Migraine Headache 

Updated: May 28, 2019
Author: Jasvinder Chawla, MD, MBA; Chief Editor: Helmi L Lutsep, MD 

Overview

Practice Essentials

Migraine is a complex disorder characterized by recurrent episodes of headache, most often unilateral and in some cases associated with visual or sensory symptoms—collectively known as an aura—that arise most often before the head pain but that may occur during or afterward (see the image below). Migraine is most common in women and has a strong genetic component.

Migraine headache. Example of a visual migraine au 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.

Signs and symptoms

Typical symptoms of migraine include the following:

  • Throbbing or pulsatile headache, with moderate to severe pain that intensifies with movement or physical activity

  • Unilateral and localized pain in the frontotemporal and ocular area, but the pain may be felt anywhere around the head or neck

  • Pain builds up over a period of 1–2 hours, progressing posteriorly and becoming diffuse

  • Headache lasts 4–72 hours

  • Nausea (80%) and vomiting (50%), including anorexia and food intolerance, and light-headedness

  • Sensitivity to light and sound

Features of migraine aura are as follows:

  • May precede or accompany the headache phase or may occur in isolation

  • Usually develops over 5–20 minutes and lasts less than 60 minutes

  • Most commonly visual but can be sensory, motor, or any combination of these

  • Visual symptoms may be positive or negative

  • The most common positive visual phenomenon is the scintillating scotoma, an arc or band of absent vision with a shimmering or glittering zigzag border

Physical findings during a migraine headache may 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 or bradycardia

  • Hypertension or hypotension

  • Hemisensory or hemiparetic neurologic deficits (ie, complicated migraine)

  • Adie-type pupil (ie, poor light reactivity, with near dissociation from light)

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of migraine is based on patient history. International Headache Society diagnostic criteria are that patients must have had at least 5 headache attacks that lasted 4–72 hours (untreated or unsuccessfully treated) and that the headache must have had at least 2 of the following characteristics:[1]

  • Unilateral location

  • Pulsating quality

  • Moderate or severe pain intensity

  • Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs)

In addition, during the headache the patient must have had at least 1 of the following:

  • Nausea and/or vomiting

  • Photophobia and phonophobia

Finally, these features must not have been attributable to another disorder. Classification of migraine is as follows:

  • 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

Migraine variants include the following:

  • Childhood periodic syndromes

  • Late-life migrainous accompaniments

  • Migraine with brainstem aura

  • Hemiplegic migraine

  • Status migrainosus

  • Retinal migraine

A migraine variant may be suggested by focal neurologic findings, such as the following, that occur with the headache and persist temporarily after the pain resolves:

  • Unilateral paralysis or weakness - Hemiplegic migraine

  • Dysarthria, vertigo, ataxia - Migraine with brainstem aura

Testing and imaging studies

Selection of laboratory and/or imaging studies to rule out conditions other than migraine headache is determined by the individual presentation (eg, erythrocyte sedimentation rate and C-reactive protein levels may be appropriate to exclude temporal/giant cell arteritis). Neuroimaging is not necessary in patients with a history of recurrent migraine headaches and a normal neurologic examination.

The American Headache Society released a list of 5 commonly performed tests or procedures that are not always necessary in the treatment of migraine and headache, as part of the American Board of Internal Medicine (ABIM) Foundation's Choosing Wisely campaign. The recommendations include:[2, 3]

  • Don't perform neuroimaging studies in patients with stable headaches that meet criteria for migraine.

  • Don't perform computed tomography imaging for headache when magnetic resonance imaging is available, except in emergency settings.

  • Don't recommend surgical deactivation of migraine trigger points outside of a clinical trial.

  • Don't prescribe opioid or butalbital-containing medications as first-line treatment for recurrent headache disorders.

  • Don't recommend prolonged or frequent use of over-the-counter pain medications for headache.

See Workup for more detail.

Management

Pharmacologic agents used for the treatment of migraine can be classified as abortive (ie, for alleviating the acute phase) or prophylactic (ie, preventive).

Acute/abortive medications

Acute treatment aims to reverse, or at least stop the progression of, a headache. It is most effective when given within 15 minutes of pain onset and when pain is mild.[4]

Abortive medications include the following:

  • Selective serotonin receptor (5-hydroxytryptamine–1, or 5-HT1) agonists (triptans)

  • Ergot alkaloids (eg, ergotamine, dihydroergotamine [DHE])

  • Analgesics

  • Nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Combination products

  • Antiemetics

Preventive/prophylactic medications

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 patient's 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 neurologic injury[5]

Prophylactic medications include the following:

  • Antiepileptic drugs

  • Beta blockers

  • Tricyclic antidepressants

  • Calcium channel blockers

  • Selective serotonin reuptake inhibitors (SSRIs)

  • NSAIDs

  • Serotonin antagonists

  • Botulinum toxin

  • Calcitonin gene-related peptide (CGRP) inhibitors

Other measures

Treatment of migraine may also include the following:

  • Reduction of migraine triggers (eg, lack of sleep, fatigue, stress, certain foods)

  • Nonpharmacologic therapy (eg, biofeedback, cognitive-behavioral therapy)

  • Integrative medicine (eg, butterbur, riboflavin, magnesium, feverfew, coenzyme Q10)

See Treatment and Medication for more detail.

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, the French translation of which was migraine.

Causes of migraine

Migraine was previously considered to be 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 associated with a sterile neurogenic inflammation (see Pathophysiology).

A genetic component to migraine is indicated by the fact that 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).

Migraine characteristics and treatment

Migraine is characterized most often by unilateral head pain that is moderate to severe, throbbing, and aggravated by activity. It may also be associated with various visual or sensory symptoms, which occur most often before the headache component but which may occur during or after the headache; these are 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 Presentation).

The head pain may also be associated with weakness. This form of migraine is termed hemiplegic migraine.

In practice, however, migraine headaches may be unilateral or bilateral and may occur with or without an aura. In the current International Headache Society categorization, the headache previously described as classic migraine is now known as migraine with aura, and the headache that was 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, to exclude other disorders; the findings are usually normal in patients with migraine. Neuroimaging is not necessary in a typical case, but other diagnostic investigations may be indicated to guide management.

A screening tool called the ID-CM may be useful in diagnosis. The ID-CM is a 12-item screening tool for chronic migraine that has a sensitivity of 82% and a specificity of 87% compared with semi-structured clinical interviews.[6]

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 eliminate, or at least prevent the progression of, a headache. Preventive treatment, which is given even in the absence of a headache, aims to reduce the frequency and severity of migraine attacks, to make acute attacks more responsive to abortive therapy, and perhaps also to improve the patient's quality of life (see Treatment).

See Migraine in Children for a pediatric perspective on migraine. Also see Migraine Variants and Childhood Migraine Variants.

Migraine classification

The third edition of the International Classification of Headache Disorders (ICHD)[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

Diagnostic criteria

According to the International Headache Society, the diagnosis of migraine requires that the patient has experienced at least 5 attacks that fulfill the following 3 criteria and that are not attributable to another disorder.[1] First, the headache attacks must have lasted 4–72 hours (untreated or unsuccessfully treated). Second, the headache must have had at least 2 of the following characteristics:

  • Unilateral location

  • Pulsating quality

  • Moderate or severe pain intensity

  • Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs)

Third, during the headache the patient experiences at least 1 of the following:

  • Nausea and/or vomiting

  • Photophobia and phonophobia

In January 2018, the International Classification of Headache Disorders, Third Edition was published.

Changes from the previous edition include the following:[7]

  • The addition of chronic migraines: Those that occur on at least 15 days of the month for more than 3 months

  • For a diagnosis of migraine with aura, the following criteria must be met: One or more visual, sensory, speech, motor, brainstem, or retinal symptoms, as well as at least 2 of the following 4 criteria: (1) at least 1 aura symptom spreading gradually over 5 or more minutes and/or 2 or more symptoms occurring in succession; (2) each aura symptom lasting 5–60 minutes; (3) at least 1 aura symptom being unilateral; and (4) the aura being accompanied by or followed shortly by headache

  • Under headaches associated with sexual activity, the subtypes of preorgasmic and orgasmic headache have been eliminated

  • For thunderclap headaches, the headache must last at least 5 minutes, but the criterion of not recurring regularly during subsequent weeks or months has been discarded

  • Hypnic headaches no longer have to first occur after age 50 years

  • A number of pain characteristics under the new daily persistent headaches section have been eliminated

  • For secondary headaches, it is not required that the causative agent be removed before a diagnosis

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.[4, 8, 9]

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. Nor did it explain 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.

No consistent flow changes have been identified in patients suffering from migraine headache without aura. Regional cerebral blood flow (rCBF) remains normal in the majority of patients. 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.[10]

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.[11] According to this theory, migraine is primarily a neurogenic process with secondary changes in cerebral perfusion.[12]

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.[13] This finding has been demonstrated in studies of transcranial magnetic stimulation and with functional magnetic resonance imaging (MRI).

This observation explains the special susceptibility of the migrainous brain to headaches.[14] 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.

Oligemia

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 to prevent migraine attacks with aura only, suggesting that CSD may but not be involved in attacks without aura.[15]

Trigeminovascular system

Activation of the trigeminovascular system by CSD stimulates nociceptive neurons on dural blood vessels to release plasma proteins and pain-generating substances such as calcitonin gene-related 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.[16]

Metalloproteinases

In addition, through a variety of molecular mechanisms, CSD upregulates genes, such as those encoding for cyclo-oxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-alpha), 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 CSD to reach and sensitize the dural perivascular trigeminal afferent endings.[17]

Increased net activity of matrix metalloproteinase–2 (MMP-2) has been demonstrated in migraineurs. Patients who have migraine without aura seem to have an increased ratio of matrix metalloproteinase–9 (MMP-9) to tissue inhibitors of metalloproteinase–1 (TIMP-1), in contrast to a lower MMP-9/TIMP-1 ratio in patients who have migraine with aura.[18] Measured levels of MMP-9 alone are the same for migraine patients with or without aura.[19]

Hypoxia

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.[20]

Vasoactive substances and neurotransmitters

Perivascular nerve activity also results in release of substances such as substance P, neurokinin A, calcitonin gene-related peptide, and nitric oxide, which interact with the blood vessel wall to produce dilation, protein extravasation, and sterile inflammation. This stimulates 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.

Neurogenically induced plasma extravasation may play a role in the expression of pain in migraine, but it may not be sufficient by itself to cause pain. The presence of other stimulators may be required.

Although some drugs that are effective for migraine inhibit neurogenic plasma extravasation, substance P antagonists and the endothelin antagonist bosentan inhibit neurogenic plasma extravasation but are ineffective as antimigraine drugs. Also, the pain process requires not only the activation of nociceptors of pain-producing intracranial structures but also reduction in the normal functioning of endogenous pain-control pathways that gate the pain.

Migraine center

A potential "migraine center" in the brainstem has been proposed, based on PET-scan results showing persistently elevated rCBF in the brainstem (ie, periaqueductal gray, midbrain reticular formation, locus ceruleus) even after sumatriptan-produced resolution of headache and related symptoms. These were the findings in 9 patients who had experienced spontaneous attack of migraine without aura. The increased rCBF was not observed outside of the attack, suggesting that this activation was 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 to 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, releasing a proinflammatory soup of neurochemicals (eg, calcitonin gene–related peptide) and causing plasma extravasation to occur. 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.[21] This observation demonstrates that, along with the previously described neurovascular events, sensitization of central pathways in the brain mediates the pain of migraine.

Dopamine pathway

Some authors have proposed a dopaminergic basis for migraine.[22] 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 5-hydroxytryptamine, which is a vasoconstrictor. In clinical studies, oral magnesium has shown benefit for preventive treatment and intravenous magnesium may be effective for acute treatment, particularly in certain subsets of migraine patients.[23]

Endothelial dysfunction

Vascular smooth muscle cell dysfunction may involve impaired cyclic guanosine monophosphate and hemodynamic response to nitric oxide.[24] Nitric oxide released by microglia is a potentially cytotoxic proinflammatory mediator, initiating and maintaining brain inflammation through activation of the trigeminal neuron system.

Nitric oxide levels continue to be increased even in the headache-free period in migraineurs.[25] In premenopausal women with migraine, particularly in those with migraine aura, increased endothelial activation, which is a component of endothelial dysfunction, is evident.[26]

Serotonin and migraine

The serotonin receptor (5-hydroxytryptamine [5-HT]) is believed to be the most important receptor in the headache pathway. Immunohistochemical studies have detected 5-hydroxytryptamine–1D (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.

All the currently available triptans (see Medication) are selective 5-HT1B/D full agonists. These agents may decrease headache by abolishing neuropeptide release in the periphery and blocking neurotransmission by acting on second-order neurons in the trigeminocervical complex.

Migraine risk factors

Predisposing vascular risk factors for migraine include the following[27] :

  • Increased levels of C-reactive protein

  • Increased levels of interleukins

  • Increased levels of TNF-alpha and adhesion molecules (systemic inflammation markers)

  • Oxidative stress and thrombosis

  • Increased body weight

  • High blood pressure

  • Hypercholesterolemia

  • Impaired insulin sensitivity

  • High homocysteine levels

  • Stroke

  • Coronary heart disease

Transformed migraine/medication overuse headache

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. Medication overuse headache can occur with any analgesic, including acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and aspirin. In addition, Bigal and Lipton identified the following associations of medication with progression to chronic migraine[28] :

  • 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 days/mo)

In the study, 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.[28]

Etiology

Migraine has a strong genetic component. Approximately 70% of migraine 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.[29]

Nonsyndromic migraine headache with or without aura generally shows a multifactorial inheritance pattern, but the specific nature of the genetic influence is not yet completely understood. Certain rarer syndromes with migraine as a clinical feature generally show an autosomal dominant inheritance pattern.[30]

However, recent genome-wide association studies have suggested 4 regions in which single-nucleotide polymorphisms influence the risk of developing migraine headache.[31, 32, 33] Other associations have been found in individual studies but could not be replicated in other populations.

Familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a rare type of migraine with aura that is preceded or followed by hemiplegia, which typically resolves. 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 other forms of migraine. Three genes have thus far been identified as being causative for FHM.

FHM type 1 is characterized clinically by episodes that commonly include nystagmus and cerebellar signs. This disorder is caused by mutations in the CACNA1A gene located on 19p13, which codes for a brain-specific calcium channel. Mutations in CACNA1A were previously thought to account for 50% of cases of FHM,[34] but a Danish study showed that only 7% of patients with a clinical diagnosis of FHM had a mutation in that gene.[35]

FHM type 2 occurs in patients who also have a seizure disorder. This condition has been attributed to mutations in the ATP1A2 gene, located on 1q21q23, which encodes a sodium/potassium pump.[36, 37] However, the Danish study found mutations in ATP1A2 in only 7% of patients with a clinical diagnosis of FHM.[35]

FHM type 3 is caused by mutations in the SCN1A gene, located on 2q24. Mutations in SCN1A are also known to cause familial febrile seizure disorders and infantile epileptic encephalopathy.[38] Although SCN1A mutation has been reported in several unrelated families, it is felt to be a rare cause of FHM.[39]

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 that causes migraine with aura, strokes before the age of 60, progressive cognitive dysfunction, and behavioral changes.

CADASIL is inherited in an autosomal dominant fashion, and most patients with the disorder have an affected parent. Approximately 90% of cases result from mutations of the < INOTCH3< I>gene, located on chromosome 19. Patients with CADASIL have significant morbidity from their ailment, and life expectancy is approximately 68 years.[40]

Migraine is also a common symptom in other genetic vasculopathies, including 2 autosomal dominant disorders: (1) RVCL (retinal vasculopathy with cerebral leukodystrophy), which is caused by mutations in the TREX1 gene,[41] and (2) HIHRATL (hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy), which is suggested to be caused by mutations in the COL4A1 gene.[42] The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear.[43]

Migraine precipitants

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

  • Hormonal changes, such as those accompanying menstruation (common),[44] pregnancy, and ovulation

  • Stress

  • Excessive or insufficient sleep

  • Medications (eg, vasodilators, oral contraceptives[45] )

  • Smoking

  • Exposure to bright or fluorescent lighting

  • Strong odors (eg, perfumes, colognes, petroleum distillates)

  • Head trauma

  • Weather changes

  • Motion sickness

  • Cold stimulus (eg, ice cream headaches)

  • Lack of exercise

  • Fasting or skipping meals

  • Red wine

Certain foods and food additives have been suggested as potential precipitants of migraine, including the following:

  • Caffeine

  • Artificial sweeteners (eg, aspartame, saccharin)

  • Monosodium glutamate (MSG)

  • Citrus fruits

  • Foods containing tyramine (eg, aged cheese)

  • Meats with nitrites

However, large epidemiologic studies have failed to substantiate most of these as triggers,[46] and no diets have been shown to help migraine. Nevertheless, patients who identify particular foods as triggers should avoid these foods.

Although chocolate has been considered a migraine trigger, data from the PAMINA study do not support this contention.[46] Instead, it has been hypothesized that ingestion of chocolate may be in response to a craving brought on at the start of a migraine, as a result of hypothalamic activation.

Migraine and other vascular disease

People who suffer from migraine headaches are more likely to also have cardiovascular or cerebrovascular disease (ie, stroke, myocardial infarction).[47] 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%.[48] Migraines during pregnancy are also linked to stroke and vascular diseases.[49]  A 2017 analysis of the Women's Health Study found that women who experience migraine headaches, particularly migraine without aura, may be at increased risk for hypertension. Compared with women without a history of migraine, those who experienced migraine with aura had about a 9% increased risk for hypertension while those who experienced migraine without aura had about a 21% increased risk.[50]

Migraine with aura for women in midlife has a statistically significant association with late-life vascular disease (infarcts) in the cerebellum. This association is not seen in migraine without aura.[51]

Results of a large, prospective cohort study in women indicate a consistent link between migraine and cardiovascular disease events, including cardiovascular mortality. Researchers analyzed data from more than 115,000 women, 15.2% (17,531) of whom reported a diagnosis of migraine. Over 20 years of follow-up, 1329 major cardiovascular disease events occurred and 223 women died from cardiovascular disease. After adjusting for the known risk factors, women with migraine had a significantly elevated risk for developing major cardiovascular disease (hazard ratio 1.50, 95% CI 1.33-1.69). The greatest increase in risk was for stroke (HR 1.62) and for angina/coronary revascularizations (HR 1.73).[52]

Migraine and iron

In a population-based MRI study by Kruit et al, migraineurs had increased local iron deposits in the putamen, globus pallidus, and red nucleus, compared with controls.[53] This increase in iron deposits may be explained as a physiologic response induced by repeated activation of nuclei involved in central pain processing or by damage to these structures secondary to the formation of free radicals in oxidative stress (possibly the cause of the disease becoming chronic).[54]

Migraine and sensory perception

In a study by Nguyen et al, quantitative sensory testing found significant differences in the perception of vibrotactile stimulation in patients with migraine compared with controls, including stimulus amplitude discrimination, temporal order judgment, and duration discrimination.[55]

Epidemiology

In the United States, more than 30 million people have 1 or more migraine headaches per year. This corresponds to approximately 18% of females and 6% of males.[56] 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 reported incidence of migraine in females of reproductive age has increased over the last 20 years, but this change probably reflects greater awareness of the condition.)

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.[57]

Before puberty, the prevalence and incidence of migraine are higher in boys than in girls. After age 12 years, the prevalence increases in 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 after age 40 years, except for women in perimenopause. A study by Hsu et al suggests that women aged 40–50 years are also more susceptible to migrainous vertigo.[58] Onset of migraine after age 50 years is rare.

Race-related differences in prevalence

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 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.

Economic impact of migraine

The economic cost resulting from migraine-related loss of productive time in the US workforce is more than $13 billion per year, most of which is in the form of reduced work productivity. In the American Migraine Study, more than 85% of women and 82% of men with severe migraine had some headache-related disability. Migraineur men required 3.8 bed-rest days per year, whereas women required 5.6 bed-rest days per year.[59]

International statistics

The World Health Organization (WHO) estimates the worldwide prevalence of current migraine to be 10% and the lifetime prevalence to be 14%. The adjusted prevalence of migraine is highest in North America, followed by South and Central America, Europe, Asia, and Africa.[23]

Approximately 3000 migraine attacks per million persons worldwide occur every day. 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. Internationally, however, a relationship between migraine and socioeconomic status is not present.

Prognosis

Migraine is a chronic condition, but prolonged remissions are common. One study showed that among persons who had migraine during childhood, 62% were migraine free for more than 2 years during puberty and as young adults but that only 40% were still migraine free at age 30 years.[60]

The severity and frequency of migraine attacks tend to diminish with increasing age. After 15 years of suffering migraines, 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 suffered ischemic stroke, risk factors such as patent foramen ovale, female gender, and oral contraceptive use were much more likely to be present; posterior circulation stroke was characteristic. Surprisingly, older patients characteristically lacked vascular risk factors (ie, previous hypertension, ischemic heart disease, cigarette smoking).[61]

Even in patients older than 45 years, women with migraine are more likely to suffer from ischemic stroke.

Migraineurs, male and female, 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.[62]

Migraineurs also have a higher incidence of adverse cardiovascular profiles (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 women who have migraine with aura are more likely to be using oral contraceptives.[63, 64]

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 risk of coronary vascularization.[65] However, those who have 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.[66] Similarly, a study by Gudmundsson et al found that men and women who have migraine with aura are at a higher risk for cardiovascular and all-cause mortality than are those without headache.[67]

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.

For patient education information, see the Headache and Migraine Center, as well as the following:

  • Causes and Treatments of Migraine and Related Headaches

  • Migraine Headache

  • Alternative and Complementary Approaches to Migraine and Cluster Headaches

  • Migraine Headache FAQs

  • Migraine and Cluster Headache Medications

 

Presentation

History

Migraine attacks commonly occur when the migraineur is awake, although an attack may have already started by the time the individual wakes. Less commonly, it may awaken the patient at night.

The typical migraine headache 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. Most patients report feeling tired and weak after the attack.

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. Lightheadedness is frequent. See Migraine-Associated Vertigo for more information on migraine-related vestibulopathy.

Other neurologic symptoms that may be observed include the following:

  • Hemiparesis (this symptom defines hemiplegic migraine)

  • Aphasia

  • Confusion

  • Paresthesias or 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, or motor or any combination of these.

Visual symptoms

Auras most commonly consist of visual symptoms, which may be negative or positive. Negative symptoms (see the images below) include negative scotomata or negative visual phenomena, such as the following:

  • Homonymous hemianopic or quadrantic field defects

  • Central scotomas

  • Tunnel vision

  • Altitudinal visual defects

  • Complete blindness

    Migraine headache. Frank visual field loss can als 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.
    Migraine headache. Example of a central scotoma as 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 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.

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 (uniform flashes of light) or visual hallucinations, which may take various shapes (see the images below).

Migraine headache. Example of a visual migraine au 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 visual changes durin Migraine headache. Example of visual changes during migraine. Multiple spotty scotomata are described by a person who experiences migraines.

Scintillating scotoma 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."

Heat waves, fractured vision, macropsia, micropsia, and achromatopsia are other visual symptoms that may occur.

Sensory symptoms

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

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.

Course and diagnostic significance

The migrainous aura generally resolves within a few minutes and then is followed by a latent period before the onset of headache. However, some patients report merging of the aura with the headache.

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 investigated fully.

Postdromal symptoms

Postdromal symptoms may persist for 24 hours after the headache and can include the following:

  • Tired, “washed out,” or irritable feeling

  • Unusually refreshed or euphoric feeling

  • Muscle weakness or myalgias

  • Anorexia or food cravings

Migraine triggers

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

  • Hormonal changes (eg, those resulting from menstruation, ovulation, oral contraceptives, or hormone replacement)

  • Head trauma

  • Lack of exercise[46]

  • Sleep changes

  • 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.[29] Migraine headache generally shows a multifactorial inheritance pattern, but the specific nature of the genetic influence is not yet completely understood.

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 neurologic deficits (ie, complicated migraine)

  • Adie-type pupil (ie, poor light reactivity, with near dissociation to light)

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-type 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 variant 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. According to diagnostic criteria established by the International Headache Society, patients must have had at least 5 headache attacks that lasted 4–72 hours (untreated or unsuccessfully treated) and the headache must have had at least 2 of the following characteristics:[1]

  • Unilateral location

  • Pulsating quality

  • Moderate or severe pain intensity

  • Aggravation by or causing avoidance of routine physical activity (eg, walking, climbing stairs)

In addition, during the headache the patient must have had at least 1 of the following:

  • Nausea and/or vomiting

  • Photophobia and phonophobia

Finally, these features must not be attributable to another disorder. (See the chart below.)

International Headache Society criteria for migrai International Headache Society criteria for migraine without aura.

The International Headache Society defines aura as reversible focal neurologic symptoms that usually develop gradually over 5–20 minutes and last for less than 60 minutes. Headache with the features of migraine without aura usually follows the aura symptoms. Less commonly, the headache lacks migrainous features or is completely absent.

Migraine Variants

Migraine variants include the following:

  • Childhood periodic syndromes

  • Late-life migrainous accompaniments

  • Migraine with brainstem aura

  • Hemiplegic migraine

  • Status migrainosus

  • Retinal migraine

See the Medscape Reference article Childhood 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.

Migraine with brainstem aura and hemiplegic migraine

Patients with migraine with brainstem aura can present without headaches but with basilar-type symptoms, such as the following:

  • Vertigo

  • Dizziness

  • Confusion

  • Dysarthria

  • Tingling of extremities

  • Incoordination

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 and retinal migraine

Ophthalmoplegic migraine

Ophthalmoplegic migraine is characterized by transient palsies of the extraocular muscle with dilated pupils and eye pain. This migraine variant has been reclassified by the International Headache Society as a neuralgia and is thought to be caused by idiopathic inflammatory neuritis. In the acute phase, enhancement of the cisternal segment of the third cranial nerve occurs.

Retinal migraine

Rarely, patients develop retinal and optic nerve involvement during or before a migraine headache and present with visual disturbance, papilledema, and retinal hemorrhages affecting 1 eye. This variant is called retinal migraine or ocular migraine.

The International Headache Society criteria for retinal migraine[68] are at least 2 attacks of fully reversible, monocular visual phenomena, positive and/or negative (eg, scintillations, scotomata, or blindness). These are to be confirmed by examination during an attack or (after proper instruction) by the patient's drawing of a monocular field defect during an attack. In addition, migraine without aura must begin during the visual symptoms or follow them within 60 minutes.

The patient must have a normal ophthalmologic examination between attacks. Other causes of transient, monocular blindness must be excluded with appropriate investigations.

Status migrainosus and chronic migraine

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

Chronic migraine is defined as migraine headache that occurs for more than 15 days a month for greater than 3 months. Most patients with chronic migraine have a history of migraine headaches that started at 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

  • Obesity

  • Posttraumatic stress disorder

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.[69] Migraine with aura had more comorbidities than migraine without aura.

According to one study, a history of asthma may predict chronic migraine in individuals who have episodic migraine. Results show that study participants with asthma had a greater than twofold risk for progression to chronic migraine compared with those without asthma. The highest risk was found among those with the greatest number of respiratory symptoms.[70]

Complications of Migraine

Complications of migraine include the following:

  • Chronic migraine

  • Migraine-triggered seizures

  • Migrainous infarction (stroke with migraine)

  • Persistent aura (eg, 30–60 minutes) without infarction

Ischemic stroke may occur as a rare, but serious, complication of migraine.[71] In migraines with aura, hemorrhagic stroke is also a possible, but rare, complication.[72] Risk factors for stroke include the following:

  • Migraine with aura

  • Female sex

  • Cigarette smoking

  • Estrogen use

 

DDx

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

  • New progressive headache that persists for days

  • Precipitation of headache with Valsalva maneuvers (ie, coughing, sneezing, bearing down)

  • The presence of associated neurologic 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, 1-sided throbbing headaches

  • Headache accompanied by 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 headaches 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 headaches are precipitated by strenuous activity (eg, running, coughing, sneezing, Valsalva maneuver) and build in intensity over minutes. They are particularly common in patients who have an inherited susceptibility to migraine. Coital headache is a type of exertional headache that can develop at the height of orgasm or it may build up through intercourse.

Intracranial aneurysm

Despite the possibility of a benign cause, a ruptured intracranial aneurysm is the primary consideration if the headache is severe and of sudden onset and reaches maximum intensity in minutes. The classic presentation of an aneurysmal subarachnoid hemorrhage (SAH) is as follows:

  • Severe headache with sudden, explosive onset

  • Stiff neck

  • Photophobia

  • Nausea and vomiting

  • Possibly, alteration of consciousness

An extensive evaluation is indicated in such cases, including an initial computed tomography (CT) scan of the head without contrast. Lumbar puncture (LP) should be considered if the scan is negative, as 25% of cases are missed by CT scanning. Questions remain over whether an angiogram should be performed if the patient has normal findings on neurologic and cerebrospinal fluid (CSF) examination, as well as on CT scan 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-scan and CSF findings, none developed SAH.[73]

In selected cases, angiography should probably be performed if an experienced angiographer is available. Patients at risk include those whose CT scan and LP are performed late after symptom onset, so that negative results are unreliable, and patients with suggestive clinical features, such as family history or past medical history of SAH, classic SAH-like symptoms, or the presence of neurologic signs (in particular a third cranial nerve palsy affecting the pupil)

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. 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 early morning brain tumor headache occurred in only 17%. Headache was intermittent in 62%, usually lasting a few hours.[74]

All patients with headaches similar to migraine had other neurologic symptoms or abnormal signs. Of note is that 32% of the patients had a history of headache; in 36% of those patients, 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.[74]

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 neurologic 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, with the patient 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 neurologic deficit, but it must be considered in younger patients who have unilateral, severe, persistent head pain of sudden onset preceding the development of neurologic signs, most commonly Horner syndrome. This differentiates spontaneous from posttraumatic cases, in which cerebral ischemic symptoms are more common.

Other secondary causes

Other secondary causes of alarming headaches should be sought, in the proper clinical setting, in the presence of the "red flags" mentioned above. Increased ICP may result from colloid cysts, ventricular tumors (such as ependymomas), or Chiari malformations. Other features needing further diagnostic workup include positional headaches, which may result from low CSF pressure.

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 response to 5-hydroxytryptamine–1 (5-HT1) agonists (sumatriptan and related compounds) is not diagnostic of a migraine headache. Because of their ability to block expression of c-fos by their action on 5-HT1 receptors, these agents may be effective in decreasing headache pain associated with meningovascular irritation from a variety of causes, such as viral and bacterial infections and subarachnoid hemorrhage.

Differential Diagnoses

 

Workup

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

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

The development of an objective, quantitative biologic measurement of headache-pain severity could help to improve the diagnosis of migraine and enable more accurate assessments of treatment efficacy. In a study by Nguyen et al, as previously mentioned, quantitative sensory testing found significant differences in the perception of vibrotactile stimulation in patients with migraine compared with controls, including stimulus amplitude discrimination, temporal order judgment, and duration discrimination.[55]

A 2013 study suggested that high peripheral blood levels of calcitonin gene-related peptide (CGRP), a neurotransmitter that causes vasodilation, can aid in the diagnosis of chronic migraine by serving as a biomarker for permanent trigeminovascular activation. The migraine patients in the study had a CGRP level of 74.90 pg/mL, significantly higher than those in the other participants. Blood samples in the study were obtained between, rather than during, migraine attacks. Additionally, patients with chronic migraine with a history of aura had significantly higher CGRP levels than chronic migraine sufferers who had never experienced an aura.[75, 76, 77]

Tests for migraine and headache

The American Headache Society released a list of 5 commonly performed tests or procedures that are not always necessary in the treatment of migraine and headache, as part of the American Board of Internal Medicine (ABIM) Foundation’s Choosing Wisely campaign. The recommendations include:[2, 3]

  • Don't perform neuroimaging studies in patients with stable headaches that meet criteria for migraine.

  • Don't perform computed tomography (CT) imaging for headache when magnetic resonance imaging (MRI) is available, except in emergency settings.

  • Don't recommend surgical deactivation of migraine trigger points outside of a clinical trial.

  • Don't prescribe opioid or butalbital-containing medications as first-line treatment for recurrent headache disorders.

  • Don't recommend prolonged or frequent use of over-the-counter (OTC) pain medications for headache.

Insurance status and migraine care

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, the investigators found evidence that patients with migraines with no insurance or with Medicaid are less likely than privately insured patients to receive either abortive or prophylactic migraine therapy.

This difference, according to the report, is at least partially due to the fact that persons who are uninsured or on Medicaid receive more medical care in emergency departments and less treatment in physicians’ offices than do persons with private insurance, resulting in a greater frequency of substandard migraine care.[78]

Indications for 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:[79]

  • First or worst severe headache

  • Change in the pattern of previous migraine

  • Abnormal neurologic examination

  • Onset of migraine after age 50 years

  • New onset of headache in an immunocompromised patient (eg, one with cancer or HIV infection)

  • 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 (especially in children, but also in adults)

CT scanning 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 MRA are more sensitive for the detection of aneurysm or arteriovenous malformation.

Lumbar Puncture Indications

Indications for LP include the following:

  • First or worst headache of a patient's life

  • Severe, rapid-onset, recurrent headache

  • Progressive headache

  • Unresponsive, chronic, intractable headache

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

 

Treatment

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 reverse, or at least stop, the progression of 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. Overview of migraine treatment. Five steps.

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.

A neurologist, neuro-ophthalmologist, and/or neurosurgeon should be consulted as deemed clinically appropriate for the treatment of patients with migraine.

Emergency Department Considerations

Emergency medical services personnel should transport patients in a way that minimizes visual and auditory stimulation. Once in the emergency department (ED), 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 who present to the ED because of headache 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 key elements of ED care. Although narcotics remain the most frequently administered medication for patients with migraine and for ED patients with headache, evidence suggests that they are potentially ineffective, and their use may lead to more prolonged ED stays.[80, 81]

Friedman et al found 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.[82]

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.[83] 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 against migraine headaches and may be used adjunctively with pharmacologic treatments. Occipital nerve stimulators may be helpful in patients whose headaches are refractory to other forms of treatment.

In December 2013, the FDA approved the Cerena Transcranial Magnetic Stimulator (Cerena TMS), the first device to relieve pain caused by migraine headache with aura for use in patients aged 18 years and older. Users hold the device with both hands to the back of the head and press a button to release a pulse of magnetic energy that stimulates the occipital cortex. The recommended daily usage of the device is not to exceed one treatment in 24 hours.[84, 85]

Approval for the Cerena TMS was based on a randomized study of 201 patients with moderate to strong migraine headaches, in which 39% of the patients using the device were pain-free 2 hours following its use, relative to 22% of control patients (therapeutic gain: 17%).[86, 87] At 24 hours, nearly 34% of patients treated with the device were pain-free, compared with 10% of the control group.

Contraindications and precautions regarding the use of the Cerena TMS include the following:[84, 85]

  • Do not use for patients with any metal in the head, neck, or upper body that is attracted by a magnet

  • Do not use for patients with an active implanted medical device (eg, pacemaker, deep brain stimulator)

  • Do not use for patients with suspected/diagnosed epilepsy or who have a personal or family history of seizures

Trials of nonpharmacologic management have produced average reduction in migraines of 40–50%, closely paralleling results obtained in trials of preventive drugs; however, the evidence base for nonpharmacologic and pharmacologic prevention remains limited. A 16-month randomized, placebo-controlled trial by Holryod et al found that the combination of beta-blocker therapy and behavioral management improved outcomes in patients with frequent migraines, while neither intervention was effective by itself.[88]

In January 2018, the FDA approved a vagus nerve stimulator (vNS) for the treatment of migraine pain in adults. The hand-held, noninvasive device was previously approved for treating episodic cluster headache pain. The prescription-only device is placed over the vagus nerve in the neck and releases a mild electrical stimulation to the nerve's afferent fibers. Approval was based on the Prospective Study of vNS for the Acute Treatment of Migraine (PRESTO) of 243 patients with episodic migraine. Significantly more patients in the nVNS group were pain free at 30 minutes (12.7%) compared to those who received sham treatment (4.2%).[89]

Another noninvasive neuromodulation device for the relief of acute migraine pain was approved by the FDA in May 2019. The device is worn on the upper arm and uses smartphone-controlled electronic pulses to relieve migraine through conditioned pain modulation. It is approved for acute migraine with or without aura in adults who do not have chronic migraine.[90]

Abortive Therapy

Numerous abortive medications are used for migraine. The choice for an individual 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 stepped-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

 

 

DHE=Dihydroergotamine; NSAIDs=nonsteroidal anti-inflammatory drugs

Simple analgesics alone or in combination with other compounds have provided relief for mild to moderately severe headaches and sometimes even for severe headaches.[91] Acute treatment is most effective when given within 15 minutes of pain onset and when pain is mild.[92]

Analgesics used in migraine include acetaminophen, NSAIDs, and narcotic analgesics (eg, oxycodone, morphine sulfate). Propoxyphene (Darvon) was formerly used; however, propoxyphene products were withdrawn from the United States market in 2010, because this agent can cause prolonged PR interval, widened QRS complex, and prolonged QT interval at therapeutic doses. For more information, see MedWatch safety information, from the US Food and Drug Administration (FDA).

For more severe pain, 5-hydroxytryptamine–1 (5-HT1) agonists (triptans) and/or opioid analgesics are used, either alone or in combination with dopamine antagonists (eg, prochlorperazine [Compazine]). 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 or 40 mg of metoclopramide is no better in the treatment of acute migraine than 10 mg of the drug.[93]

A systematic review by Taggart et al found that ketorolac is an effective alternative agent for the relief of acute migraine headache in the ED. Ketorolac provides pain relief similar to that with meperidine (with less potential for addiction) and is more effective than sumatriptan; however, it may not be as effective as metoclopramide/phenothiazine agents. Side-effect profiles were similar with ketorolac and these other agents.[94]

Triptans and ergot alkaloids

The 2 categories of migraine-specific oral medications are triptans and ergot alkaloids. The specific ergot alkaloids include ergotamine and dihydroergotamine (DHE).[95] The specific triptans include the following[96] :

  • 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 the delivery of sumatriptan, and one such product has received FDA approval.[97] The sumatriptan iontophoretic transdermal system (Zecuity, NuPathe Inc) was approved by the FDA in January 2013 for the acute treatment of migraine with or without aura in adults. The single-use patch also treats migraine-related nausea. In phase 3 trials involving 800 patients, the patches safely and effectively relieved migraine pain, migraine-related nausea, sonophobia, and photophobia within 2 hours of activation.[97]

The FDA approved a low-dose intranasal sumatriptan powder for migraine in January 2016. The product consists of 22 mg of sumatriptan powder and is the first breath-powered intranasal medication delivery system to treat migraines. Approval was based on data from phase 2 and phase 3 trials, reference data on the use of sumatriptan, and safety data from more than 300 patients.[98, 99]

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 time frame.

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 one 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.

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 FDA in 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%) than after use of placebo (8% and 7%) or either sumatriptan (16% and 14%) or naproxen sodium (10%) alone.[100]

Patients with severe headaches need subcutaneous, intravenous, or oral formulations of an ergot alkaloid or triptan. 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.

Treatment of nausea and vomiting

Antiemetics (eg, chlorperazine, promethazine) are used to treat the emesis associated with acute migraine attacks. 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.

Antiemetics 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.[101]

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 patient’s 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 neurologic injury[5]

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 gamma-aminobutyric acid-ergic (GABAergic) inhibition - Valproic acid, gabapentin

  • Prevention of acetylcholine from presynaptic membrane – Botulinum toxin

  • Calcitonin gene-related peptide (CGRP) inhibitors – Erenumab, fremanezumab, galcanezumab

Another notable mechanism is alteration of neuronal oxidative metabolism by riboflavin and reduction of neuronal hyperexcitability by magnesium replacement.

As with abortive medications, the selection of a preventive medication must take into consideration comorbid conditions and the side-effect profile (see Tables 2 and 3, below). Most preventive medications have modest efficacies and have therapeutic gains of less than 50% when compared with 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.

Table 2. Preventive Drugs for Migraine (Open Table in a new window)

First line

High efficacy

Beta blockers

Tricyclic antidepressants

Divalproex

Topiramate

Low efficacy

Verapamil

Second line

 

High efficacy

Methysergide

Flunarizine

MAOIs

CGRP inhibitors

Botulinum toxin

 

Unproven efficacy

Cyproheptadine

Gabapentin

MAOIs = monoamine oxidase inhibitors

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

Overweight

Topiramate, protriptyline

Underweight

Tricyclic antidepressants (nortriptyline, protriptyline)

Epilepsy

Valproic acid, topiramate

Mania

Valproic acid

SSRIs = selective serotonin reuptake inhibitors

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.[102]

Misra et al reported that in migraineurs with allodynia, prophylactic therapy with divalproex and amitriptyline were equally effective in relieving allodynia. In study patients, the presence of allodynia was related to the duration, severity, and frequency of migraine and to female gender.[103]

The NSAID naproxen sodium has also been used for prophylaxis. In controlled clinical trials, naproxen sodium demonstrated better efficacy than placebo and similar efficacy to propranolol. However, this agent should be reserved for short-term use, such as for menstrual migraines.[104] Tolfenamic acid has also been tried for migraine prophylaxis, but its clinical efficacy is not as good as that of beta blockers, valproate, or methysergide.

Of note, an open pilot study reported 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 would be necessary to confirm their observations.[105]

Classes of prophylactic drugs

The classes of medications that are effective for migraine prevention include:

  • Antiepileptics

  • Antidepressants

  • Antihypertensives

  • Botulinum toxin

  • Calcitonin gene-related peptide (CGRP) inhibitors

Antiepileptics, antidepressants, and antihypertensives may be considered initially since they are more affordable. For any of these initial prophylactic agents, prophylaxis should not be considered a failure until it has been given at the maximum tolerable dose for at least 30 days.

Antiepileptics

Antiepileptics are generally well tolerated. The main adverse effects of topiramate are weight loss and dysesthesia.[106] 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,[107] lamotrigine, oxcarbazepine) are limited in migraine.

Topiramate is approved in the U.S. for migraine prophylaxis in adults and adolescents aged 12 years or older. The safety and effectiveness of topiramate in preventing migraine headaches in adolescents were established in a clinical trial of 103 participants. Frequency of migraine decreased by approximately 72% in treated patients, compared with 44% in participants receiving placebo.[108, 109]

Antidepressants

Tricyclic antidepressants are good second-line alternatives because of their adverse-effect profile and efficacy. Head-to-head comparisons of agents in this class have not been conducted, but amitriptyline and nortriptyline are commonly used.

Although selective serotonin reuptake inhibitors (SSRIs) are widely used, data regarding their efficacy in migraine prevention are lacking; consequently, SSRIs are not recommended for migraine prevention. However, limited data do support the use of serotonin/norepinephrine reuptake inhibitors (SNRIs) such as duloxetine (Cymbalta) and venlafaxine (Effexor) for migraine prevention.

Antihypertensives

Antihypertensives such as beta blockers should be tailored if the patient is young and anxious. Moreover, 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. Angiotensin-converting enzyme (ACE) inhibitors (eg, lisinopril) and angiotensin-receptor blockers (eg, candesartan)[110] have also been shown to be effective for migraine prevention.[111]

Botulinum toxin

Botulinum toxin A (onabotulinumtoxinA; BOTOX®) may be beneficial in patients with intractable, chronic migraine that has failed to respond to at least 3 conventional preventive medications. 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.[112] A review by Schulte-Mattler and Martinez-Castrillo found no evidence of a beneficial effect from botulinum toxin. These authors do not recommend the widespread use of botulinum toxin therapy in headaches.[113]

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.[114]

In 2016, the American Academy of Neurology updated its 2008 guidelines on using botulinum toxin for brain disorders. Botulinum toxin A is now recommended for the management of chronic migraine, defined as attacks lasting 4 or more hours on at least 15 days each month for 3 months. Botulinum toxin A is not recommended for less frequent, "episodic" migraine.[115]

Calcitonin gene-related peptide inhibitors

Inhibiting the calcitonin gene-related peptide (CGRP) pathway is a new method to prevent migraines. CGRP is a potent vasodilator and is a key neuropeptide that is central to migraine pathophysiology. CGRP concentrations decrease following administration of triptans when treating a migraine attack. Three monoclonal antibodies that bind to the CGRP receptor were approved in the United States in 2018 (ie, erenumab, fremanezumab, galcanezumab).

The first CGRP inhibitor approved by the FDA for migraine prophylaxis was erenumab (Aimovig) in May 2018. Approval was based on findings from the LIBERTY, ARISE, and STRIVE clinical trials.[116, 117, 118]

The LIBERTY trial studied difficult-to-treat patients (n=246) with episodic migraine who had failed 2 to 4 previous treatment. Patients treated with erenumab 140 mg had about a 3-fold higher odds of having their migraine days cut by half or more compared with placebo.[116]

In the ARISE trial, 577 adults with episodic migraine were randomized to placebo or 70 mg erenumab (570 were included in efficacy analysis). Patients receiving erenumab experienced -2.9 days change in monthly migraine days, compared with -1.8 days for placebo (p < 0.001). A ≥50% reduction in monthly migraine days was achieved by 39.7% (erenumab) and 29.5% (placebo) of (p = 0.010). Migraine-specific medication treatment days were reduced by -1.2 (erenumab) and -0.6 (placebo) days, a treatment difference of -0.6 (p = 0.002).[117]

The STRIVE clinical trial compared erenumab doses of 70-mg (n=317) or 140-mg (n=319) to placebo (n=319). The mean number of migraine days per month at baseline was 8.3 in the overall population; by months 4 through 6, the number of days was reduced by 3.2 in the 70-mg erenumab group and by 3.7 in the 140-mg erenumab group, as compared with 1.8 days in the placebo group (P< 0.001 for each dose vs. placebo).[118]

Two additional CGRP inhibitors, fremanezumab (Ajovy) and galcanezumab (Emgality), were approved in September 2018.

Approval of fremanezumab was based on the HALO study. Fremanezumab was administered monthly or quarterly and compared with matching placebo. The percentage of patients with a reduction of at least 50% in the average number of headache days per month was 38% in the fremanezumab-quarterly group, 41% in the fremanezumab-monthly group, and 18% in the placebo group (P< 0.001 for both comparisons with placebo).[119]

Galcanezumab’s approval was based on the EVOLVE clinical trials. Mean monthly migraine headache days were reduced by 4.3-4.7 and 4.2-4.6 days by galcanezumab 120 and 240 mg, respectively, and 2.3-2.8 days by placebo (both P < 0.001).[120, 121]

Devices

In March 2014, the FDA approved the first device for the preventive treatment of migraine headaches for adults, a transcutaneous electrical nerve stimulation (TENS) device that is worn for 20 minutes a day. The device fits across the forehead and over the ears and stimulates the trigeminal nerve with a self-adhesive electrode in the center of the forehead. Approval was based on a study of 67 migraine patients in which the device reduced the number of migraine days per month and medication use, and on a patient satisfaction study of 2313 device users, in which more than 53% of patients were satisfied with the device.[122]

Walling et al looked into developing a non-invasive treatment for medically refractory chronic migraine. Their work has shown some evidence that pulsed focused ultrasound in a rodent headache model of cutaneous allodynia may provide therapeutic option for patients suffering from chronic migraines.[123]

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), that is, 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.[124]

Treatment of Menstrual Migraine

Abortive therapy for menstrual migraine is the same as for nonmenstrual migraine. Patients with frequent and severe attacks may benefit from short-term, perimenstrual use of preventive agents (eg, frovatriptan[125] ). Patients with menstrual and nonmenstrual migraine who are receiving continuous preventive therapy and experiencing breakthrough menstrual migraine headaches may benefit from perimenstrual elevation of the dose of the preventive medication.

Patients who do not respond to standard preventive measures may benefit from hormonal therapy. Perimenstrual estrogen supplementation with estradiol (0.5 mg orally twice a day, or a 1-mg transdermal patch) may be beneficial. A study by De Leo et al of oral contraceptive use in women with menstrual migraine without aura found that a regimen of 24 ethinyl estradiol/drospirenone pills and 4 inert pills was more effective than a regimen of 21 active pills and 7 inert pills.[126]

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.[127] 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.

Good studies have demonstrated the effectiveness of the herb butterbur (Petasites hybridus) in preventing migraines.[128] A guideline from the American Academy of Neurology and the American Headache Society (AAN/AHS) recommends offering butterbur to patients with migraine to reduce the frequency and severity of migraine attacks (level A recommendation).[104] Patients on butterbur require monitoring of liver enzymes.

The AAN/AHS found moderate evidence of effectiveness for riboflavin (vitamin B2), magnesium, and feverfew. A 3-month, randomized, controlled trial of high-dose riboflavin (400 mg) found that riboflavin was superior to placebo in reducing attack frequency and headache days.[129]

A randomized, controlled trial of coenzyme Q10 (CoQ10) documented that CoQ10 is effective and well tolerated for migraine prophylaxis.[130] Results of a trial in children and adolescents suggested that prophylaxis with CoQ10 may lead to earlier improvement in headache severity than does placebo-based prophylaxis, but the trial found no long-term difference in headache outcomes between the CoQ10 and placebo groups.[131]

Melatonin has also been used for migraine prevention. Alstadhaug et al conducted a randomized, controlled, 8-week trial of prolonged-release melatonin (2 mg 1 hour before bedtime) in adult patients experiencing 2-7 migraine attacks per month. Although the investigators found that in the melatonin group the average attack frequency fell from 4.2 to 2.8 per month, this result was not significantly superior statistically to the reduction seen with placebo.[125]

A variety of other CAM techniques are not bolstered by solid scientific data, but they may be perceived to be of benefit to patients.[132] Techniques that some patients use for headache relief include the following:

  • Body work - Eg, chiropractic, massage, and craniosacral therapy[133] )

  • Nutritional/herbal supplements - Eg, vitamins and herbs

  • Yoga[134]

  • Acupressure and acupuncture[135]

  • Biofeedback[136, 137]

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.[138]

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 include the lack of standardization of either the practice or the dispensing of the therapies and techniques. In addition, for many of these modalities, no standard format exists to ensure that practitioners are adequately trained in the techniques they use.

Surgical Care

Surgical therapy for migraine is highly controversial. In a study of 60 patients, Dirnberger and Becker reported that corrugator muscle resection produced total relief of migraine in 28.3% of patients, essential improvement in 40%, and minimal or no change in 31.7%. The more severe their migraine, however, the less likely patients were to experience improvement. In addition, 11 patients who had a very favorable short-term response experienced a gradual return of their headaches to preoperative intensity within about 4 weeks postoperatively.[139]

Diet

The significance of diet as a migraine trigger is controversial.[140] Nevertheless, individual patients often can identify these triggers. Common dietary triggers include the following:

  • Alcohol - Particularly wine and beer

  • Caffeine overuse or caffeine withdrawal

  • Chocolate

  • Aspartame - eg, NutraSweet and Equal

  • Monosodium glutamate (MSG) - May be found in Asian food, canned soup, frozen or processed foods, and the seasoning product Accent

  • Fruits - Citrus fruits, bananas, avocados, and dried fruit

  • Nuts - Peanuts, soy nuts, and soy sauce

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

  • Dairy - Aged cheese

  • Meat - Bacon, sausage, luncheon meat, deli meat, pepperoni, and 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 the aforementioned vitamin B2, CoQ-10, magnesium, and butterbur (Petadolex).[141]

Activity

One study of exercise for migraine prevention (40 minutes 3 times weekly for 3 months) reported a mean attack reduction of 0.93 during the final month of treatment, which was not significantly different from the reductions achieved in the control groups using topiramate or a relaxation program.[142] However, most studies of aerobic exercise in migraine patients have not found a significant reduction of headache attacks or headache duration, although regular exercise has been shown to reduce pain intensity in many patients.[143]

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.[144] In a randomized, double-blind, placebo-controlled crossover trial, preventive therapy with tonabersat reduced the frequency of aura attacks with or without headache but had no efficacy on non-aura attacks.[15]

The pipeline of future compounds for the treatment of acute migraine headaches also includes the following medications:

  • Transient receptor potential vanilloid type 1 antagonists

  • Prostaglandin E receptor 4 receptor antagonists

  • Serotonin 5HT1(F) receptor agonists

  • Nitric oxide synthase inhibitors

The immediate future of preventive treatment for migraine headaches will likely involve glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonists and gap-junction blockers.[145]

It is worth mentioning here that so far there is insufficient evidence to support the use of intranasal lidocaine in acute management of primary headaches and requires further research.[146]

 

Guidelines

US Headache Consortium

Pharmacologic treatment for episodic migraine prevention in adults

According to guidelines released by the American Academy of Neurology and the American Headache Society,[147] the following medications are established as effective and should be offered for migraine prevention (level A recommendation):

  • Antiepileptic drugs (AEDs): divalproex sodium, sodium valproate, topiramate

  • β-Blockers: metoprolol, propranolol, timolol

  • Triptans: frovatriptan for short-term MAMs prevention

The following medications are probably effective and should be considered for migraine prevention (level B recommendation):

  • Antidepressants: amitriptyline, venlafaxine

  • β-Blockers: atenolol, nadolol

  • Triptans: naratriptan, zolmitriptan for short-term MAMs prevention

The following medications are possibly effective and may be considered for migraine prevention (level C recommendation):

  • ACE inhibitors: lisinopril

  • Angiotensin receptor blockers: candesartan

  • α-Agonists: clonidine, guanfacine

  • AEDs: carbamazepine

  • β-Blockers: nebivolol, pindolol

NSAIDs and other complementary treatments for episodic migraine prevention in adults

The American Academy of Neurology and the American Headache Society also released guidelines regarding the use of NSAIDs and complementary treatments in preventing episodic migraine.[148]

The following therapy is established as effective and should be offered for migraine prevention (level A recommendation):

  • Petasites (butterbur)

The following therapies are probably effective and should be considered for migraine prevention (level B recommendation):

  • NSAIDS: fenoprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium

  • Herbal therapies, vitamins, and minerals: riboflavin, magnesium, MIG-99 (feverfew)

  • Histamines: histamine SC

The following therapies are possibly effective and may be considered for migraine prevention (level C recommendation):

  • NSAIDs: flurbiprofen, mefenamic acid

  • Herbal therapies, vitamins, and minerals: Co-Q10, estrogen

  • Antihistamines: cyproheptadine

American Headache Society

Emergency department treatment

In 2016, the American Headache Society (AHS) released guidelines for the management of adults with acute migraine in the emergency department. They recommend intravenous metoclopramide, intravenous prochlorperazine, and subcutaneous sumatriptan to treat these patients (level B recommendation). Dexamethasone should be offered to these patients to prevent recurrence of headache (level B). Opioids (injectable morphine and hydromorphone) should be avoided.[149, 150]

Preventive and acute treatment

An updated position statement from AHS in 2019 offers guidance on preventive and acute treatment of migraine.[151, 152] Recommendations include:

Preventive migraine treatment

Consider preventive treatment for migraine patients in any of the following situations:

  • Migraine attacks are frequent (≥4 migraine headache days per month) and/or the attacks interfere with patients’ daily routines even with acute treatment
  • There is contradiction to, failure, or overuse of acute treatments
  • Acute treatments lead to adverse events

Oral treatments should be offered for migraine prevention. These include antiepileptic drugs, beta-blockers, and frovatriptan. Do not prescribe valproate sodium and topiramate to women who are not using birth control and who may become pregnant.

Start oral treatments at a low dose and titrate slowly.

Give oral treatments for at least 8 weeks to optimize therapeutic response.

Acute migraine treatment

Use evidence-based treatment at the first sign of a migraine attack.

Use NSAIDs (including aspirin), nonopioid analgesics, acetaminophen, or caffeinated analgesic combinations for mild‐to‐moderate attacks and migraine‐specific agents (triptans, dihydroergotamine) for moderate or severe attacks and mild‐to‐moderate attacks that respond poorly to NSAIDs or caffeinated combinations. 

Use a nonoral option for select patients, including those with nausea or vomiting or those who have trouble swallowing.

Options for outpatient rescue include SC sumatriptan, DHE injection or intranasal spray, or corticosteroids. Inpatient options may include parenteral formulations of triptans, DHE, antiemetics, NSAIDs, anticonvulsants (eg, valproate sodium and topiramate, except in women of childbearing age who are not using reliable birth control), corticosteroids, and magnesium sulfate.

 

Medication

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

  • Calcitonin gene-related peptide (CGRP) inhibitors

Serotonin 5-HT-Receptor Agonists

Class Summary

Triptans are used as abortive medications for moderately severe to severe migraine headaches. These drugs 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. The first combination product of a triptan and an NSAID was approved by the US Food and Drug Administration in April 2008.

The most common side effects of triptans are as follows:

- Asthenia

- Nausea/vomiting

- Dizziness

- Somnolence

- Chest, throat, or jaw tightness/discomfort

- Worsening of head pain (often transient)

Drug interactions occur with potent CYP450 3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir), which may increase toxicity, and with concurrent administration of ergot-containing drugs, which may increase vasospastic reactions. Zolmitriptan, eletriptan, and naratriptan are primarily metabolized by CYP450 3A4.

Sumatriptan (Imitrex, Sumavel DosePro, Alsuma, Onzetra, Sumavel, Zeculty, Zembrace

Sumatriptan has the most options for drug delivery. It is available in intranasal, subcutaneous, and oral formulations. The efficacy of sumatriptan is 82% at 20 minutes when administered by injection, 52-62% at 2 hours when administered intranasally, and 67-79% at 4 hours when administered orally.[132, 133, 134]

Naratriptan (Amerge)

A selective agonist for serotonin 5-HT1 receptors, naratriptan has higher bioavailability and a longer half-life than sumatriptan, which may contribute to a lower rate of headache recurrences. Naratriptan has a slow onset of action and 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 hours of treatment and maintained for up to 24 hours in 49-67% of patients. Naratriptan is one of the few triptans that is not contraindicated for use in combination with monoamine oxidase inhibitors (MAOIs).

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 an efficacy of 62% at 2 hours and of 75-78% within 4 hours.

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 a reported early onset of action (30 min) and an efficacy of 71% at 2 hours. It has the fastest onset of action of the triptans.

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, inhibits neuropeptide release, and reduces pain transmission in trigeminal pathways.

Frovatriptan (Frova)

Frovatriptan is a selective 5-HT1B/1D receptor agonist with a long half-life (26-30 h) and a low headache recurrence rate within 24 hours of taking the drug. It constricts cranial vessels, inhibits neuropeptide release, and reduces pain transmission in trigeminal pathways. Frovatriptan is one of the few triptans that is not contraindicated for use in combination with MAOIs.

Eletriptan (Relpax)

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

Eletriptan is primarily metabolized by CYP3A4 and should not be used within at least 72 hours of potent CYP3A4 inhibitors. Eletriptan is one of the few triptans that is not contraindicated for use in combination with MAOIs.

Sumatriptan and naproxen (Treximet)

This is a combination product containing sumatriptan, a selective 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 the activity of cyclo-oxygenase (COX), thereby interrupting prostaglandin synthesis.

Sumatriptan intranasal (Imitrex Intranasal, Onzetra Xsail)

Selective 5-HT1 receptor agonist in cranial arteries. Elicits vasoconstrictive and anti-inflammatory effects, It is associated with antidromic neuronal transmission and relief of migraine headache. It is indicated for treatment of acute attack of migraine headache with or without aura. Available as a liquid nasal spray or a dry powder administered using the Xsail breath-powered delivery device.

Sumatriptan transdermal (Zecuity)

Indicated for treatment of acute migraine attack with or without aura. Delivered as a transdermal patch along with iontophoresis.

Ergot Derivatives

Class Summary

Ergot derivatives 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.

Ergotamine tartrate (Ergomar)

Ergotamine counteracts episodic dilation of extracranial arteries and arterioles. It has partial agonist and/or antagonist activity against tryptaminergic, dopaminergic, and alpha-adrenergic receptors. Ergotamine causes constriction of peripheral and cranial blood vessels. The drug is available in a sublingual dosage form.

Dihydroergotamine (DHE-45, Migranal)

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 of the 5HT1 system; it also binds to dopamine. Thus, dihydroergotamine 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 intravenous, intramuscular, subcutaneous, and intranasal preparations. The intravenous 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, Other

Class Summary

These agents are used for initial abortive therapy for patients with infrequent migraines. They can be used in combination with NSAIDs to alleviate headaches. Many oral analgesics, including acetaminophen, are not recommended for patients who require frequent medication, because they have been associated with rebound headaches.

Acetaminophen (Tylenol, FeverAll, Mapap, Acephen, Aspirin Free Anacin Extra Strength, Cetafen Extra, Little Fevers, Non-Aspirin-Pain Reliever, Nortemp Children's, Ofirmev, Pain & Fever Children's, Pain Eze, Pharbetol Extra Strength, Q-pap, Silapap, Triaminic Children's Fever Reducer Pain Reliever, Valorin)

A potent analgesic and antipyretic activity with weak anti-inflammatory activity, acetaminophen is used to treat mild to moderate pain from migraine.

Opioid Analgesics

Class Summary

Patients who not respond to routine abortive treatment may require additional analgesics. Practice guidelines recommend nonopioid medications as first-line therapy. Opioid analgesics should be used sparingly, but they remain an option.[4] Opioids should not be used long-term, because they are habit-forming. Also, they can contribute to rebound headaches. A review of opioid equivalents and conversions may be found in the following reference article:  http://emedicine.medscape.com/article/2138678-overview

Oxycodone (OxyContin, Roxicodone, Oxecta, Oxaydo, Xtampza ER)

Oxycodone is an opioid 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. It can be used as adjunctive therapy when patients do not respond to abortive treatment for migraines. It is habit-forming and should not be used long-term.

Morphine (Arymo ER, Astramorph, Depodur, MS Contin, Duramorph, Avinza, Infumorph, Kadian, MorphaBond)

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 intravenously may be dosed in a number of ways and is commonly titrated until the desired effect is obtained. However, the use of morphine for aborting migraine should be very limited; it can be tried as adjunctive therapy when patients do not respond to first-line abortive treatment for migraines. It is habit-forming and should not be used long-term. Arymo ER is a morphine sulfate abuse-deterrent formulation.

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.

Hydromorphone (Dilaudid, Dilaudid-HP, Exalgo)

Hydromorphone is a potent semisynthetic opiate agonist similar in structure to morphine. It is approximately 7-8 times as potent as morphine on a milligram-to-milligram basis, with a shorter or similar duration of action. It can be used as adjunctive therapy when patients do not respond to abortive treatment for migraines. It is habit-forming and should not be used long-term.

NSAIDs

Class Summary

NSAIDs inhibit 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 they are used as abortive medications.

Aspirin (Bayer Aspirin, Bufferin, Ecotrin, Ascriptin, Halfprin, Aspercin, Aspir-low, Aspirtab, Buffinol, Durlaza, St. Joseph Adult Aspirin, Tri-Buffered Aspirin)

Aspirin is a mild analgesic that can be used to treat infrequent migraine episodes.

Ketorolac intranasal (Sprix)

Ketorolac is indicated for short-term (up to 5 days) management of moderate to moderately severe acute pain requiring analgesia at the opioid level. The bioavailability of a 31.5-mg intranasal dose (2 sprays) is approximately 60% of the 30-mg intramuscular dose. Intranasal spray delivers 15.75 mg per 100-µL spray; each 1.7-g bottle contains 8 sprays. Onset of analgesia is within 20 minutes, and time to peak is 0.5-0.75 hours.

Ibuprofen (Motrin, Advil, Neoprofen, Caldolor, Addaprin, EnovaRx-Ibuprofen, Goodsense Ibuprofen Children's, I-Prin, IBU-200, Ibuprofen Comfort Pac, NeoProfen, Provil))

Ibuprofen is used for the 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 COX, resulting in prostaglandin synthesis.

Naproxen (Naprosyn, Naprelan, Anaprox, Aleve, Midol Extended Relief, All Day Relief, Anaprox, EC-Naprosyn, EnovaRX-Naproxen, Equipto-Naproxen, Flanax Pain Relief, GoodSense Naproxen Sodium, Mediproxen, Naprelan, Naproderm,)

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 cyclo-oxygenase, resulting in prostaglandin synthesis.

Ketoprofen (Active-Ketoprofen, Ketophene Rapidpaq)

Ketoprofen reversibly inhibits COX-1 and COX-2 enzymes. It is indicated for mild to moderate pain. Administer small dosages initially to patients with small body size, elderly patients, and patients with renal or liver disease. Doses above 75 mg do not have increased therapeutic effects. Administer high doses with caution, and closely observe the patient for response.

Analgesics, Opioid Combos

Class Summary

Acetaminophen is often used as abortive therapy for migraines. The combination of acetaminophen and codeine is indicated for the relief of mild to moderate pain.

Codeine/acetaminophen (Tylenol #3, Tylenol #4, Tylenol with Codeine)

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

Analgesics, Other Combos

Class Summary

A combination drug containing isometheptene, dichloralphenazone, and acetaminophen is FDA approved for the relief of migraines and tension headaches.

Isometheptene, dichloralphenazone, and acetaminophen (Midrin, Epidrin)

This combination drug has sympathomimetic properties. Isometheptene, in particular, dilates cranial and cerebral arterioles, causing a reduction in the stimuli that lead to vascular headaches. Dichloralphenazone has sedative and analgesic properties. Acetaminophen inhibits the synthesis of prostaglandins in the central nervous system (CNS) and blocks pain impulses generated in the periphery.

Analgesics, Barbiturates Combos

Class Summary

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 may worsen headache symptoms.

Butalbital, aspirin, and caffeine (Fiorinal)

This combination drug is effective for mild to moderately severe migraine headache. The barbiturate component has a generalized depressant effect on the 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 may worsen headache symptoms.

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 the 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 may worsen headache symptoms.

Antipsychotics, Phenothiazine

Class Summary

Chlorpromazine can be used as monotherapy for acute migraine headaches.

Chlorpromazine (Thorazine)

The mechanisms of chlorpromazine include blocking postsynaptic mesolimbic dopamine receptors, anticholinergic effects, and depression of the reticular activating system. The drug blocks alpha-adrenergic receptors and depresses the release of hypophyseal and hypothalamic hormones. As a rule, dopamine antagonists are avoided in patients with traumatic brain injury.

Antiemetic Agents

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.

Antiemetic 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 administered intravenously to emergency department patients.[113]

Prochlorperazine (Compro, Compazine)

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.

Anticonvulsants

Class Summary

These drugs can be effective in prophylaxis of migraine headache.

Valproic acid (Depakote, Depacon, Depakene, Stavzor)

Valproic acid reduces the frequency of migraines. This agent is believed to enhance gamma-aminobutyric acid (GABA) neurotransmission, which may suppress events related to migraine that occur in the cortex, perivascular sympathetics, or trigeminal nucleus caudalis. Divalproex has been shown to reduce migraine frequency by 50%.

Topiramate (Topamax, Qudexy XR, Topiragen, Trokendi XR)

Topiramate is indicated for migraine headache prophylaxis in adults and adolescents aged 12 years or older. Its precise mechanism of action is unknown, but the following properties may contribute to its efficacy:

• Blockage of voltage-dependent sodium channels

• Augmentation of activity of the neurotransmitter GABA at some GABA-A receptor subtypes

• Antagonization of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate subtype of the glutamate receptor

• Inhibition of carbonic anhydrase, particularly isozymes II and IV

Antihistamines, 1st Generation

Class Summary

Agents in this class with potent serotonin antagonist activity have been reported to be effective in the treatment of migraine.

Promethazine (Phenergan, Phenadoz, Promethagan)

Promethazine is a phenothiazine derivative that possesses antihistaminic, sedative, anti ̶ motion-sickness, antiemetic, and anticholinergic effects. It is commonly used in children older than 2 years.

Beta Blockers, Beta-1 Selective

Class Summary

Among antihypertensive medications, the evidence for migraine prevention is strongest with beta blockers. 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.

Beta blockers should not be used as first-line agents for migraine prophylaxis in smokers over age 60 years. Compared with other antihypertensive medications, beta blockers pose a higher risk of cardiovascular events.

Propranolol (Inderal, Inderal LA, Hemangeol, InnoPran XL)

Propranolol is FDA approved for migraine prevention. The dose may be increased gradually to achieve optimum migraine prophylaxis. The long-acting form can be taken once daily.

Timolol (Apo-Timol, Nu-Timolol, Teva-Timolol)

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

Tricyclic Antidepressants

Class Summary

Amitriptyline, nortriptyline, doxepin, and protriptyline have been used for migraine prophylaxis, but only amitriptyline has proven efficacy. It appears to exert its antimigraine effect independent of its effect on depression.

Amitriptyline (Elavil)

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

Nortriptyline (Pamelor)

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

Doxepin (Silenor)

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

Protriptyline (Vivactil)

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

Calcium Channel Blockers

Class Summary

Calcium channel blockers are commonly used as prophylactic medication for migraine, 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 class of drugs is particularly useful in patients with comorbid hypertension and in those with contraindications to beta blockers, such as asthma and Raynaud disease. Calcium channel blockers may have particular advantage in patients with prolonged aura, basilar-type migraine, or hemiplegic migraine.

Calcium channel blockers are considered second-line agents for patients with chronic migraines. Tolerance can develop with these drugs but can be overcome by increasing the dose or switching to another calcium channel blocker.

Verapamil (Calan, Isoptin SR, Verelan)

Verapamil inhibits calcium ions from entering slow channels or voltage-sensitive areas of vascular smooth muscle during depolarization. Verapamil has an off-label indication for migraines. The drug is frequently the first choice for prophylactic therapy because of ease of use and a favorable side-effect profile. Patients may report an initial increase in headaches, with improvement after weeks of treatment.

Antidepressants, SSRIs

Class Summary

SSRIs have limited efficacy for migraine prophylaxis in adults. Due to a lack of clinical studies, they are not recommended for this purpose in children.

Paroxetine (Paxil, Paxil CR, Pexeva, Brisdelle)

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

Fluoxetine (Prozac, Prozac Weekly, Sarafem)

Fluoxetine is a second-line agent for patients with chronic migraines. It is an atypical, nontricyclic antidepressant with potent, specific inhibition of 5-HT uptake and with fewer anticholinergic and cardiovascular side effects than tricyclic antidepressants have.

Sertraline (Zoloft)

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

CGRP Monoclonal Antibodies

Class Summary

Calcitonin gene-related peptide (CGRP) is a potent vasodilator and is a key neuropeptide that is central to migraine pathophysiology.

Erenumab (Aimovig)

Human monoclonal antibody. Binds to the calcitonin gene-related peptide (CGRP) receptor, which is thought to be causally involved in migraine pathophysiology. It is indicated for preventive treatment of migraines in adults.

Fremanezumab (Ajovy, fremanezumab-vfrm)

Human monoclonal antibody against human calcitonin gene-related peptide (CGRP), which may be causally involved in the pathophysiology of migraines. Fremanezumab in indicated for migraine prophylaxis.

Galcanezumab (Emgality, galcanezumab-gnlm)

Monoclonal antibody that targets CGRP. Inhibition of CGRP interrupts migraine pathway. It is indicated for preventive treatment of migraine.

Neuromuscular Blocker, Botulinum Toxins

Class Summary

Injections of botulinum toxin A may be beneficial in patients with intractable migraine headaches that fail to respond to at least 3 conventional preventive medications. This agent is not recommended for use in the preventive treatment of episodic migraines.

OnabotulinumtoxinA (Botox)

One of several toxins produced by Clostridium botulinum, onabotulinumtoxinA blocks neuromuscular transmission. Injections of the drug, which are administered to the scalp and temple, may reduce the frequency and severity of migraine attacks after 2-3 months of injections. This agent is FDA approved for the prophylaxis of chronic migraine headaches.

 

Questions & Answers

Overview

What is migraine headache?

What are the signs and symptoms of migraine headache?

What are some features of migraine aura?

Which physical findings are characteristic of migraine headache?

What are the International Headache Society diagnostic criteria for migraine headache?

What are the classifications of migraine headache?

What are some migraine variants?

What is the role of lab and imaging studies in the diagnosis of migraine headaches?

Which common management practices for migraine headache were deemed unnecessary by the American Headache Society as part of the American Board of Internal Medicine (ABIM) Foundation&#39;s Choosing Wisely campaign?

Which types of pharmacologic agents are used in the treatment of migraine headaches?

What are acute (abortive) medications used to treat migraine headache?

When is prophylactic therapy indicated for migraine headache?

Which prophylactic medications are used for migraine headache?

Which nonpharmacological treatments may be used for migraine headache?

What is migraine headache?

What is the origin of the term migraine?

What are the causes of migraine headache?

How is migraine headache characterized?

How is migraine headache diagnosed?

What are the treatment options for migraine headache?

How are migraine headaches classified?

What are the International Headache Society criteria for diagnosing a migraine headache?

What changes were made to the International Classification of Headache Disorders for migraine headache in 2018?

Where can guidelines for the diagnosis, treatment, and prevention of migraine headaches be found?

What is the migraine center theory of migraine headache pathogenesis?

What is the vascular theory of migraine headache pathophysiology?

What are limitations of the vascular theory of migraine headache pathophysiology?

What is the neurovascular theory for migraine headache pathophysiology?

What is the role of cortical spreading depression (CSD) in the pathogenesis of migraine headache with aura?

What is the role of oligemia in the pathogenesis of migraine headache?

What is the role of the trigeminovascular system in the pathogenesis of migraine headaches?

What is the role of metalloproteinases in the pathogenesis of migraine headache?

What is the role of hypoxia in the pathogenesis of migraine headaches?

What are the neurogenic aspects of migraine headache pathogenesis?

What is the role of brainstem activation in the pathogenesis of migraine headaches?

What is the role of cutaneous allodynia in the pathogenesis of migraine headache?

Why is the dopaminergic theory of migraine headache pathogenesis?

What is the role of magnesium deficiency in the pathogenesis of migraine headache?

What is the role of endothelial dysfunction in the pathogenesis of migraine headache?

What is the role of serotonin in the pathogenesis of migraine headache?

What are the predisposing vascular risk factors for migraine headache?

How does medication overuse affect migraine headache?

What are the genetics factors in the etiology of migraine headache?

What is familial hemiplegic migraine (FHM)?

What is the genetic cause of familial hemiplegic migraine (FHM) type 1?

What is the genetic cause of familial hemiplegic migraine (FHM) type 2?

What is the genetic cause of familial hemiplegic migraine (FHM) type 3?

Which genetic disorders are associated with migraine headaches?

What is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)?

How are migraine headaches caused by genetic vasculopathies?

What are migraine headache precipitants?

Which foods are precipitants of migraine headache?

What are the vascular risks associated with migraine headache?

What is the role of iron in the etiology of migraine headache?

What is the association between migraine headache and sensory perception deficits?

What is the prevalence of migraine headache in the US?

How does the prevalence of migraine headache vary by sex and age?

How does the prevalence of migraine headache vary by race?

What is the economic impact of migraine headache in the US?

What is the global prevalence of migraine headache?

What is the relationship between socioeconomic status and migraine headache prevalence?

What is the prognosis of migraine headache?

What are the risk factors for stroke in patients with migraine headache?

Which factors increase the risk of vascular diseases in patients with migraine headache?

Where can patients go to learn more about migraine headache?

Presentation

What are the typical characteristics of migraine headache?

What are the signs and symptoms of migraine headache?

What are prodromal symptoms of migraine headache?

What is migraine headache aura?

What are the negative visual symptoms of migraine headache aura?

What are the positive visual symptoms of migraine headache aura?

What are symptoms of migraine headache sensory aura?

What are motor symptoms of migraine headache?

What is the course and significance of the aura in migraine headache?

What are the postdromal symptoms of migraine headache?

What are migraine headache triggers?

How much does a family history increase the risk of migraine headache?

How is disability assessed in patients with migraine headache?

Which findings on neurological exam suggest migraine headache?

How is a non-migraine headache differentiated from migraine during the physical exam?

Which physical findings suggest a more serious cause of headache other than migraine?

What are ophthalmic migraines?

What are the diagnostic criteria for migraine headache?

How does the International Headache Society define migraine headache aura?

What are migraine variants?

What is the childhood periodic syndromes o migraine variant?

What are symptoms of basilar-type migraine?

What is the late-life migrainous accompaniments migraine variant?

What is hemiplegic migraine?

What is ophthalmoplegic migraine?

What is retinal migraine?

What is status migrainosus?

What is chronic migraine?

What are comorbidities of migraine headache?

How prevalent are migraine headache comorbidities?

How much does asthma increase the risk for migraine headache?

What are complications of migraine headache?

Which risk factors for stroke are correlated with migraine headache?

DDX

How is primary headache disorder differentiated from migraine headache?

Which features of a secondary headache disorder should be considered in the differential diagnosis of migraine headache?

What is a crash migraine?

What is an exertional headache?

How is an intracranial aneurysm differentiated from a migraine headache?

How is aneurysmal subarachnoid hemorrhage (SAH) evaluated in the differential diagnosis of migraine headache?

Why are space-occupying lesions included in the differential diagnosis of migraine headaches?

How is cerebral venous thrombosis differentiated from migraine headache?

When should spontaneous internal carotid artery dissection be included in the differential diagnosis of migraine headache?

When should secondary causes of migraine headache be considered?

What are the differential diagnoses for Migraine Headache?

Workup

How is migraine headache diagnosed?

What is the role of lab testing and imaging studies in the evaluation of migraine headache?

Which diagnostic tests for migraine headache may be unnecessary according to the American Headache Society&#39;s Choosing Wisely recommendations?

How does insurance status affect migraine care?

What is the role of neuroimaging in the evaluation of migraine headaches?

What is the role of CT scanning and MRI in the evaluation of migraine headaches?

When is lumbar puncture (LP) indicated in the evaluation of migraine headache?

Treatment

What are the goals of migraine headache treatment?

Which specialists should be consulted in the treatment of migraine headache?

What is the initial emergency department (ED) treatment of migraine headache?

What are the options for emergency department (ED) care of migraine headache?

When is hospitalization indicated in the treatment of migraine headache?

How are migraine headache triggers managed?

What are nonpharmacologic therapy options for migraine headache?

What is the efficacy of Cerena Transcranial Magnetic Stimulator (Cerena TMS) for the treatment of migraine headache?

What are contraindications for the use of the Cerena Transcranial Magnetic Stimulator (Cerena TMS) to treat migraine headache?

What is the efficacy of nonpharmacologic management for migraine headache?

What is the role of a vagus nerve stimulator in the treatment of migraine headache?

Which medications are used for abortive treatment of migraine headache?

What is the role of analgesics in the treatment of migraine headaches?

Which analgesics are used for the treatment of migraine headache?

Which medications are used to treat severe pain of migraine headaches?

What treatment options for acute migraine?

Which triptans and ergot alkaloids are used in the treatment of migraine headache?

What is the role of triptans in the treatment of migraine headache?

What are contraindications for the use of triptans and ergot alkaloids for migraine headache?

How are migraine headache-related nausea and vomiting treated?

When is prophylactic migraine therapy indicated?

What are the goals of preventive therapy for migraine headache?

How do prophylactic medications for migraine work?

What should be considered before administering preventive drugs for migraine headache?

Which drugs have been FDA approved for migraine prophylaxis?

Which medication are used to relieve allodynia caused by migraine headache?

What is the role of naproxen sodium in the management of migraine headache?

What is the role of quetiapine in the treatment of migraine headache?

Which classes of medications are effective for migraine prevention?

What is the role of antiepileptics in migraine prevention?

What is the role of antidepressants in migraine prevention?

What is the role of antihypertensives in migraine prevention?

What is the role of botulinum toxin A (onabotulinumtoxinA; BOTOX®) in migraine prevention?

What is the role of calcitonin gene-related peptide (CGRP) inhibitors in migraine prevention?

Which devices are used for migraine prophylaxis?

What are the treatment options for status migrainosus?

What are the treatment options for menstrual migraines?

What is the role of complementary and alternative medicine (CAM) in migraine treatment?

What is the efficacy of herb butterbur as a prophylactic treatment for migraine headaches?

What is the efficacy of riboflavin as a prophylactic treatment for migraine headaches?

What is the effectiveness of coenzyme Q10 (CoQ10) as a prophylactic treatment for migraine headaches?

What is the effectiveness of melatonin as a prophylactic treatment for migraine headaches?

Which complementary and alternative medicine (CAM) techniques lack proven efficacy in the prevention of migraine headache?

What are the advantages and disadvantages to complementary and alternative medicine (CAM) therapies for the prevention of migraine headaches?

What is the role of surgical therapy for migraine headaches?

What are common dietary triggers of migraine headaches?

What are some sources of tyramine that may dietary trigger for migraine headaches?

What is the role of nutraceuticals in migraine prophylaxis?

What is the role of activity modification in the management of migraine headaches?

What is the role of tonabersat in the treatment of migraine headache?

What medications are being investigated as possible treatments for acute migraine headaches?

Guidelines

Which medications are recommend by the AAN and AHS as effective for migraine prevention?

Which medications are probably effective for migraine prevention according to AAN and AHS guidelines?

Which medications are possibly effective for migraine prevention according to AAN and AHS guidelines?

Which CAM therapy is established as effective for migraine prevention according to AAN and AHS guidelines?

Which NSAIDS and CAM therapies are probably effective for migraine prevention according to AAN and AHS guidelines?

Which NSAIDS and CAM therapies are possibly effective for migraine prevention according to AAN and AHS guidelines?

What are the AHS guidelines for ED management of acute migraine?

What are the updated AHS guidelines on the prevention and acute treatment of migraine headache?

Medications

What are the classifications for pharmacologic agents used to treat migraine headaches?

What are abortive medications for the treatment of migraine headache?

What are prophylactic medications for the treatment of migraine headache?

Which medications in the drug class Neuromuscular Blocker, Botulinum Toxins are used in the treatment of Migraine Headache?

Which medications in the drug class CGRP Monoclonal Antibodies are used in the treatment of Migraine Headache?

Which medications in the drug class Antidepressants, SSRIs are used in the treatment of Migraine Headache?

Which medications in the drug class Calcium Channel Blockers are used in the treatment of Migraine Headache?

Which medications in the drug class Tricyclic Antidepressants are used in the treatment of Migraine Headache?

Which medications in the drug class Beta Blockers, Beta-1 Selective are used in the treatment of Migraine Headache?

Which medications in the drug class Antihistamines, 1st Generation are used in the treatment of Migraine Headache?

Which medications in the drug class Anticonvulsants are used in the treatment of Migraine Headache?

Which medications in the drug class Antiemetic Agents are used in the treatment of Migraine Headache?

Which medications in the drug class Antipsychotics, Phenothiazine are used in the treatment of Migraine Headache?

Which medications in the drug class Analgesics, Barbiturates Combos are used in the treatment of Migraine Headache?

Which medications in the drug class Analgesics, Other Combos are used in the treatment of Migraine Headache?

Which medications in the drug class Analgesics, Opioid Combos are used in the treatment of Migraine Headache?

Which medications in the drug class NSAIDs are used in the treatment of Migraine Headache?

Which medications in the drug class Opioid Analgesics are used in the treatment of Migraine Headache?

Which medications in the drug class Analgesics, Other are used in the treatment of Migraine Headache?

Which medications in the drug class Ergot Derivatives are used in the treatment of Migraine Headache?

Which medications in the drug class Serotonin 5-HT-Receptor Agonists are used in the treatment of Migraine Headache?