Migrain Medscape

10/6/2018 https://emedicine.medscape.
com/article/1142556-print
emedicine.medscape.com
Migraine Headache
Updated: Jan 30, 2018
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 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

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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
Basilar-type migraine
Hemiplegic migraine
Status migrainosus
Ophthalmoplegic migraine
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
Aphasia, syncope, and balance problems - Basilar-type migraine
Third nerve palsy with ocular muscle paralysis and ptosis, including or sparing the pupillary response - Ophthalmoplegic
migraine
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 second edition of the International Classification of Headache Disorders (ICHD)[7] 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
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:
In June 2013, the International Classification of Headache Disorders, Third Edition (ICHD-III, beta version) was published and is
available for field testing, which will take place for several years before the final version is published.
Changes from the previous edition include the following[8] :
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, 9, 10]
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.[11]
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.[12] According to this
theory, migraine is primarily a neurogenic process with secondary changes in cerebral perfusion.[13]
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.[14] 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.[15] 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.[16]
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.[17]
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.[18]
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.[19]
Measured levels of MMP-9 alone are the same for migraine patients with or without aura.[20]
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.[21]
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.[22] 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.[23] 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.[24]
Endothelial dysfunction
Vascular smooth muscle cell dysfunction may involve impaired cyclic guanosine monophosphate and hemodynamic response to
nitric oxide.[25] 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.[26] In premenopausal women with
migraine, particularly in those with migraine aura, increased endothelial activation, which is a component of endothelial
dysfunction, is evident.[27]
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[28] :
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[29] :
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.[29]
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.[30]
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.[31]
However, recent genome-wide association studies have suggested 4 regions in which single-nucleotide polymorphisms
influence the risk of developing migraine headache.[32, 33, 34] 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,[35] but a Danish study showed that only 7% of patients
with a clinical diagnosis of FHM had a mutation in that gene.[36]
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.[37, 38] However, the Danish study found mutations in
ATP1A2 in only 7% of patients with a clinical diagnosis of FHM.[36]
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.[39] Although SCN1A mutation has been reported in several
unrelated families, it is felt to be a rare cause of FHM.[40]
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.[41]
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,[42] and (2) HIHRATL
(hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy), which is suggested to be caused by
mutations in the COL4A1 gene.[43] The mechanisms by which these genetic vasculopathies give rise to migraine are still
unclear.[44]
Migraine precipitants
Various precipitants of migraine events have been identified, as follows:
Hormonal changes, such as those accompanying menstruation (common),[45] pregnancy, and ovulation
Stress
Excessive or insufficient sleep
Medications (eg, vasodilators, oral contraceptives[46] )
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,[47] 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.[47]
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).[48] 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%.[49] Migraines during pregnancy are also linked to stroke and vascular diseases.[50] 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.[51]
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.[52]
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).[53]
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.[54] 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).[55]
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.[56]
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.[57] 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.[58]
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.
[59] 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.[60]
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.[24]
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.[61]
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).[62]
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.[63]
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.[64, 65]
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.[66] 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.[67] 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.[68]
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 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 described by a person who experiences migraines. Note the
visual loss in the center of vision.
Migraine headache. Example of a central scotoma as described by a person who experiences migraine headaches.
Again note the visual loss in the center of vision.
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 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 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[47]
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.[30] 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
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:
Finally, these features must not be attributable to another disorder. (See the chart below.)
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:
Basilar-type migraine
Hemiplegic migraine
Status migrainosus
Retinal migraine
See the Medscape Reference article Childhood Migraine Variants for more information on these topics.
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.
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.
Basilar-type and hemiplegic migraine
Patients with basilar-type migraine 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 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[69] 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.[70] 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.[71]
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.[72] In migraines with aura, hemorrhagic stroke is
also a possible, but rare, complication.[73] 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.[74]
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.[75]
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.[75]
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
Cerebral Aneurysms
Chronic Paroxysmal Hemicrania
Cluster Headache
Dissection Syndromes
Herpes Simplex Encephalitis
Intracranial Hemorrhage
Muscle Contraction Tension Headache
Temporal/Giant Cell Arteritis
Tolosa-Hunt Syndrome
Viral Meningitis
Workup
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.[56]
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.[76, 77, 78]
American Headache Society's top 5 unnecessary 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.[79]
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[80] :
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.
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.[81, 82]
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.[83]
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.[84] 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.[85, 86]
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%).[87, 88] 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[85, 86] :
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.[89]
In January 2018, the FDA approved a vagus nerve stimulator (nVS) 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%).[149]
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.[90] Acute treatment is most effective when given within 15 minutes of pain onset
and when pain is mild.[91]
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.[92]
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.[93]
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).[94] The specific triptans include the following[95] :
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.[96] 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.[96]
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.[97, 98]
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.[99]
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.[100]
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
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
Divalproex
Topiramate
Low efficacy Verapamil
Methysergide
Flunarizine
MAOIs
High efficacy
CGRP inhibitors
Second line
Botulinum toxin
Cyproheptadine
Unproven efficacy 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.[101]
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.[102]
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.[103] 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.[104]
Classes of prophylactic drugs
The 3 principal classes of medications that are effective for migraine prevention are as follows:
Antiepileptics
Antidepressants
Antihypertensives
For any of these prophylactic agents, prophylaxis should not be considered a failure until it has been given at the maximum
tolerable dose for at least 30 days. Some additional drug classes that are also used for migraine prevention include botulinum
toxin and monoclonal antibodies that bind to the calcitonin gene-related peptide (CGRP) receptor.
Antiepileptics
Antiepileptics are generally well tolerated. The main adverse effects of topiramate are weight loss and dysesthesia.[105]
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,[106] 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.[107, 108]
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)[109] have also been shown to be effective for migraine prevention.[110]
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.[111] 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.[112]
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.[113]
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.[114]
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. The first monoclonal antibody that binds to the CGRP receptor is
erenumab (Aimovig). It was approved by the FDA in May 2018 for migraine prophylaxis. Approval was based on findings from
the LIBERTY, ARISE, and STRIVE clinical trials.[150, 151, 152]
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.[150]
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).[151]
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).[152]
Other CGRP monoclonal antibodies (eg, fremanezumab, galcanezumab) are awaiting FDA approval.
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.
[115]
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.[116]
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[117] ). 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.[118]
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.[119] 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.[120] 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).[103]
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.[121]
A randomized, controlled trial of coenzyme Q10 (CoQ10) documented that CoQ10 is effective and well tolerated for migraine
prophylaxis.[122] 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.[123]
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.[117]
A variety of other CAM techniques are not bolstered by solid scientific data, but they may be perceived to be of benefit to
patients.[124] Techniques that some patients use for headache relief include the following:
Body work - Eg, chiropractic, massage, and craniosacral therapy[125] )
Nutritional/herbal supplements - Eg, vitamins and herbs
Yoga[126]
Acupressure and acupuncture[127]
Biofeedback[128, 129]
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.[130]
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.[131]
Diet
The significance of diet as a migraine trigger is controversial.[132] 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).[133]
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.[134] 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.[135]
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.[136] 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.[16]
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.[137]
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,[138] 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.[139]
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

In 2016, the American Headache Society 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.[140, 141]
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
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.[112]
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.
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.
Contributor Information and Disclosures
Author
Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University
Medical Center
Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American
Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical
Association
Disclosure: Nothing to disclose.
Chief Editor
Helmi L Lutsep, MD Professor and Vice Chair, Department of Neurology, Oregon Health and Science University School of
Medicine; Associate Director, OHSU Stroke Center
Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology, American Stroke
Association
Disclosure: Medscape Neurology Editorial Advisory Board for: Stroke Adjudication Committee, CREST2; Executive Committee
for the NINDS-funded DEFUSE3 Trial; Physician Advisory Board for Coherex Medical.
Acknowledgements
Michelle Blanda, MD Chair, Department of Emergency Medicine, Summa Health System Akron City/St. Thomas Hospital;
Professor of Emergency Medicine, Northeastern Ohio Universities College of Medicine
Michelle Blanda, MD, is a member of the following medical societies: American College of Emergency Physicians and Society
for Academic Emergency Medicine
Ronald Braswell, MD Associate Professor, Department of Ophthalmology, University of Alabama-Birmingham
Ronald Braswell, MD is a member of the following medical societies: American Academy of Ophthalmology and North American
Neuro-Ophthalmology Society
Joseph Carcione Jr, DO, MBA Consultant in Neurology and Medical Acupuncture, Medical Management and Organizational
Consulting, Central Westchester Neuromuscular Care, PC; Medical Director, Oxford Health Plans
Joseph Carcione Jr, DO, MBA is a member of the following medical societies: American Academy of Neurology
Jane W Chan, MD Professor of Neurology/Neuro-ophthalmology, Department of Medicine, Division of Neurology, University of

Nevada School of Medicine
Jane W Chan, MD is a member of the following medical societies: American Academy of Neurology, American Academy of
Ophthalmology, American Medical Association, North American Neuro-Ophthalmology Society, and Phi Beta Kappa
Pamela L Dyne, MD Professor of Clinical Medicine/Emergency Medicine, University of California, Los Angeles, David Geffen
School of Medicine; Attending Physician, Department of Emergency Medicine, Olive View-UCLA Medical Center
Pamela L Dyne, MD is a member of the following medical societies: American Academy of Emergency Medicine, American
College of Emergency Physicians, and Society for Academic Emergency Medicine
Robert A Egan, MD Director of Neuro-Ophthalmology, St Helena Hospital
Robert A Egan, MD is a member of the following medical societies: American Academy of Neurology, American Heart
Association, North American Neuro-Ophthalmology Society, and Oregon Medical Association
Eric R Eggenberger, DO, MS, FAAN Professor, Vice-Chairman, Department of Neurology and Ophthalmology, Colleges of
Osteopathic Medicine and Human Medicine, Michigan State University; Director of Michigan State University Ocular Motility
Laboratory; Director of National Multiple Sclerosis Society Clinic, Michigan State University
Eric R Eggenberger, DO, MS, FAAN is a member of the following medical societies: American Academy of Neurology, American
Academy of Ophthalmology, American Osteopathic Association, and North American Neuro-Ophthalmology Society
Jacqueline Freudenthal, MD Co-Investigator, Ophthalmic Consultants Centre, Toronto
Jacqueline Freudenthal, MD is a member of the following medical societies: American Academy of Ophthalmology, Association
for Research in Vision and Ophthalmology, and Canadian Ophthalmological Society
Deborah I Friedman, MD, MPH Professor of Ophthalmology and Neurology, University of Rochester School of Medicine and
Dentistry; Consulting Staff, Strong Memorial Hospital
Deborah I Friedman, MD, MPH is a member of the following medical societies: American Academy of Neurology, American
Academy of Ophthalmology, American Headache Society, American Neurological Association, Association for Research in
Vision and Ophthalmology, North American Neuro-Ophthalmology Society, Society for Neuroscience, and United Council of
Neurologic Subspecialties, Certification in Headache Medicine
Disclosure: MAP Pharmaceuticals Grant/research funds Site PI (through university); AGA Medical Grant/research funds Site PI
(through university); Teva Grant/research funds Site PI (through university); Pfizer Grant/research funds Site PI; Neurology
Reviews Honoraria Editorial board; Merck Grant/research funds Site PI
J Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine,
University of Virginia School of Medicine
J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American
Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Edsel Ing, MD, FRCSC Associate Professor, Department of Ophthalmology and Vision Sciences, University of Toronto Faculty
of Medicine; Consulting Staff, Toronto East General Hospital, Canada
Edsel Ing, MD, FRCSC is a member of the following medical societies: American Academy of Ophthalmology, American
Association for Pediatric Ophthalmology and Strabismus, American Society of Ophthalmic Plastic and Reconstructive Surgery,
Canadian Ophthalmological Society, North American Neuro-Ophthalmology Society, and Royal College of Physicians and
Surgeons of Canada
David Y Ko, MD Associate Professor of Clinical Neurology, Associate Director, USC Adult Epilepsy Program, Keck School of
Medicine of the University of Southern California
David Y Ko, MD is a member of the following medical societies: American Academy of Neurology, American Clinical
Neurophysiology Society, American Epilepsy Society, and American Headache Society
Disclosure: GSK Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching; Lundbeck Consulting fee
Consulting; Westward Consulting fee Consulting
Amelito Malapira, MD Consulting Staff, Northwest Neurology
Jorge E Mendizabal, MD Consulting Staff, Corpus Christi Neurology
Jorge E Mendizabal, MD is a member of the following medical societies: American Academy of Neurology, American Headache
Society, National Stroke Association, and Stroke Council of the American Heart Association
Edward A Michelson, MD Associate Professor, Program Director, Department of Emergency Medicine, University Hospital
Health Systems of Cleveland
Edward A Michelson, MD is a member of the following medical societies: American College of Emergency Physicians, National
Association of EMS Physicians, and Society for Academic Emergency Medicine
Joseph Quinn, MD Assistant Professor, Department of Neurology, Portland VA Medical Center, Oregon Health Sciences
University
Hampton Roy Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College
of Surgeons, and Pan-American Association of Ophthalmology
Soma Sahai-Srivastava, MD Director of Neurology Ambulatory Care Services, LAC and USC Medical Center; Assistant
Professor, Department of Neurology, Keck School of Medicine of the University of Southern California
Soma Sahai-Srivastava, MD is a member of the following medical societies: American Academy of Neurology, American
Headache Society, and American Medical Association
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Reference Salary Employment
Jeff T Wright, MD Instructor, Department of Emergency Medicine, Summa Health System; Corporation President and Consulting
Staff, Summa Emergency Associates, Inc
Jeff T Wright, MD is a member of the following medical societies: American College of Emergency Physicians
Brian R Younge, MD Professor of Ophthalmology, Mayo Clinic School of Medicine
Brian R Younge, MD is a member of the following medical societies: American Medical Association, American Ophthalmological
Society, and North American Neuro-Ophthalmology Society
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10/6/2018 https://emedicine.medscape.

Signs and symptoms

Headache lasts 4-72 hours

Sensitivity to light and sound

Features of migraine aura are as follows:

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

Visual symptoms may be positive or negative

Physical findings during a migraine headache may include the following:

Cranial/cervical muscle tenderness

Hemisensory or hemiparetic neurologic deficits (ie, complicated migraine)

See Clinical Presentation for more detail.

Moderate or severe pain intensity

Nausea and/or vomiting

Photophobia and phonophobia

Migraine without aura (formerly, common migraine)

Probable migraine without aura

Migraine with aura (formerly, classic migraine)

Probable migraine with aura

Chronic migraine associated with analgesic overuse

Migrainous disorder not fulfilling above criteria

Migraine variants include the following:

Childhood periodic syndromes

Late-life migrainous accompaniments

Unilateral paralysis or weakness - Hemiplegic migraine

Aphasia, syncope, and balance problems - Basilar-type migraine

Testing and imaging studies

See Workup for more detail.

Abortive medications include the following:

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

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

Nonsteroidal anti-inflammatory drugs (NSAIDs)

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

Abortive therapy fails or is overused

Symptomatic medications are contraindicated or ineffective

Use of abortive medications more than twice a week

Prophylactic medications include the following:

Calcium channel blockers

Selective serotonin reuptake inhibitors (SSRIs)

Calcitonin gene-related peptide (CGRP) inhibitors

Treatment of migraine may also include the following:

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

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

See Treatment and Medication for more detail.

Migraine characteristics and treatment

Migraine without aura (formerly, common migraine)

Probable migraine without aura

Migraine with aura (formerly, classic migraine)

Probable migraine with aura

Chronic migraine associated with analgesic overuse

Migrainous disorder not fulfilling above criteria

Moderate or severe pain intensity

Nausea and/or vomiting

Photophobia and phonophobia

Changes from the previous edition include the following[8] :

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

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

Cortical spreading depression

Vasoactive substances and neurotransmitters

Serotonin and migraine

Migraine risk factors