Clinical Review & Education

JAMA | Review

Diagnosis and Management of Headache

A Review
Matthew S. Robbins, MD

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IMPORTANCE Approximately 90% of people in the US experience headache during their Supplemental content
lifetime. Migraine is the second leading cause of years lived with disability worldwide.
CME Quiz at
OBSERVATIONS Primary headache disorders are defined as headaches that are unrelated to an jamacmelookup.com
underlying medical condition and are categorized into 4 groups: migraine, tension-type
headache, trigeminal autonomic cephalalgias, and other primary headache disorders. Studies
evaluating prevalence in more than 100 000 people reported that tension-type headache
affected 38% of the population, while migraine affected 12% and was the most disabling.
Secondary headache disorders are defined as headaches due to an underlying medical
condition and are classified according to whether they are due to vascular, neoplastic,
infectious, or intracranial pressure/volume causes. Patients presenting with headache should
be evaluated to determine whether their headache is most likely a primary or a secondary
headache disorder. They should be evaluated for symptoms or signs that suggest an urgent
medical problem such as an abrupt onset, neurologic signs, age 50 years and older, presence
of cancer or immunosuppression, and provocation by physical activities or postural changes.
Acute migraine treatment includes acetaminophen, nonsteroidal anti-inflammatory drugs,
and combination products that include caffeine. Patients not responsive to these treatments
may require migraine-specific treatments including triptans (5-HT1B/D agonists), which
eliminate pain in 20% to 30% of patients by 2 hours, but are accompanied by adverse effects
such as transient flushing, tightness, or tingling in the upper body in 25% of patients. Patients
with or at high risk for cardiovascular disease should avoid triptans because of
vasoconstrictive properties. Acute treatments with gepants, antagonists to receptors for the
inflammatory neuropeptide calcitonin gene–related peptide, such as rimegepant or
ubrogepant, can eliminate headache symptoms for 2 hours in 20% of patients but have
adverse effects of nausea and dry mouth in 1% to 4% of patients. A 5-HT1F agonist,
lasmiditan, is also available for acute migraine treatment and appears safe in patients with
cardiovascular risk factors. Preventive treatments include antihypertensives, antiepileptics,
antidepressants, calcitonin gene–related peptide monoclonal antibodies, and
onabotulinumtoxinA, which reduce migraine by 1 to 3 days per month relative to placebo. Author Affiliation: Department of
Neurology, Weill Cornell Medical
CONCLUSIONS AND RELEVANCE Headache disorders affect approximately 90% of people College, New York, New York.
during their lifetime. Among primary headache disorders, migraine is most debilitating and Corresponding Author: Matthew S.
can be treated acutely with analgesics, nonsteroidal anti-inflammatory drugs, triptans, Robbins, MD, Weill Cornell Medicine,
520 E 70th St, Starr Pavilion 607,
gepants, and lasmiditan.
New York, NY 10021 (mar9391@med.
cornell.edu).
JAMA. 2021;325(18):1874-1885. doi:10.1001/jama.2021.1640 Section Editor: Mary McGrae
McDermott, MD, Deputy Editor.

H
eadache disorders affect approximately 90% of people
during their lifetime.1 More than 50% of outpatient vis-
its for headache occur in primary care,2 and headache is
the fourth leading cause of emergency department visits in the US.2
Primary headache disorders are headaches that are not caused
by an underlying medical condition and are believed to have a
genetic etiology. Primary headache disorders are categorized into 4
types: migraine, tension-type headache (TTH), trigeminal auto-
nomic cephalalgias (TACs) including cluster headache, and other
primary headache disorders such as new daily persistent headache
and other relatively rare disorders (Table 1).3 Studies evaluating
prevalence in more than 100 000 people reported that TTH
affected 38% of the population, that migraine affected 12% and
was the most disabling of primary headache disorders, and that
TACs, including cluster headache, affected 0.05% of the
population.4 Cluster headache is characterized by unilateral pain
with ipsilateral cranial autonomic symptoms such as conjunctival
injection, tearing, ptosis, and rhinorrhea.
Secondary headache disorders are due to an underlying medi-
cal disorder and are distinct from primary headache disorders. In
2018, the International Classification of Headache Disorders up-
dated the recommended organization and diagnostic criteria for
headache disorders by the International Headache Society (eBox in
the Supplement).3

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 Diagnosis and Management of Headache Review Clinical Review & Education

Table 1. Characteristics of the Major Primary Headache Disorders

Typical characteristic Migraine Tension-type headache Cluster headache

Pain
Associated symptoms
Headache and activity
Attack duration
Attack frequency
Other features
Chronic form
Pathophysiology
Acute treatments
Preventive treatments
Abbreviations: CGRP, calcitonin gene–related peptide; NSAIDs, nonsteroidal
anti-inflammatory drugs.
a
Varies from at least 5 attacks in a lifetime to constant.
Throbbing; unilateral or bilateral; any Pressurelike; bilateral; frontal, temporal; Searing, sharp, throbbing; unilateral; orbital,
aspect of the head; moderate to mild to moderate frontal; severe
severe
Nausea, vomiting; photophobia; Uncommon Ipsilateral cranial autonomic symptoms
phonophobia (conjunctival injection, ptosis, miosis, tearing,
rhinorrhea); migraine-associated symptoms may
be present; photophobia typically unilateral
Aggravated by movement No significant change Restlessness
4 to 72 h 30 min to 7 d 30 min to 3 h
Variablea Variableb Every other day to 8/d
Premonitory symptoms; aura; Attack triggers common Circadian attack periodicity; circannual attack
postdrome; attack triggers periods; restricted triggers during attack periods
only
Chronic migraine: ≥15 d/mo for ≥3 Chronic tension-type headache: ≥15 Chronic cluster headache: no remission period
mo, of which half of all days fulfill d/mo for ≥3 mo or with remission period lasting <3 mo for ≥1 y
migraine attack criteria or respond to
a migraine-specific treatment
Primary neuronal dysfunction, altered Peripheral myofascial activation or Central (hypothalamic) activation of the
cortical hyperexcitability and sensitization of nociceptors may underlie trigeminoautonomic reflex, with ipsilateral
connectivity; hypothalamic and episodic tension-type headache; trigeminovascular activation
brainstem activation; cortical secondary sensitization with repeated
spreading depression (aura); peripheral activation of central nervous
trigeminovascular activation, with system pain pathways may be associated
release of inflammatory with chronic tension-type headache
neuropeptides such as CGRP, pituitary
adenylate cyclase–activating peptide;
sensitization of peripheral and central
pain processing pathways
Simple analgesics; NSAIDs (aspirin, Simple analgesics; NSAIDs (aspirin, Triptans (intranasal or subcutaneous); high-flow
diclofenac, ibuprofen, ketorolac, diclofenac, ibuprofen, ketorolac, oxygen (10-15 L/min); external vagus nerve
naproxen); triptans (almotriptan, naproxen) stimulation (episodic cluster headache only)
eletriptan, frovatriptan, naratriptan,
rizatriptan, sumatriptan,
zolmitriptan); ergots
(dihydroergotamine); gepants
(rimegepant, ubrogepant); ditans
(lasmiditan); neuromodulation
devices (single-pulse transcranial
magnetic stimulation, external
trigeminal nerve stimulation, external
vagus nerve stimulation, remote
electrical neuromodulation [episodic
migraine only])
β-Blockers (propranolol, metoprolol, Tricyclic antidepressants (amitriptyline, Verapamil; lithium; CGRP-targeting monoclonal
timolol); tricyclic antidepressants nortriptyline); venlafaxine; mirtazapine antibody (galcanezumab); corticosteroids
(amitriptyline, nortriptyline); (short-term); occipital nerve injection
antiepileptics (topiramate, valproic (short-term); external vagus nerve stimulation
acid); candesartan; botulinum toxin (adjunctive)
(chronic migraine only);
CGRP-targeting monoclonal
antibodies (eptinezumab, erenumab,
fremanezumab, galcanezumab);
neuromodulation devices
(single-pulse transcranial magnetic
stimulation, external trigeminal nerve
stimulation, external vagus nerve
stimulation)
b
Varies from at least 10 attacks in a lifetime to constant.

Many structures in the head and neck are pain sensitive, includ-
ing extracranial tissues, cervical and intracranial arteries, venous si-
nuses, veins, the meninges, and select cranial (V, VII, IX, X) and up-
per cervical nerves. Head pain or discomfort from any etiology is
generated by pressure, traction, irritation, or inflammation of these
structures. Both primary and secondary headache disorders in-
volve these structures either by endogenous (genetic) causes or ex-
ogenous (vascular or traumatic) causes. Headache often involves re-
lease of vasoactive, inflammatory substances including calcitonin
gene–related peptide by dural nociceptive axonal terminals. These
substances or their receptors are targets for pharmacologic therapy.5
Diagnosing headache begins with distinguishing secondary from pri-
mary headache disorders.
Methods
A PubMed search was performed for the period between January 1,
2010, and January 25, 2021, for studies of the diagnosis and treat-
ment of headache, migraine, TTH, cluster headache, and secondary

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 Clinical Review & Education Review
Box. Common Questions About Headache Diagnosis
and Treatment
When Do Patients Presenting With New Headaches
Require Diagnostic Testing?
Diagnostic testing, including neuroimaging, should be performed
for patients who present with headache with abrupt onset,
neurologic signs, age ⱖ50 years, comorbidities including cancer
or immunosuppression, or provocation by physical activities
or postural changes.
What Are the Most Effective Treatments
for Acute Migraine Attacks?
Acetaminophen, 1000 mg; NSAIDs, such as naproxen sodium,
550 mg; and combination products that include caffeine may be
effective for many people for migraine attacks. If ineffective,
contraindicated, or intolerable, triptans, such as rizatriptan, 10 mg,
or eletriptan, 40 mg, may be prescribed. If ⱖ2 trials of different
triptan medications are ineffective, contraindicated, or not
tolerated, gepants, such as rimegepant or ubrogepant,
or lasmiditan may be prescribed.
What Are the Safety Concerns Associated With
Prescribing Triptans for Patients With Migraine?
Triptans are safe for most people with migraine, but should be
avoided in patients with established coronary artery disease,
stroke, peripheral artery disease, and uncontrolled or multiple risk
factors for cardiovascular disease. There is no strong evidence that
triptans and antidepressants used together elevate the risk for
serotonin syndrome. Gepants, lasmiditan, NSAIDs, and other
analgesics are options for patients unable to tolerate triptans
or when they are contraindicated.
What Are the Most Effective Preventive Therapies
for Patients With Migraine?
Antihypertensives, such as propranolol or candesartan;
antidepressants, such as amitriptyline or venlafaxine; and
antiepileptic agents, such as topiramate, are considered first-line
preventive treatments. A typical therapy consists of candesartan,
16 mg, daily or topiramate, 50 mg, twice daily. For patients who do
not respond to a ⱖ6-week trial, have contraindications, or do not
tolerate these treatments, monoclonal antibodies to calcitonin
gene–related peptide or its receptor, as well as onabotulinumtoxinA
(for chronic migraine only) are preventive treatment options.
Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.
headache disorders in adults. Clinical trials, systematic reviews,
guidelines, and medical society position papers were prioritized.
References in selected articles were reviewed to identify additional
studies. A total of 94 articles formed the basis of this review, includ-
ing 32 randomized clinical trials, 6 meta-analyses and systematic
reviews, 1 quality measurement set (a tool measuring or quantify-
ing health care processes and outcomes), 7 articles that reported
guidelines, 4 position papers, and other papers (such as observa-
tional studies, narrative reviews).
Diagnostic Approach
A thorough history and physical examination, focused on neuro-
logical signs and symptoms, is important for accurate headache
diagnosis (eTable 1 in the Supplement and the Box). The history is
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Diagnosis and Management of Headache
important because most patients evaluated for headache have nor-
mal physical examination and diagnostic testing.4 The history
should consist of a chronologic description of headache since onset
including frequency, duration (typically ⱖ4 hours for migraine),
location (typically unilateral with migraine and TACs), and character
(commonly throbbing in migraine). Migraine is characterized by
nausea, vomiting, photophobia, phonophobia, and osmophobia.
Movement typically exacerbates migraine. Perimenstrual migraine
attacks (either before or after menses) are common in women.
TACs are characterized by unilateral headache with autonomic
symptoms and signs (tearing, conjunctival injection, eyelid ptosis,
miosis, nasal congestion).
Transient focal neurologic symptoms in the setting of a mi-
graine attack, such as unilateral, dynamic visual, or sensory symp-
toms, suggest migraine aura, further defined as a combination of
positive (bright lights, paresthesia) and negative (loss of vision,
numbness) symptoms. Persistent focal neurologic symptoms for at
least several hours or days with or without headache resolution sug-
gest cerebrovascular or neoplastic etiologies. The most common mi-
graine aura is visual, such as a gradual onset of shimmering lights or
a zigzag pattern along with blurred vision in a visual field over 5 to
60 minutes. In contrast, a transient ischemic attack in the occipital
lobe affecting vision occurs abruptly and typically is not associated
with shimmering or zigzag lights. Sensory aura may consist of uni-
lateral paresthesias or numbness beginning in a limb or face and mov-
ing along the same side of the body. In contrast, a transient ische-
mic attack is characterized by sudden onset of simultaneous
unilateral face, arm, and/or leg sensory symptoms. Aura occurs
gradually and evolves before dissipating. Migraine aura can include
transient language symptoms, such as dysphasia, or rarely brain-
stem or motor symptoms, such as diplopia, tinnitus, diminished hear-
ing, and hemiparesis. Though not included in diagnostic criteria,
mood changes, neck pain, polyuria, and food cravings may be pre-
monitory symptoms associated with migraine attacks.6 A post-
drome consisting of nonpain symptoms, such as fatigue, may de-
velop after headache subsides.7 The pathophysiologic basis for aura
is cortical spreading depression, defined as a transient cortical neu-
ronal and glial depolarization followed by dysfunction of affected
brain regions. Premonitory symptoms are likely related to hypotha-
lamic activation before headache develops. The etiology of post-
drome symptoms (such as fatigue) is unknown.5
Patients with new headaches should be evaluated for second-
ary headache disorders by a clinical assessment that may require
diagnostic testing such as neuroimaging or lumbar puncture.8,9
Abrupt onset of a severe headache (ie, maximal intensity within 60
seconds of onset) increases the likelihood of a cerebrovascular
cause such as aneurysmal subarachnoid hemorrhage or reversible
cerebral vasoconstriction syndrome, defined as temporary multifo-
cal vasoconstriction of intracranial arteries.3 New-onset headache
in patients aged 50 years and older may be due to neoplasm
or giant cell arteritis.10 New-onset headache in women who are
pregnant or postpartum may be due to cerebrovascular disease,
hypertensive disorders of pregnancy, or postdural puncture
headache.11,12 Secondary headaches are more common in people
with cancer (brain or leptomeningeal metastases)13 and those tak-
ing anticoagulants (intracranial hemorrhage), immunosuppressive
drugs (intracranial infection), or estrogen (cerebrovascular dis-
ease). Fever and weight loss are more common in inflammatory,
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 Diagnosis and Management of Headache
neoplastic, or infectious disorders. In older patients, jaw claudica-
tion may indicate giant cell arteritis, typically characterized by the
new onset of constant headache in temporal or other locations as
well as weight loss, visual disturbance, and myalgias.14 Patients
with an established diagnosis of migraine may require reassess-
ment when headache pattern changes or new neurologic symp-
toms develop.
Clinical judgment regarding diagnostic testing should be used
in these circumstances.15,16 Brain imaging may be necessary for pa-
tients with unilateral headache and ipsilateral cranial autonomic
symptoms, such as eyelid ptosis, tearing, and rhinorrhea, because
some of these patients may have secondary causes of headache, in-
cluding pituitary lesions such as an adenoma.9,17 Although TTH is the
most common primary headache disorder and is characterized by
a dull, bilateral headache, symptoms of TTH may also occur due to
intracranial neoplasm (23.5% of 98 patients with intracranial ma-
lignancy presented with TTH, while 13.3% presented with mi-
graine symptoms).13 Neuroimaging (magnetic resonance imaging)
should be considered for patients at higher risk of cancer, such as
patients aged 50 years or older. The possibility of a specific second-
ary headache disorder should guide the choice of imaging modal-
ity. If neoplasm, infection, inflammatory disease, or low intracra-
nial pressure is suspected, magnetic resonance imaging of the brain
with and without contrast is recommended.
Primary Headache Disorders
Migraine
Migraine is typically characterized by severe, unilateral throbbing
headache lasting 4 to 72 hours that is aggravated by routine physi-
cal activity and accompanied by symptoms such as photophobia and
phonophobia, nausea, vomiting, aura, premonitory symptoms, and
a postdrome after headache subsides.5
In the American Migraine Prevalence and Prevention Study of
162 576 individuals in the US, migraine symptoms were reported in
11.7% of participants, including in 17.1% of women and 5.6% of men.
Migraine prevalence is highest in people aged 20 to 50 years.18 Most
people with migraine have episodic migraine, defined by attack fre-
quency of fewer than 15 days per month. However, each year, 2.5%
of patients with established episodic migraine progress to chronic
migraine,19 defined as headache 15 days or more per month over 3 con-
secutive months or more in which the headache on at least half of such
days meets diagnostic criteria for migraine attacks or responds to a
migraine-specific medication. People with chronic migraine in a popu-
lation survey of 24 000 people were approximately twice as likely as
those with episodic migraine to have depression (30% vs 17%), anxi-
ety (30% vs 19%), and chronic pain (31% vs 15%) and were more likely
to have pulmonary disorders such as asthma, hypertension (34% vs
28%),hyperlipidemia(34%vs26%),andobesity(26%vs21%).20 Fac-
tors associated with progression from episodic to chronic migraine in-
clude overuse of medications (such as opioids, barbiturates, trip-
tans, and nonsteroidal anti-inflammatory drugs [NSAIDs]), excessive
caffeine intake, allodynia (the perception of a nonnoxious sensation
as painful), persistent nausea, obesity, snoring, obstructive sleep ap-
nea, pain disorder, depression, and anxiety (eTable 2 in the
Supplement).21 Twenty-six percent of people with chronic migraine
revert to episodic migraine over 2 years. People with a lower head-
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Review Clinical Review & Education
ache frequency and those without allodynia are more likely to revert
from chronic to episodic migraine.22
In women, declining endogenous or exogenous estrogen lev-
els trigger migraine. Migraine severity and frequency are more com-
mon at menarche, before and after menstruation, in the postpar-
tum period, and during perimenopause.23 Migraine with aura occurs
in up to 25% to 30% of people with migraine and is associated with
an approximately 2-fold increased risk of stroke in women aged
younger than 45 years. In women aged 20 to 44 years, the abso-
lute risk of stroke is 2.5 per 100 000 for those without migraine, 4.0
per 100 000 in those with migraine without aura, and 5.9 per
100 000 in those with migraine with aura. This rate is higher in
women using estrogen-containing oral contraception, including 6.3
per 100 000 for those without migraine, 25.4 per 100 000 in those
with migraine without aura, and 36.9 per 100 000 in those with mi-
graine with aura.24 In women with migraine with aura, estrogen-
containing contraception should be avoided or require a risk vs ben-
efit discussion. In a US population study of 11 345 individuals (median
age, 24.0 years for patients with migraine vs 20.4 years for con-
trols) followed up for 5 years, 3.85% of those with migraine and aura
reported a stroke compared with 1.12% of those with migraine with-
out aura and 1.26% of nonheadache controls.25 In 27 858 women
aged 45 years and older followed up for 23 years, the incidence rate
adjusted for cardiovascular risk factors per 1000 person-years of ma-
jor cardiovascular disease (nonfatal stroke, myocardial infarction, or
death) was 3.36 in patients with migraine with aura vs 2.11 in pa-
tients with migraine without aura or no migraine (P < .001).26 There-
fore, the stroke and cardiovascular risk seems greatest for those with
migraine with aura.
Migraine therapy consists of acute treatments (Table 2)27-35 to
relieve headache attacks and preventive treatment (Table 3)36-54 de-
signed to reduce migraine frequency and/or severity.
Acute treatment for migraine includes acetaminophen, NSAIDs,
and combination products that include caffeine (Box). Acetamino-
phen, 1000 mg, and NSAIDs, such as aspirin, 500 mg, naproxen, 550
mg, and ibuprofen, 400 mg, are 9% to 20% more effective than pla-
cebo for achieving pain freedom after 2 hours of taking the medi-
cation, and more than 50% of patients achieve some degree of pain
relief 2 hours after taking the medication. Opioids and barbiturate
combination products should be avoided because of risks of depen-
dency and medication overuse and because other options are
available.35,49 Other options include migraine-specific acute treat-
ments such as triptans (5-HT1B/D agonists) and the more recently
available ditans (5-HT1F agonists), both of which act on presynaptic
neuronal terminals to prevent release of inflammatory neuropep-
tides such as calcitonin gene–related peptide as well as gepants (di-
rect calcitonin gene–related peptide receptor antagonists). These
acute treatments for migraine are indicated for moderate or severe
attacks as well as for mild or moderate attacks that do not respond
well to other analgesics such as acetaminophen and NSAIDs.49 Pain
relief and shorter time to pain reduction are treatment goals.55,56
Acute treatment for migraine typically eliminates pain within 2
hours in 20% to 30% of patients.28,57 All of the triptan therapies are
available as tablet formulations. Some are available as nasal spray
(sumatriptan, zolmitriptan), orally disintegrating tablets (rizatrip-
tan, zolmitriptan), and subcutaneous injections (sumatriptan).
Efficacy is highest when the medication is taken closer to head-
ache onset. Lack of efficacy may be due to underdosing or delayed
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 Clinical Review & Education Review Diagnosis and Management of Headache

Table 2. Commonly Used Acute Migraine Treatments for Adultsa

Therapeutic gain at 2 h
after treatment in trials
(pain freedom proportion
in patients receiving
active treatment
subtracted by proportion
Likely or possible in patients
Treatment class Examples (dose per use) mechanisms receiving placebo) Adverse effects Relative cost
NSAIDs Aspirin, 500 mg; diclofenac, Anti-inflammatory 9%-20%27 Common: esophageal or gastric +
50 and 100 mg; ibuprofen, irritation. Uncommom:
200 and 400 mg; ketorolac, kidney injury
30 and 60 mg, intramuscular;
15.75-mg nasal spray;
naproxen, 500 and 550 mg
Combination Acetaminophen/aspirin/caffeine, Synergistic effects from 15%-20%27 See individual categories +/++
analgesics 500/500/130 mg; individual agents
sumatriptan/naproxen,
85/500 mg
Triptans Almotriptan, 6.25 and 12.5 mg; 5-HT1B/D agonists 16%-32%28 Common: warmth, tightness, ++
eletriptan, 20 and 40 mg; discomfort in torso, neck, and
frovatriptan, 2.5 mg; head; sedation. Uncommon:
naratriptan, 1 and 2.5 mg; arterial ischemia in patients with
rizatriptan, 5 and 10 mg (also preexisting coronary artery
orally disintegrating tablet); disease or risk factors
sumatriptan, 25, 50, and 100
mg oral, 10 and 20 mg nasal
spray, 4 and 6 mg subcutaneous;
zolmitriptan, 2.5 and 5 mg oral
(also orally disintegrating
tablet), 2.5 and 5 mg nasal spray
Ergot derivatives Dihydroergotamine, 0.5-2 mg, Activates multiple 18%-37%27 Common: warmth, tightness, ++
nasal spray, 0.5-1 mg serotonin, noradrenergic, discomfort in torso, neck, and
intramuscular or subcutaneous dopaminergic receptors. head; nausea. Uncommon: arterial
Blocks trigeminocervical ischemia in patients with
complex activation and preexisting coronary artery
glial prostaglandin disease, peripheral artery disease,
release cerebrovascular disease, or other
risk factors
Gepants Rimegepant, 75 mg, orally CGRP receptor 5%-9%29,30 Common: dry mouth, dizziness +++
disintegrating tablet only; antagonists
ubrogepant, 50 and 100 mg
Ditans Lasmiditan, 50-200 mg 5-HT1F agonists 8%-17%31,32 Common: sedation, dizziness, +++
impaired driving for up to 8 h
33
Neuromodulation Single-pulse transcranial Magnetic stimulation to 10%-19% Common: dizziness (transcranial +++
devices magnetic stimulation, external cortex or peripheral magnetic stimulation), sedation
trigeminal nerve stimulation, stimulation of sensory or (trigeminal nerve stimulation),
external vagus nerve autonomic afferents hoarseness (vagus nerve
stimulation, remote electrical stimulation), local discomfort
neuromodulation (all devices)
Abbreviations: CGRP, calcitonin gene–related peptide; NSAIDs, nonsteroidal guidelines27,34 and quality measures.35 Treatments, efficacy, and adverse
anti-inflammatory drugs. events may vary according to dose and formulation. The use of antiemetics
a
Treatments selected from medications and devices that are Food and Drug may be indicated in patients with nausea and vomiting.
b
Administration approved or cleared as well as treatments endorsed in + indicates low; ++, intermediate; and +++, high.

administration. Some patients respond better to nonoral routes, such
as nasal spray and subcutaneous injection, given higher bioavail-
ability of such formulations or the presence of nausea, vomiting, or
gastroparesis. Triptans cause vasoconstriction based on their 5-HT1B
receptor agonism and should be avoided in patients with preexist-
ing atherosclerotic arterial disease including coronary artery dis-
ease, stroke, peripheral artery disease, or multiple risk factors for
these conditions.58 Newer-generation migraine-specific medica-
tions, including ditans, such as lasmiditan (selective 5-HT1F ago-
nists), and gepants, such as rimegepant and ubrogepant (postsyn-
aptic calcitonin gene–related peptide receptor antagonists), are not
associated with vasoconstriction or adverse cardiovascular out-
comes, even in higher-risk populations.59,60 Triptans, including su-
matriptan, eletriptan, rizatriptan, almotriptan, zolmitriptan, naratrip-
tan, and frovatriptan, can cause adverse effects in up to 25% of
patients, including transient flushing, tightness, or tingling sensa-
tion in the jaw, neck, or chest.57 Gepants have lower efficacy rates
at 2 hours after administration (an additional 5%-9% relative to pla-
cebo), but have few adverse effects aside from dry mouth.29,30,61,62
Lasmiditan eliminates migraine pain in 8% to 17% of recipients, com-
pared with placebo, but can cause dizziness and drowsiness. Pa-
tients who take lasmiditan should not drive or operate heavy ma-
chinery for at least 8 hours after ingestion.31,32 Because they are
costly and their safety profile is somewhat unclear, gepants and di-
tans are recommended only after 2 or more triptans have been in-
effective, are poorly tolerated, or are contraindicated.49 Serotonin
syndrome is a theoretical concern with coprescription of triptans and
antidepressants such as tricyclic antidepressants, selective seroto-
nin reuptake inhibitors, and serotonin and norepinephrine reuptake
inhibitors. However, the incidence is rare (2.3 cases per 10 000 per-
son-years of exposure).63 The American Headache Society does not
recommend limiting triptan prescription for patients taking
antidepressants.64 However, gepants may be a reasonable alterna-
tive for patients taking antidepressants.

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 Table 3. Migraine Preventive Therapies in Adultsa
Benefit, relative to placebo

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or control (mean reduction
Examples (typical daily target FDA approval (medication) in migraine or headache days
Drug or class dose unless otherwise indicated) Likely mechanisms or clearance (device) per month) Adverse effects Relative cost
Medications and supplements
Angiotensin receptor Candesartan, 16 mg; lisinopril, Decreases glutamate release; No 1-2 Common: hypotension, lightheadedness, +
blockers36; 10-20 mg enhances GABAergic tone cough (ACE inhibitors)
ACE inhibitors
β-Blockers Metoprolol, 50-200 mg; Inhibits norepinephrine Metoprolol; propranolol; timolol 1 Common: hypotension, bradycardia, +
propranolol, 120-160 mg; release; reduces neuronal asthma exacerbation, vivid dreams
timolol, 10-30 mg excitability; antagonizes 5-HT2 (nightly dosing), anorgasmia
Diagnosis and Management of Headache

receptors; inhibits nitric oxide

production
Botulinum toxin 155 U every 12 wk Peripheral inhibition of OnabotulinumtoxinA (chronic 1-2 Common: neck pain, brow ptosis +++
inflammatory migraine only)37
neurotransmitter/peptide
release
Butterbur 150 mg Antileukotriene activity; No 1-2 Common: eructation; rare/severe: liver ++
calcium channel inhibition toxicity
CGRP monoclonal Eptinezumab, 100 mg or 300 mg Bind to CGRP or its receptor Eptinezumab38,39; erenumab40-42; 1-3 Common: injection site reaction, brief +++
antibodies quarterly; erenumab, 70 mg or fremanezumab43,44; upper respiratory infectionlike
140 mg monthly; galcanezumab45-47 symptoms, constipation (erenumab);
fremanezumab, 225 mg monthly rare/severe: hypersensitivity reaction
or 675 mg quarterly; (erenumab), elevated blood pressure
galcanezumab, 240-mg loading (erenumab)
dose, then 120 mg monthly
Magnesium 400-800 mg Impedes NMDA-R functioning No 1 Common: diarrhea, stomach upset +
Melatonin48 3 mg Hypothalamic regulation No 2 Common: morning tiredness +
Serotonin- Venlafaxine, 75-150 mg Norepinephrine, 5-HT No 1-3 Common: nausea, insomnia, tremor, +
norepinephrine reuptake inhibition anorgasmia, erectile dysfunction;
reuptake inhibitors rare/severe: elevated blood pressure
Topiramate 100 mg Phosphorylation-mediated Topiramate 2 Common: paresthesia, taste perversion, +
inhibition of sodium-calcium cognitive impairment, weight loss;
channels; suppression of rare/severe: angle closure glaucoma,
glutamate transmission at kidney stones, teratogenicity
AMPA receptors; enhanced
GABA-A activity; carbonic

© 2021 American Medical Association. All rights reserved.

anhydrase II, IV inhibitor
Tricyclic antidepressants Amitriptyline or nortriptyline Norepinephrine, 5-HT No 1 Common: sedation, dry mouth, +

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25-50 mg reuptake inhibition; sodium
channel blockade; increases
GABA-mediated inhibition
Valproic acid 500-1000 mg Enhances postsynaptic GABA
response; increases GABA in
synaptosomes; increased
potassium conductance of
GABA receptors; stops raphe
5-HT neuronal firing
Vitamin B2, Riboflavin, 400 mg; Coenzyme Improves deficits in cerebral
Coenzyme Q10 Q10, 300 mg mitochondrial functioning
constipation, tachycardia, weight gain;
rare/severe: lowers seizure threshold
Divalproex sodium 1 Common: weight gain, tremor, sedation, +
hair loss; rare/severe: liver injury,
thrombocytopenia, marked
teratogenicity
No 1-2 Common: orange-colored urine +/++
(vitamin B2)

(continued)

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Review Clinical Review & Education

1879
 1880
Table 3. Migraine Preventive Therapies in Adultsa (continued)
Benefit, relative to placebo
or control (mean reduction
Examples (typical daily target FDA approval (medication) in migraine or headache days
Drug or class dose unless otherwise indicated) Likely mechanisms or clearance (device) per month) Adverse effects Relative cost
Neuromodulation devices33
Transcranial magnetic Single-pulse transcranial Inhibition of cortical spreading Yes 2 Common: dizziness, tinnitus, tingling, +++
stimulation magnetic stimulation depression and reduction of scalp irritation, local pain; rare/severe:
cortical hyperexcitability; seizures (contraindicated in patients with
modulates corticothalamic underlying epilepsy)
activation; modulates
Clinical Review & Education Review

spontaneous and
C-fiber–evoked
trigeminovascular activity in
third-order thalamic neurons;
modulates neurotransmitter
levels (eg, β-endorphin)
Trigeminal nerve External trigeminal nerve Suppression of small fiber Yes 2 Common: drowsiness, uncomfortable +++
stimulation stimulation nociceptive input; restoration scalp feeling
of cortical metabolic activity in

JAMA May 11, 2021 Volume 325, Number 18 (Reprinted)

orbitofrontal and anterior
cingulate cortex
Vagus nerve stimulation External vagus nerve stimulation Co-localization with upper Yes 0-1 Common: lip or facial pulling or +++
cervical dural afferents; twitching, local neck/throat pain
connections to numerous
primary and modulatory pain
pathways; inhibits cortical
spreading depression;
reduction of allodynia and
glutamatergic tone
Abbreviations: ACE, angiotensin-converting enzyme; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic include patients with either migraine or chronic migraine. Treatments featuring either emerging evidence not
acid; CGRP, calcitonin gene–related peptide; FDA, Food and Drug Administration; GABA, γ-aminobutyric acid; included in these guidelines and/or evidence for select clinical situations where aura may be a treatment target
NMDA-R, N-methyl-D-aspartate receptor. or not widely available may include memantine, verapamil, lamotrigine, and flunarizine. Dosing and formulation
a may vary.
Treatment list selected from medications and devices that are FDA approved or cleared, treatments endorsed in
b
guidelines,49-52 and quality measures.35 Data abstracted from guidelines unless otherwise cited within the table. + indicates low; ++, intermediate; and +++, high.
Treatment mechanisms of action from sources cited within the table and elsewhere.33,53,54 Study data may

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Diagnosis and Management of Headache
 Diagnosis and Management of Headache
Status migrainosus, defined by a migraine attack 72 hours or
longer in duration, typically requires emergency department or
urgent care visits.3 Outpatient therapy consists of repeated doses
of acute medications such as triptans, NSAIDs, or peripheral nerve
blocks, oral corticosteroids, or a long-acting triptan such as
naratriptan, intramuscular ketorolac, or intramuscular or intranasal
dihydroergotamine.65
Acute medication overuse occurs in as many as 15% of people
with migraine and 1% to 2% of the general population, and it con-
sists of repeated, frequent use of acute migraine treatments that
leads to an increase in attack frequency and progression of mi-
graine to chronic migraine. The diagnosis is defined by regular use
of acute medications for 10 or more (triptans, ergotamines, opi-
oids) or 15 or more (acetaminophen, NSAIDs) days per month over
at least 3 months.3 In an observational study of 11 094 participants
with migraine followed up over 1 year, the rate of progressing from
episodic to chronic migraine, compared with acetaminophen use
when controlling for potential confounders, was highest for barbi-
turates (6.4% episodic vs 12.9% chronic migraine; odds ratio, 2.06
[95% CI, 1.3-3.1] relative to acetaminophen) and opioids (12.5% epi-
sodic vs 21.1% chronic migraine; odds ratio, 1.98 [95% CI, 1.4-2.2] rela-
tive to acetaminophen).19 Acute medication overuse has not been
demonstrated with regular use of ditans or gepants. The optimal ap-
proach for treating acute medication overuse remains unclear. Re-
moving or weaning the acute medication is recommended.66
Preventive therapy is indicated when migraine attacks inter-
fere with functioning or are frequent or debilitating. Treatment
should be prescribed for patients with 6 headache days or more per
month, 4 headache days or more with at least some impairment (able
to function, but with reduced performance), or 3 headache days or
more with severe impairment (unable to function, requiring bed rest).
Preventive therapy should be considered with 4 or 5 migraine days
per month with normal functioning, 3 migraine days with some im-
pairment, or 2 migraine days with severe impairment. Indications
for preventive therapy also include lack of efficacy of acute treat-
ment or adverse effects, safety concerns, or overuse of acute treat-
ments, patient preferences, and uncommon migraine disorders
where nonheadache symptoms are prolonged or severe (such as
hemiplegic migraine defined as paralysis with attacks).34,49 Chronic
migraine is defined by its high attack frequency and preventive
therapy is indicated for all such patients.
Oral preventive medications include antihypertensive agents
such as β-blockers and angiotensin receptor blockers, antiepileptic
drugs, and antidepressants. Until recently, the therapeutic choice
for prevention was influenced mainly by comorbidities and ad-
verse effects. The approval of onabotulinumtoxinA (for chronic mi-
graine prevention only) and monoclonal antibodies to calcitonin ge-
ne–related peptide or its receptor (for migraine prevention of any
frequency), such as eptinezumab, erenumab, fremanezumab, and
galcanezumab, are options for patients with frequent migraine who
have not responded to more established oral medications. These
medications target the peripheral trigeminovascular system and do
not significantly penetrate the blood-brain barrier. Therefore, they
are typically better tolerated than alternative treatments. How-
ever, cost and access may limit use, and existing guidance from the
American Headache Society recommends that monoclonal antibod-
ies to calcitonin gene–related peptide or its receptor should be of-
fered when established treatments are ineffective. Treatment is con-
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Review Clinical Review & Education
sidered inadequate when there is no response after 6 weeks of
therapy or when discontinuation is necessary due to adverse
effects.49 The American Headache Society defined effective pre-
ventive therapy by any of the following: a 50% reduction in days of
migraine or headache frequency, a significant decrease in attack du-
ration or severity as defined by the patient, an improved response
to acute treatment, diminished migraine-related disability, or im-
provements in functioning, health-related quality of life, or psycho-
logical distress due to migraine. Efficacy rates of these newer as well
as established treatments are similar and typically consist of 1 to 3
fewer monthly migraine days. It is unclear whether more costly
monoclonal antibodies targeting calcitonin gene–related peptide are
more effective than other treatments. Calcitonin gene-related pep-
tid–targeting monoclonal antibodies have demonstrated efficacy in
patients who have medication overuse67 and in patients who have
failed multiple prior preventive treatments.68-70 Studies of onabo-
tulinumtoxinA generally show similar efficacy but better tolerabil-
ity than oral preventive therapies,71 although few clinicians may have
procedural expertise72 and the requirement for in-person visits can
present challenges.73
Based on their tolerability, 4 noninvasive, externally applied neu-
romodulation devices have been cleared by the US Food and Drug
Administration for use in migraine. These are handheld devices that
apply an electrical current or magnetic stimulation to the head or
body; they include a single-pulse transcranial magnetic stimulation
device applied to the occiput, an external trigeminal nerve stimu-
lation device applied to the forehead, an external vagus nerve stimu-
lation device applied to the neck, and a remote electrical neuro-
modulation armband device. Randomized clinical trials have
demonstrated their tolerability and efficacy with significant thera-
peutic gains in acute (10%-19% 2-hour freedom from pain rates) and
preventive (reduction of up to 2 migraine days/month) treatment
trials.33 These devices are recommended for patients unable or un-
willing to take medications because of adverse effects or contrain-
dications. Three of the 4 treatments are approved for both acute and
preventive therapy and 1 (remote electrical neuromodulation) is ap-
proved only for acute therapy. Randomized trials of neuromodula-
tion devices vs medications are lacking.
Behavioral therapies are recommended by the American Acad-
emy of Neurology34 and the American Headache Society,49 particu-
larly for patients who prefer nondrug options, are unable to take
medications, have acute medication overuse, or need stress cop-
ing skills. Mindfulness addresses the relationship of a patient with
their migraine experience. Biofeedback and cognitive behavioral
therapy teach skills to reduce attack frequency, distress, and mal-
adaptive thoughts. Behavioral therapy combined with preventive
drug therapy is superior to either treatment alone.74 A randomized
trial of 232 adults with migraine demonstrated that a β-blocker and
a behavioral migraine management strategy (individualized plan in-
cluding muscle stretching, deep breathing, progressive muscle re-
laxation, relaxation imagery, cognitive behavioral therapy, or ther-
mal biofeedback) reduced migraine attacks per 30 days (−3.3)
significantly more than either a β-blocker alone (−2.1), behavioral mi-
graine management alone (−2.2), or acute treatment alone (−2.1)
after 10 months.74 Benefits persisted at 16 months. In another
randomized trial of 60 patients with frequent migraine, compared
with a waitlist control group, mindfulness reduced the Headache Dis-
ability Index score (−14.3 vs −0.2), but did not reduce headache
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 Clinical Review & Education Review
frequency or intensity over a 4-month period.75 A second random-
ized trial of mindfulness-based stress reduction vs headache edu-
cation of 89 participants similarly demonstrated a 12-week reduc-
tion in migraine disability (Migraine Disability Assessment score, 13.3
vs 19.1) but not monthly migraine days (days with migraine symp-
toms) (−1.6 vs −2.0).76 In addition to in-person treatment, a smart-
phone-based approach to behavioral therapy for migraine and its
comorbidities may be preferred.77
Pregnancy
Migraine generally improves during pregnancy, but treatment
may be required. Preventive therapies are usually discontinued
prior to conception because migraine typically improves during
pregnancy and to avoid teratogenicity. Acetaminophen and
metoclopramide are safe in pregnancy, and evidence suggests
sumatriptan use is not associated with adverse pregnancy
outcomes.78 Peripheral nerve blocks (involving occipital and tri-
geminal nerve branches) are appropriate for more refractory
attacks or short-term preventive therapy.
Tension-Type Headache
TTH is the most common headache disorder, with a prevalence of
40.5% in the US.79 TTH is more common in men than women (preva-
lence ratio of 1.2 to 3:1) and is most common among those between
ages 30 and 39 years.80 Chronic TTH, defined as attacks occurring
15 days or more per month for 3 months or more,3 has a prevalence
of 2% to 3% and is associated with acute medication overuse, anxi-
ety, and depression.80 TTH can be disabling. Eight percent of 5981
people with episodic TTH reported missing workdays. Those with
chronic TTH missed work an average of 27 days per year.79
Acute treatment of TTH consists of analgesics such as NSAIDs,
acetaminophen, and combinations with caffeine in the same doses
used for migraine. Triptans are not effective for TTH, unless the pa-
tient also has migraine.81 TTH can be treated with preventive therapy
including biobehavioral therapies, such as biofeedback or cogni-
tive behavioral therapy, and medications, of which antidepres-
sants, particularly tricyclic antidepressants, are most effective. Guide-
lines for TTH generally recommend tricyclic antidepressants such
as amitriptyline starting at 10 to 25 mg nightly as a first-line therapy
to prevent TTH, followed by mirtazapine (an antagonist of α2-
adrenergic receptors on noradrenergic and serotonergic presynap-
tic neurons), 15 to 30 mg, before bed and venlafaxine (a serotonin
and norepinephrine reuptake inhibitor), up to 150 mg, daily.82 No
thresholds for the number of headache days per month have been
established for initiating preventive treatment for TTH. Preventive
therapy should be prescribed when attacks are frequent (ⱖ10 at-
tacks per month) or associated with significant disability and for those
with chronic TTH. Acupuncture83 and trigger point injections84 may
also be helpful.
Trigeminal Autonomic Cephalalgias
TACs are characterized by unilateral pain in the distribution of the
first division of the trigeminal nerve, accompanied by ipsilateral cra-
nial parasympathetic activation, including tearing, conjunctival in-
jection, miosis, ptosis, and rhinorrhea. There are 4 types of TACs: clus-
ter headache, paroxysmal hemicrania, short-lasting unilateral
neuralgiform headache attacks, and hemicrania continua.3 Each TAC
has a different pattern of headache attack frequency, duration, and
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Diagnosis and Management of Headache
treatment response. Most TACs have episodic and chronic sub-
forms, distinguished by the presence of a remission period of 3
months or more annually.3
Cluster headache is characterized by severe pain and restless-
ness. Cluster headache attacks are more common at night. Cluster
headache has an estimated lifetime prevalence of 0.1%, has a 3:1
male to female ratio, and approximately 10% of patients have
chronic cluster headache, which is particularly severe and more
resistant to treatment.85 Nonoral triptans (subcutaneous or intra-
nasal sumatriptan; intranasal zolmitriptan) and high-flow oxygen
are recommended for acute treatment. The calcium channel
blocker verapamil (with an initial target dose of 240 mg per day),
lithium up to 900 mg per day, and galcanezumab, 300 mg,
injected monthly are preventive therapies recommended by expert
opinion.86,87 Chronic therapies require at least 1 week after initia-
tion to prevent cluster headache. Bridge treatments, defined as
short-term preventive therapies used to reduce attacks while wait-
ing for preventive treatment to become effective, consist of a short
course of oral steroid for around 2 weeks or a greater occipital
nerve injection with steroid ipsilateral to the pain.86 External vagus
nerve stimulation is a tolerable adjunctive acute and preventive
treatment. Although not readily available, implanted sphenopala-
tine ganglion stimulation is one of a few therapies effective for
patients with chronic cluster headache.33,86
Other Primary Headaches
Less common primary headache disorders include headaches pro-
voked by cough, exertion, or sexual activity.3 New daily persistent
headache is an additional headache in this category featuring the
abrupt onset of a daily headache lasting for 3 months or more with
secondary causes excluded. This disorder may be intractable and
usually requires treatments also used for chronic migraine or
chronic TTH.88
Secondary Headaches
Secondary headache disorders are due to an underlying sympto-
matic cause and have numerous etiologies. In addition to the pos-
sible causes previously noted, intracranial pressure disorders
should be considered such as idiopathic intracranial hypertension
(IIH) and spontaneous intracranial hypotension (SIH). Pseudotu-
mor cerebri syndrome is defined as intracranial hypertension with-
out a structural or vascular cause. A diagnosis of IIH requires
excluding drug-induced, metabolic, or hormonal causes of intra-
cranial hypertension.3,89 IIH has an annual incidence of 1 to 2 per
100 000 and is more common in individuals with obesity. 90
Headache is the most common IIH symptom, though visual symp-
toms, including persistent blurred vision, transient visual obscura-
tions, and horizontal diplopia, as well as pulsatile tinnitus are fre-
quent, and if untreated can lead to irreversible visual loss. The
syndrome is most common in women aged 20 to 40 years who
are overweight.90 Patients should undergo fundoscopy to evalu-
ate for optic disc edema. Testing with brain MRI and magnetic
resonance venography can exclude other causes of intracranial
hypertension, such as neoplasm and cerebral venous thrombosis.
Additional diagnostic testing includes lumbar puncture to confirm
an elevated opening pressure (typically >250 mm of cerebrospinal
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 Diagnosis and Management of Headache Review Clinical Review & Education

fluid [CSF]) and ensure CSF constituents are normal and neuro-
ophthalmological evaluation. Treatment goals include vision pres-
ervation, which can be attained with weight loss and prescription
of acetazolamide to reduce CSF production. Patients with more se-
vere visual loss may require surgery to lower intracranial pressure.91
Headache improvement may not accompany visual improvement
and may require treatment with migraine therapies.92
Headache is an important symptom of low intracranial pres-
sure (intracranial hypotension) and may be precipitated by a spinal
CSF leak, leading to lower intracranial pressure or volume, down-
ward brain sagging with traction on intracranial structures, and com-
pensatory venous engorgement. Headache due to intracranial hy-
potension can be secondary to postdural puncture headache after
a diagnostic lumbar puncture, lumbar anesthesia, another spine pro-
cedure, or SIH.3 SIH has an estimated annual incidence of 2 to 5 per
100 000,93 and onset of SIH is often associated with an inciting event
such as a Valsalva maneuver. SIH can be caused by 3 types of CSF
leaks: focally weakened dura often in a nerve root sleeve, osteo-
phytic or discogenic ventral tears, or CSF-venous fistulas.94 The clas-
sic presentation of postdural puncture headache or SIH is an ortho-
static headache, developing within minutes of standing and
disappearing within minutes of becoming supine, though other head-
ache characteristics (exertional, “second-half-of-the-day head-
ache”) and nonheadache symptoms, including muffled hearing, may
be reported. Treatment includes hydration, nonspecific analge-
sics, and caffeine; however, the underlying cause may require more
definitive therapy if no improvement, including lumbar or targeted
autologous epidural blood patches and potentially surgical repair of
the leak or fistula site.
Limitations
This review has some limitations. First, relevant studies may have been
missed during the literature review. Second, this review does not cover
many secondary headache disorders such as posttraumatic head-
ache,othercerebrovasculardisorders,orinfectiousdiseases.Third,this
review is limited by the quality of included evidence.
Conclusions
Headache disorders affect approximately 90% of people during their
lifetime. Among primary headache disorders, migraine is most de-
bilitating and can be treated acutely with analgesics, NSAIDs, trip-
tans, gepants, and lasmiditan.

ARTICLE INFORMATION
Accepted for Publication: February 1, 2021.
Author Contributions: Dr Robbins had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Robbins.
Acquisition, analysis, or interpretation of data:
Robbins.
Drafting of the manuscript: Robbins.
Critical revision of the manuscript for important
intellectual content: Robbins.
Conflict of Interest Disclosures: Dr Robbins
reported serving on the board of directors for the
American Headache Society, the editorial board for
Headache, and is a section editor for Current Pain
and Headache Reports. He has received book
royalties from Wiley.
Submissions: We encourage authors to submit
papers for consideration as a Review. Please
contact Mary McGrae McDermott, MD, at
mdm608@northwestern.edu.
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