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Migraine

By

Stephen D. Silberstein

, MD, Sidney Kimmel Medical College at Thomas Jefferson University

Last full review/revision Apr 2020| Content last modified Apr 2020
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Migraine is an episodic primary headache disorder. Symptoms typically last 4 to 72 hours and may be severe. Pain is often unilateral, throbbing, worse with exertion, and accompanied by symptoms such as nausea and sensitivity to light, sound, or odors. Auras occur in about 25% of patients, usually just before but sometimes after the headache. Diagnosis is clinical. Treatment is with triptans, dihydroergotamine, antiemetics, and analgesics. Preventive regimens include lifestyle modifications (eg, of sleeping habits or diet) and drugs (eg, beta-blockers, amitriptyline, topiramate, divalproex, monoclonal antibodies).

Epidemiology

Migraine is the most common cause of recurrent moderate to severe headache; 1-year prevalence is 18% for women and 6% for men in the US. Migraine most commonly begins during puberty or young adulthood, waxing and waning in frequency and severity over the ensuing years; it often diminishes after age 50. Studies show familial aggregation of migraine.

Evidence based on evaluation of veterans of the Iraq and Afghanistan conflicts suggests that migraine may frequently develop after mild traumatic brain injury.

Pathophysiology

Migraine is thought to be a neurovascular pain syndrome with altered central neuronal processing (activation of brain stem nuclei, cortical hyperexcitability, and spreading cortical depression) and involvement of the trigeminovascular system (triggering neuropeptide release, which causes painful inflammation in cranial vessels and the dura mater).

Many potential migraine triggers have been identified; they include the following:

  • Drinking red wine

  • Skipping meals

  • Excessive afferent stimuli (eg, flashing lights, strong odors)

  • Weather changes

  • Sleep deprivation

  • Stress

  • Hormonal factors, particularly menstruation

  • Certain foods

Food triggers vary from person to person.

Head trauma, neck pain, or temporomandibular joint dysfunction sometimes triggers or exacerbates migraine.

Fluctuating estrogen levels are a potent migraine trigger. Many women have onset of migraine at menarche, severe attacks during menstruation (menstrual migraine), and worsening during menopause. For most women, migraines remit during pregnancy (but sometimes they worsen during the 1st or 2nd trimester); they worsen after childbirth, when estrogen levels decrease rapidly.

Oral contraceptives and other hormone therapy occasionally trigger or worsen migraine and have been associated with stroke in women who have migraine with aura.

Familial hemiplegic migraine, a rare subtype of migraine, is associated with genetic defects on chromosomes 1, 2, and 19. The role of genes in the more common forms of migraine is under study. In some families, the migraine phenotype varies considerably, causing primarily headache in some family members, vertigo in others, and hemiplegia or an aura in others. This finding suggests that migraine may actually be a more generalized disorder and not just a headache disorder.

Symptoms and Signs

Often, a prodrome (a sensation that a migraine is beginning) heralds attacks. The prodrome may include mood changes, neck pain, food cravings, loss of appetite, nausea, or a combination.

An aura precedes attacks in about 25% of patients. Auras are temporary neurologic disturbances that can affect sensation, balance, muscle coordination, speech, or vision; they last minutes to an hour. The aura may persist after headache onset. Most commonly, auras involve visual symptoms (fortification spectra—eg, binocular flashes, arcs of scintillating lights, bright zigzags, scotomata). Paresthesias and numbness (typically starting in one hand and marching to the ipsilateral arm and face), speech disturbances, and transient brain stem dysfunction (causing, for example, ataxia, confusion, or even obtundation) are less common than visual auras. Some patients have an aura with little or no headache.

Headache varies from moderate to severe, and attacks last from 4 hours to several days, typically resolving with sleep. The pain is often unilateral but may be bilateral, most often in a frontotemporal distribution, and is typically described as pulsating or throbbing.

Migraine is more than a headache. Associated symptoms such as nausea (and occasionally vomiting), photophobia, sonophobia, and osmophobia are prominent. Patients report difficulty concentrating during attacks. Routine physical activity usually aggravates migraine headache; this effect, plus the photophobia and sonophobia, encourages most patients to lie in a dark, quiet room during attacks. Severe attacks can be incapacitating, disrupting family and work life.

Attacks vary significantly in frequency and severity. Many patients have several types of headache, including milder attacks without nausea or photophobia; they may resemble tension-type headache but are a forme fruste of migraine.

Chronic migraine

Patients with episodic migraine can develop chronic migraine. These patients have headaches 15 days/month. This headache disorder used to be called combination or mixed headache because it had features of migraine and tension-type headache. These headaches often develop in patients who overuse drugs for acute treatment of headaches.

Other symptoms

Other, rare forms of migraine can cause other symptoms:

  • Basilar artery migraine causes combinations of vertigo, ataxia, visual field loss, sensory disturbances, focal weakness, and altered level of consciousness.

  • Hemiplegic migraine, which may be sporadic or familial, causes unilateral weakness.

Diagnosis

  • Clinical evaluation

Diagnosis of migraine is based on characteristic symptoms and a normal physical examination, which includes a thorough neurologic examination.

Red flag findings that suggest an alternate diagnosis (even in patients known to have migraine) include the following:

  • Pain that reaches peak intensity within a few seconds or less (thunderclap headache)

  • Onset after age 50

  • Headaches that increase in intensity or frequency for weeks or longer

  • History of cancer (brain metastases) or an immunosuppressive disorder (eg, HIV infection, AIDS)

  • Fever, meningismus, altered mental status, or a combination

  • Persistent focal neurologic deficits

  • A clear change in an established headache pattern

Patients with characteristic symptoms and no red flag findings do not require testing. Patients with red flag findings often require testing, including brain imaging and sometimes lumbar puncture.

Common diagnostic errors include the following:

  • Not realizing that migraine often causes bilateral pain and is not always described as throbbing

  • Misdiagnosing migraine as sinus headache or eye strain because autonomic and visual symptoms of migraine are absent

  • Assuming that any headache in patients known to have migraine represents another migraine attack (a thunderclap headache or a change in the previous headache pattern may indicate a new, potentially serious disorder)

  • Mistaking migraine with aura for a transient ischemic attack, especially when the aura occurs without headache, in older people

  • Diagnosing a thunderclap headache as migraine because a triptan relieves it (a triptan can also relieve a headache due to subarachnoid hemorrhage)

Several unusual disorders can mimic migraine with aura:

  • Dissection of the carotid or vertebral artery

  • Cerebral vasculitis

  • Moyamoya disease

  • CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)

  • MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) syndrome

Prognosis

For some patients, migraine is an infrequent, tolerable inconvenience. For others, it is a devastating disorder resulting in frequent periods of incapacity, loss of productivity, and severely impaired quality of life.

Treatment

  • Elimination of triggers

  • Yoga or behavioral interventions

  • For mild headaches, acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs)

  • For severe attacks, triptans, lasmiditan, or dihydroergotamine plus a dopamine antagonist antiemetic

A thorough explanation of the disorder helps patients understand that although migraine cannot be cured, it can be controlled, enabling them to better participate in treatment.

Patients are urged to keep a written headache diary to document the number and timing of attacks, possible triggers, and response to treatment. Identified triggers are eliminated when possible. Patients should be encouraged to avoid triggers.

For patients who use analgesics frequently (eg, > 2 days/week), particularly those with medication overuse headache, preventive drugs (see table Drugs for Migraine and Cluster Headaches) should be combined with a program for stopping overused analgesics.

Clinicians sometimes recommend behavioral interventions (biofeedback, stress management, psychotherapy) to manage migraine, especially when stress is a major trigger or when analgesics are being overused.

Yoga can reduce headache frequency and intensity; it enhances vagal tone and decreases sympathetic drive, thus improving cardiac autonomic balance.

Treatment of acute migraine headache is based on frequency, duration, and severity of attacks. It may include analgesics, antiemetics, triptans, and/or dihydroergotamine (1). If patients wish to avoid drug treatment or if drug treatment has been ineffective, neuromodulatory treatments can sometimes be used.

Mild to moderate attacks

NSAIDs or acetaminophen is used to treat mild to moderate migraine attacks.

If these drugs are ineffective, clinicians should consider using triptans, lasmiditan (a new selective serotonin [5-HT] 1F receptor agonist), dihydroergotamine, or ubrogepant (a small-molecule calcitonin gene–related peptide [CGRP] receptor antagonist).

An antiemetic (eg, metoclopramide, prochlorperazine) alone may be used to relieve mild or moderate attacks.

Severe attacks

If mild attacks evolve into incapacitating migraine or if attacks are severe from the onset, triptans or lasmiditan can be used. Triptans are selective serotonin 1B,1D receptor agonists. They are not analgesic per se but specifically block the release of neuropeptides that trigger migraine pain. Triptans are most effective when taken at the onset of attacks. They are available in oral, intranasal, and subcutaneous forms (see table Drugs for Migraine and Cluster Headaches); subcutaneous forms are more effective but have more adverse effects. Overuse of triptans can also lead to medication overuse headache. When nausea is prominent, combining a triptan with an antiemetic at the onset of attacks is effective.

IV fluids (eg, 1 to 2 L of 0.9% normal saline solution) can help relieve headache and increase a sense of well-being, especially in patients who are dehydrated from vomiting.

IV dihydroergotamine with a dopamine antagonist antiemetic (eg, metoclopramide 10 mg IV, prochlorperazine 5 to 10 mg IV) helps abort very severe, persistent attacks. Dihydroergotamine is also available in a subcutaneous form and as a nasal spray. A pulmonary-delivery formulation is being developed.

Triptans and dihydroergotamine can cause coronary artery constriction and are thus contraindicated in patients with coronary artery disease or uncontrolled hypertension; these drugs must be used with caution in older patients and in patients with vascular risk factors. Lasmiditan, which has a much greater affinity for serotonin 1F receptors than for 1B receptors, has no cardiovascular contraindications. (Triptans cause vasoconstriction by activating 5-HT1B receptors.) Ubrogepant is an alternative; as of this time, it has no cardiovascular precautions or contraindications and has no serious cardiovascular and gastrointestinal effects.

A good response to dihydroergotamine or a triptan should not be interpreted as diagnostic for migraine because these drugs may relieve headache due to subarachnoid hemorrhage and other structural abnormalities.

Prochlorperazine suppositories (25 mg) or tablets (10 mg) are an option for patients who cannot tolerate triptans and other vasoconstrictors.

Opioids should be used as a last resort (rescue drug) for severe headache when other measures are ineffective.

Chronic migraines

The same drugs used to prevent episodic migraine, including monoclonal antibodies that block CGRP, are used to treat chronic migraine. Also, supporting evidence is strong for onabotulinumtoxinA and, to a lesser extent, topiramate.

Some evidence supports use of neurostimulation for treatment of chronic migraine headaches. Noninvasive options include supraorbital stimulation, vagus nerve stimulation, and single-pulse transcranial magnetic stimulation. Invasive options include occipital nerve stimulation, sphenopalatine ganglion stimulation, and ventral tegmental area deep brain stimulation (2).

Table
icon

Drugs for Migraine Headaches*

Drug

Dosage

Comments

Prevention

Amitriptyline

10–100 mg orally at bedtime

Has anticholinergic effects; causes weight gain

Helpful for patients with insomnia

Small doses often effective

Beta-blockers

Atenolol 25–100 mg orally once a day

Metoprolol 50–200 mg orally once a day

Nadolol 20–160 mg orally once a day

Propranolol 20–160 mg orally 2 times a day

Timolol 5–20 mg orally once a day

Only beta-blockers without intrinsic sympathomimetic activity used

Avoided in patients with bradycardia, hypotension, diabetes, or asthma

Divalproex

Regular-release: 250–500 mg orally 2 times a day

Extended-release: 500–1000 mg orally once a day

Can cause alopecia, gastrointestinal upset, hepatic dysfunction, thrombocytopenia, tremor, and weight gain

Contradicted in pregnant women as prevention of migraines (risk clearly outweighs any possible benefit)

Erenumab (a monoclonal antibody)

70 or 140 mg subcutaneously once a month

Can be used for episodic and chronic migraine

Fremanezumab (a monoclonal antibody)

225 mg subcutaneously once a month or 675 mg subcutaneously every 3 months

Can be used for episodic and chronic migraine

Galcanezumab (a monoclonal antibody)

240 mg loading dose subcutaneously, then 120 mg subcutaneously once a month

Can be used for episodic or chronic migraine

OnabotulinumtoxinA

155 units IM once every 12 weeks, with 5 units/0.1 mL injected into 31 sites, divided among 7 specific areas in head and neck*

First-line treatment for chronic migraine

Topiramate

50–200 mg orally usually once a day

Can cause weight loss and central nervous system (CNS) adverse effects (eg, confusion, depression)

Treatment (1)

Acetaminophen

650 to 1000 mg every 4 to 6 hours as needed, not to exceed 4 g in 24 hours

May need dose modification in patients with liver disorders or alcoholism

Antiemetics

Metoclopramide 10 mg IV or orally

Prochlorperazine 5 to 10 mg IV, 10 mg orally, or 25 mg rectally

May be used alone to relieve mild or moderate attacks

For severe attacks, used with triptans or dihydroergotamine

Dihydroergotamine

0.5–1 mg subcutaneously or IV

4 mg/mL nasal spray

Can cause nausea

Contraindicated in patients with hypertension or coronary artery disease

Cannot be used concurrently with triptans

Pulmonary-inhaled formulation under development

Ditans

Lasmiditan 50 to 200 mg/dose

For patients with cardiovascular contraindications to triptans and dihydroergotamine

Gepants

Ubrogepant 50 mg or 100 mg orally

Contraindicated with concomitant use of strong CYP3A4 inhibitors

Ketorolac

30 mg IM every 6 hours as needed

60 mg IM once; alternatively, 10 to 30 mg IM every 4 to 6 hours as needed, up to 120 mg in 24 hours

Usually not a first-line treatment

Used in its injectable form for emergency treatment of severe migraine, particularly in patients with contraindications to triptans or other headache drugs

Triptans†

Almotriptan 12.5 mg orally

Eletriptan 20–40 mg orally

Frovatriptan 2.5 mg orally

Naratriptan 2.5 mg orally

Rizatriptan 10 mg orally

Sumatriptan 50–100 mg orally, 5–20 mg nasal spray, 6 mg subcutaneously, or one 6.5-mg transdermal patch, followed, if needed, by a 2nd patch after 2 hours (not to exceed 2 patches in 24 hours)

Zolmitriptan 2.5–5 mg orally or 5 mg nasal spray

Can cause flushing, paresthesias, and sense of pressure in chest or throat

Can repeat doses up to 3 times/day if headache recurs

Contraindicated in patients with coronary artery disease, uncontrolled hypertension, hemiplegic migraine, or intracranial vascular disease

Injections or nasal spray used for cluster headache

* Only practitioners experienced in giving onabotulinumtoxinA injections should give them..

† Triptans are given once, then repeated as needed.

Neuromodulatory treatments

Neuromodulatory treatments can be noninvasive, using commercially available devices, or invasive. Some can also be used for prevention.

Noninvasive transcranial magnetic stimulation, using a handheld device applied to the back of the head may relieve acute migraine with aura (3). A device that uses an armband to deliver a nonpainful electrical skin stimulus (called remote electrical neuromodulation) appears capable of relieving acute migraine pain. A handheld device that delivers noninvasive vagus nerve stimulation can also be used.

Trigeminal nerve stimulation, with a device applied to the forehead, can be used in patients who are ≥ 18 to treat acute migraine attacks (with or without an aura) or to reduce the frequency of attacks in some patients.

Invasive treatments tend to be available only at specialized centers and have greater risks than noninvasive treatments.

Treatment references

  • 1. Marmura MJ, Silberstein SD, Schwedt TJ: The acute treatment of migraine in adults: The American Headache Society evidence assessment of migraine pharmacotherapies. Headache 55 (1):3–20, 2015.

  • 2. Miller S, Sinclair AJ, Davies B, Matharu M: Neurostimulation in the treatment of primary headaches. Pract Neurol 16 (5):362–375, 2016. doi: 10.1136/practneurol-2015-001298. Epub 2016 May 5.

  • 3. Lipton RB, Dodick DW, Silberstein SD, et al: Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: A randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol 9:373–380, 2010.  doi: 10.1016/S1474-4422(10)70054-5. Epub 2010 Mar 4.

Prevention

Daily preventive therapy is warranted when frequent migraines interfere with activity despite acute treatment. Some experts consider onabotulinumtoxinA the drug of choice.

For patients who use analgesics frequently (eg, > 2 days/week), particularly those with medication overuse headache, preventive drugs (see table Drugs for Migraine and Cluster Headaches) should be combined with a program for stopping overused analgesics. Choice of drug can be guided by coexisting disorders, as for the following:

  • A small bedtime dose of amitriptyline for patients with insomnia

  • A beta-blocker for patients with anxiety or coronary artery disease

  • Topiramate, which can induce weight loss, for obese patients or for patients who wish to avoid weight gain

  • A monoclonal antibody (eg, erenumab, fremanezumab, galcanezumab) if other drugs are ineffective

Monoclonal antibodies that are used to prevent migraines block the activation of calcitonin gene-related peptide (CGRP), which can precipitate migraines (1).

Neuromodulatory treatments may also help. Transcutaneous supraorbital nerve stimulation, using a device applied to the forehead, can reduce the frequency of migraines (2). Transcranial magnetic stimulation, using by a device applied to the back of the skull, is indicated for the acute and prophylactic treatment of migraine headache in adolescents (≥ 12) and adults.

Treatment references

  • 1. Jain S, Silberstein SD: Invited commentary on preventive anti-migraine therapy (PAMT). Curr Treat Options Neurol 21 (4):14, 2019. doi:10.1007/s11940-019-0555-4.

  • 2. Schoenen J, Vandersmissen B, Jeangette S, et al: Migraine prevention with a supraorbital transcutaneous stimulator: A randomized controlled trial. Neurol 80 (8):697–704, 2013. doi: https://doi.org/10.1212/WNL.0b013e3182825055. Epub 2013.

Key Points

  • Migraine is a common primary headache disorder with multiple potential triggers.

  • Symptoms can include throbbing unilateral or bilateral pain, nausea, sensitivity to sensory stimuli (eg, light, sounds, smells), nonspecific prodromal symptoms, and temporary neurologic symptoms that precede headache (auras).

  • Diagnose migraine based on clinical findings; if patients have red flag findings, imaging and other tests are often needed.

  • Involve patients in their care, including avoiding triggers and using biofeedback, stress management, and psychotherapy as appropriate.

  • Treat most headaches with analgesics, IV dihydroergotamine, or triptans.

  • If attacks are frequent and interfere with activities, use preventive therapy (eg, monoclonal antibodies that block calcitonin gene-related peptide [CGRP], amitriptyline, a beta-blocker, topiramate, divalproex), onabotulinumtoxinA, or sometimes neuromodulatory treatments.

Drugs Mentioned In This Article

Drug Name Select Trade
BOTOX
D.H.E. 45, MIGRANAL
COMPRO
REGLAN
No US brand name
TYLENOL
ZOMIG
FROVA
INDERAL
AXERT
MAXALT
AMERGE
IMITREX
RELPAX
TOPAMAX
LOPRESSOR, TOPROL-XL
MIACALCIN
SPRIX
Erenumab
TENORMIN
CORGARD
TIMOPTIC
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