results in cranial vessel constriction, inhibition of neuropeptide release, and reduced pain transmission in trigeminal pathways. It induces cranial vessel constriction, inhibition of neuropeptide release, and reduces pain transmission in trigeminal pathways. View full drug information

Frovatriptan (Frova)

Frovatriptan is a selective 5-HT1B/1D receptor agonist with a long half-life (ie, 26-30 h) and low headache recurrence rate within 24 hour of taking the drug. It constricts cranial vessels, inhibits neuropeptide release, and reduces pain transmission in trigeminal pathways. View full drug information

Eletriptan (Relpax)

A selective serotonin agonist, eletriptan specifically acts at 5-hydroxytryptamine 1B/1D/1F (5HT1B/1D/1F) receptors on intracranial blood vessels and sensory nerve endings to relieve pain associated with acute migraine.

Ergot Alkaloids
Class Summary
Ergot alkaloids are nonselective 5-HT1 agonists that have a wider spectrum of receptor affinities outside of the 5-HT1 system, including dopamine receptors. They can be used for the abortive treatment of moderately severe to severe migraine headache. View full drug information

Ergotamine tartrate (Ergomar)

Ergotamine counteracts episodic dilation of extracranial arteries and arterioles. View full drug information

Dihydroergotamine (DHE-45, Migranal)

Dihydroergotamine is an alpha-adrenergic blocking agent with a direct stimulating effect on smooth muscle of peripheral and cranial blood vessels. It depresses central vasomotor centers. Its mechanism of action is similar to that of ergotamine; it is a nonselective 5HT1 agonist with a wide spectrum of receptor affinities outside 5HT1 system; it also binds to dopamine. Thus, it has an alpha-adrenergic antagonist and serotonin antagonist effect. Dihydroergotamine is indicated to abort or prevent vascular headache when rapid control is needed or when other routes of administration are not feasible. It tends to cause less arterial vasoconstriction than ergotamine tartrate. It is usually administered in conjunction with antiemetics such as metoclopramide, which is a 5HT3-receptor antagonist and a dopamine antagonist, to treat migraine-associated nausea. Dihydroergotamine is available in IV or intranasal preparations. The IV route is used when more rapid results are desired. A dose of 1 mg intravenously every 8 hours with or without metoclopramide is safe and effective for treatment of status migrainosus.

Analgesics
Class Summary
These agents are used as initial abortive therapy for patients with infrequent migraines. View full drug information

Acetaminophen (Tylenol)

These agents are used as initial abortive therapy for patients with infrequent migraines. View full drug information

Oxycodone (OxyContin, Roxicodone)

Oxycodone is an analgesic with multiple actions similar to those of morphine. However, it may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine. View full drug information

Morphine sulfate (Duramorph, MS Contin, Astramorph)

Morphine is the drug of choice for narcotic analgesia because of its reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate administered IV may be dosed in a number of ways and is commonly titrated until the desired effect is obtained. View full drug information

Meperidine (Demerol)

Meperidine is an analgesic with multiple actions similar to those of morphine. However, it may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine. View full drug information

Hydromorphone (Dilaudid)

Hydromorphone is a potent semisynthetic opiate agonist similar in structure to morphine. It is approximately 7-8 times as potent as morphine on mg-to-mg basis, with a shorter or similar duration of action. View full drug information

Butorphanol (Stadol)

A mixed agonist-antagonist narcotic with central analgesic effects for moderate to severe pain, butorphanol causes less smooth muscle spasm and respiratory depression than morphine or meperidine. Weigh these advantages against the higher cost of butorphanol.

Nonsteroidal Anti-inflammatory Drugs

Class Summary
NSAIDs inhibit cyclo-oxygenase (COX), an early component of the arachidonic acid cascade, resulting in reduced synthesis of prostaglandins, thromboxanes, and prostacyclin. They elicit anti-inflammatory, analgesic, and antipyretic effects. NSAIDs are generally used as abortive therapy in mild to moderately severe migraine headaches. However, these agents, especially ketorolac, may also be effective for severe headaches. NSAIDs are also used as prophylactic agents, but they are associated with a higher risk of adverse effects, particularly gastropathy or nephropathy, than when used as abortive medications. View full drug information

Aspirin (Bayer Aspirin, Anacin)

Aspirin is a mild analgesic that can be used to treat infrequent migraine episodes. View full drug information

Ketorolac (Sprix [intranasal])

Ketorolac is indicated for short-term (up to 5 d) management of moderate to moderately severe pain. The bioavailability of a 31.5-mg intranasal dose (2 sprays) is approximately 60% of 30-mg IM dose. Intranasal spray delivers 15.75 mg per 100-L spray; each 1.7-g bottle contains 8 sprays. View full drug information

Ibuprofen (Motrin, Advil)

Ibuprofen is used for treatment of mild to moderate pain if no contraindications are present. It inhibits inflammatory reactions and pain, probably by decreasing the activity of the enzyme cyclo-oxygenase, resulting in prostaglandin synthesis. View full drug information

Naproxen (Naprosyn, Naprelan, Anaprox)

Naproxen is used for relief of mild to moderate pain, as an abortive agent, and for prophylaxis. It inhibits inflammatory reactions and pain by decreasing the activity of the enzyme cyclooxygenase, resulting in prostaglandin synthesis. View full drug information

Ketoprofen

Ketoprofen is used for relief of mild to moderately severe headaches and inflammation. Administer small dosages initially to patients with small body size, elderly patients, and patients with renal or liver disease. Doses >75 mg do not have increased therapeutic effects. Administer high doses with caution, and closely observe the patient for response.

Combination Analgesics
Class Summary
The first combination product of a 5HT receptor agonist and an NSAID was approved by the US Food and Drug Administration in April 2008. Other combination products that contain ergots, sedatives, and analgesics may be used when simple analgesics are not effective and the patient is not a candidate for treatment with 5-HT1 agonists or when the patient needs an alternative drug. Some agents are used in combination with aspirin and acetaminophen for pain relief and to induce sleep. Caffeine is also used to increase GI absorption. Analgesics like butalbital and narcotics are associated with rebound headaches. Increasing the use of combination preparations may fail to provide pain relief and worsen headache symptoms. View full drug information

Sumatriptan and naproxen (Treximet)

This is a combination product containing sumatriptan, a selective 5-hydroxytryptamine (5-HT1) receptor agonist, and naproxen sodium, an arylacetic acid NSAID in a fixed combination of sumatriptan 85 mg and naproxen sodium 500 mg. It is indicated for acute migraine. Sumatriptan mediates vasoconstriction of the basilar artery and vasculature of dura mater, which correlates with migraine relief. Naproxen provides analgesic, anti-inflammatory, and antipyretic properties. It decreases activity of cyclooxygenase, thereby interrupting prostaglandin synthesis. View full drug information

Butalbital, aspirin, and caffeine (Fiorinal)

This combination drug is effective for mild to moderately severe migraine headache. . The barbiturate component has generalized depressant effect on CNS. Caffeine is used to increase GI absorption. However, butalbital and narcotics are associated with rebound headaches. Increasing the use of combination preparations may fail to provide pain relief and worsen headache symptoms. View full drug information

Isometheptene, dichloralphenazone, and acetaminophen (Midrin, Epidrin)

This combination drug has sympathomimetic properties. It dilates cranial and cerebral arterioles, causing a reduction in the stimuli that lead to vascular headaches. View full drug information

Butalbital, acetaminophen, and caffeine (Fioricet)

This combination drug is effective for mild to moderately severe migraine headache. . The barbiturate component has a generalized depressant effect on CNS. Caffeine is used to increase GI absorption. However, butalbital and narcotics are associated with rebound headaches. Increasing the use of combination preparations may fail to provide pain relief and worsen headache symptoms.

Acetaminophen and codeine (Tylenol No. 3)

This drug combination is indicated for treatment of mild to moderately severe headache. Note that some patients may respond to maximal acetaminophen alone, without codeine.

Antiemetics
Class Summary
As dopamine antagonists, these agents are effective if nausea and vomiting are prominent features. They also may act as prokinetics to increase gastric motility and enhance absorption.

These agents are used to treat migraine and the emesis associated with acute attacks. Drugs in this category are commonly combined with diphenhydramine to minimize the risk of akathisia. This combination of drugs has been found to be superior to subcutaneous sumatriptan when given intravenously in emergency patients.[73] View full drug information

Chlorpromazine (Thorazine)

The mechanisms of chlorpromazine include blocking postsynaptic mesolimbic dopamine receptors, anticholinergic effects, and depression of reticular activating system. Blocks alphaadrenergic receptors and depresses release of hypophyseal and hypothalamic hormones. As a rule, dopamine antagonists are avoided in patients with traumatic brain injury. View full drug information

Droperidol (Inapsine)

Used alone or in combination with other analgesics as adjuncts, especially if migraine attack associated with significant nausea and vomiting. Its role in migraine based on findings that increased dopamine concentration is associated with prominent migraine symptomatology. View full drug information

Prochlorperazine (Compro)

An antidopaminergic drug that blocks postsynaptic mesolimbic dopamine receptors, prochlorperazine has an anticholinergic effect. It can also depress the reticular activating system, a possible mechanism for relieving nausea and vomiting. View full drug information

Promethazine (Phenergan, Phenadoz)

Promethazine is a phenothiazine derivative that possesses antihistaminic, sedative, antimotion sickness, antiemetic, and anticholinergic effects. View full drug information

Droperidol

Droperidol is used alone or in combination with other analgesics as adjuncts, especially in migraine attacks associated with significant nausea and vomiting. Its role in migraine is based on findings that increased dopamine concentration is associated with prominent migraine symptoms.

Antiepileptics
Class Summary
These drugs are effective in prophylaxis of migraine headache. View full drug information

Divalproex sodium/valproate (Depakote, Depacon, Depakene)

Divalproex is now considered first-line preventive medication for migraine. This agent is believed to enhance GABA neurotransmission, which may suppress events related to migraine that occur in cortex, perivascular sympathetics, or trigeminal nucleus caudalis. Divalproex has been shown to reduce migraine frequency by 50%. View full drug information

Gabapentin (Neurontin)

Gabapentin is used for migraine headache prophylaxis. It has shown efficacy in migraine and transformed migraine. View full drug information

Topiramate (Topamax)

Topiramate is indicated for migraine headache prophylaxis. Its precise mechanism of action is unknown, but the following properties may contribute to its efficacy: 1) blockage of voltagedependent sodium channels, 2) augmentation of activity of the neurotransmitter GABA at some

GABA-A receptor subtypes, 3) antagonization of the AMPA/kainate subtype of the glutamate receptor, and 4) inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV.

Beta-blockers
Class Summary
Beta-blockers may prevent migraines by blocking vasodilators, decreasing platelet adhesiveness and aggregation, stabilizing the membrane, and increasing the release of oxygen to tissues. Significant to their activity as migraine prophylactic agents is the lack of partial agonistic activity. Latency from initial treatment to therapeutic results may be as long as 2 months. View full drug information

Metoprolol (Lopressor, Toprol XL)

Metoprolol is not FDA approved for migraine prevention. Efficacy in prophylactic therapy is presumably by the same mechanism as with other beta-blockers. View full drug information

Propranolol (Inderal)

Beta-blockers may prevent migraines by blocking vasodilators, decreasing platelet adhesiveness and aggregation, stabilizing the membrane, and increasing the release of oxygen to tissues. Significant to their activity as migraine prophylactic agents is the lack of partial agonistic activity. Latency from initial treatment to therapeutic results may be as long as 2 months. View full drug information

Timolol

Timolol is FDA approved for migraine prophylaxis, although there is less scientific evidence of efficacy for timolol than for propranolol. View full drug information

Nadolol (Corgard)

Nadolol is not FDA approved for migraine prevention. Efficacy in prophylactic therapy is presumably by the same mechanism as with other beta-blockers. View full drug information

Atenolol (Tenormin)

Atenolol is not FDA approved for migraine prevention. Efficacy in prophylactic therapy is presumably by the same mechanism as with other beta-blockers.

Tricyclic Antidepressants
Class Summary
Amitriptyline, nortriptyline, doxepin, and protriptyline have been used for migraine prophylaxis, but only amitriptyline has proven efficacy and appears to exert its antimigraine effect independent of its effect on depression. View full drug information

Amitriptyline

Amitriptyline has efficacy for migraine prophylaxis that is independent of its antidepressant effect. Its mechanism of action is unknown, but it inhibits activity of such diverse agents as histamine, 5-HT, and acetylcholine. View full drug information

Doxepin (Adapin)

Doxepin has efficacy for migraine prophylaxis that is independent of its antidepressant effect. Its mechanism of action is unknown, but it increases concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. It also inhibits histamine and acetylcholine activity. View full drug information

Nortriptyline (Pamelor)

Nortriptyline has efficacy for migraine prophylaxis that is independent of its antidepressant effect. Its mechanism of action is unknown, but it inhibits activity of such diverse agents as histamine, 5-HT, and acetylcholine. View full drug information

Protriptyline (Vivactil)

Protriptyline has efficacy for migraine prophylaxis that is independent of its antidepressant effect. It inhibits activity of such diverse agents as histamine, 5-HT, and acetylcholine.

Calcium Channel Blockers

Class Summary
This group is commonly used as prophylactic medication, although studies of their effectiveness have shown mixed results. Flunarizine has the best-documented efficacy but is not available in the United States. The efficacy of verapamil is supported by studies. This group is particularly useful in patients with comorbid hypertension and in those with contraindications to beta-blockers such as asthma and Raynaud disease. This group may have particular advantage in patients with prolonged aura, vertebrobasilar migraine, or hemiplegic migraine. View full drug information

Verapamil (Calan, Covera, Verelan)

During depolarization, verapamil inhibits calcium ion from entering slow channels or voltagesensitive areas of vascular smooth muscle.

Selective Serotonin Reuptake Inhibitors

Class Summary
These may be considered first-line drugs, but they have low efficacy.

View full drug information

Paroxetine (Paxil, Pexeva)

Paroxetine is an atypical non-tricyclic antidepressant with potent specific 5HT-uptake inhibition and fewer anticholinergic and cardiovascular adverse effects than tricyclic antidepressants. View full drug information

Fluoxetine (Prozac)

Fluoxetine has been shown to be of benefit in migraine prophylaxis. It is an atypical, nontricyclic antidepressant with potent specific 5-HT-uptake inhibition with fewer anticholinergic and cardiovascular side effects than tricyclic antidepressants. View full drug information

Sertraline (Zoloft)

Sertraline is an atypical nontricyclic antidepressant with potent specific 5-HT uptake inhibition and fewer anticholinergic and cardiovascular adverse effects than tricyclic antidepressants.

Histamine H1 Antagonists
Class Summary
Agents in this class with potent serotonin antagonist activity have been reported to be effective in the treatment of migraine. View full drug information

Cyproheptadine (Periactin)

Cyproheptadine acts primarily as antagonist of cerebral vascular 5-HT2 receptors and has been used traditionally for pediatric migraine prevention despite minimal objective evidence of its efficacy.

Neuromuscular Blocker Agents, Toxin

Class Summary
Botulinum toxin A may be beneficial in patients with intractable migraine headaches that fail to respond to at least 3 conventional preventive medications. View full drug information

Onabotulinumtoxin A (BOTOX)

This is one of several toxins produced by Clostridium botulinum. It blocks neuromuscular transmission through a 3-step process, as follows: (1) blockade of neuromuscular transmission; botulinum toxin type A (BTA) binds to the motor nerve terminal. The binding domain of the type A molecule appears to be the heavy chain, which is selective for cholinergic nerve terminals. (2) BTA is internalized via receptor-mediated endocytosis, a process in which the plasma membrane of the nerve cell invaginates around the toxin-receptor complex, forming a toxin-containing vesicle inside the nerve terminal. After internalization, the light chain of the toxin molecule, which has been demonstrated to contain the transmission-blocking domain, is released into the cytoplasm of the nerve terminal. (3) BTA blocks acetylcholine release by cleaving SNAP-25, a cytoplasmic protein that is located on the cell membrane and that is required for the release of this transmitter. The affected terminals are inhibited from stimulating muscle contraction. The injections are administered to the scalp and temple. They may reduce the frequency and severity of migraine attacks after 2-3 months of injections.