Migraine headache

Acronyms

ACP - American College of Physicians
AAFP - American Academy of Family Physicians
AAN - American Academy of Neurology
AAP - American Academy of Pediatrics
AHS - American Headache Society
CGRP - Calcitonin gene-related peptide
IHS - International Headache Society
MBS - Most bothersome symptom

EPIDEMIOLOGY

In the U.S. adult population, 18% of women and 6% of men report at least one migraine attack in the past year. The prevalence of migraine headaches increases until the age of 40, reaching a peak of approximately 40% in women and 10% in men, after which it steadily declines. Asians have the lowest prevalence, blacks have an intermediate prevalence, and whites have the highest prevalence. [7,10,11,22]
In children, the prevalence of migraine headache is as follows:

3 to 7: 1 - 3%
7 to 11: 4 - 11%
12 to 15: 8 - 23%

PATHOPHYSIOLOGY

The pathophysiology of migraine headache is complex and not completely understood. Briefly, it is believed that a migraine headache is initiated by the release of vasoactive peptides from sensory neurons that innervate meningeal blood vessels. The peptides trigger the following chain of events: (1) meningeal arterial dilation; (2) perivascular trigeminal nerve activation, causing brainstem stimulation; and (3) ascending brainstem stimulation to the thalamus and cortex, causing heightened sensitivity to pain and other stimuli.
The auras that precede some migraines are thought to result from a slow wave of oligemia (reduced blood flow) that spreads across the cerebral cortex [1,8]

DIAGNOSIS / DEFINITIONS

Overview

Migraine headaches are classified into two subtypes based on the presence or absence of aura. Diagnostic criteria from the International Headache Society (IHS) are provided in the tables below.
Migraine syndromes are categorized as as episodic or chronic, depending on headache frequency. Medication oversuse headache is a another recurrent headache syndrome associated with migraines.

^✝In children and adolescents, the headache may be 2 - 72 hours

Reference [6]
IHS Migraine Without Aura Criteria
A. At least five attacks fulfilling criteria B, C, and D
B. Headache attacks lasting 4 - 72^✝ hours (untreated or unsuccessfully treated)
C. Headache has at least 2 of the following 4 characteristics: Unilateral location (typically frontal and/or temporal region) Pulsating quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs)
D. At least one of the following during headache: Nausea and/or vomiting Sensitivity to light and sound

Reference [6,7]
IHS Migraine With Aura Criteria
Migraine headache with aura is a migraine headache (see above) that is preceded by the following:
A. At least 2 attacks fulfilling criteria B and C
B. One or more of the following fully reversible aura symptoms: Visual - most common aura occurring in up to 90% of patients. Consists of scotomata (blind spots), simple flashes (phosphenes), specks, geometric forms, and shimmering in the visual field. Sensory - second most common aura. Consists of "pins and needles" sensation affecting one side of the body, face, and/or tongue. Numbness may also occur. Speech and/or language - less common. Marked by aphasia (inability to speak). Motor - unilateral weakness. Also called hemiplegic migraine. Brainstem - may include symptoms of dysarthria (difficulty speaking), vertigo, tinnitus, hearing impairment, double vision, ataxia, and decreased level of consciousness. Also called basilar migraine. Retinal - monocular positive and/or negative visual phenomena (e.g. scintillations, scotomata, or blindness)
C. At least 2 of the following 4 characteristics: At least one aura symptom spreads gradually over 5 minutes, and/or two or more symptoms occur in succession Each individual aura symptom lasts 5 - 60 minutes At least one aura symptom is unilateral The aura is accompanied, or followed within 60 minutes, by headache (see above)

Episodic migraine - Headache days occur on fewer than 15 days per month

Chronic migraine - Headache occurs on 15 or more days per month for more than 3 months, with at least 8 of those days per month having features of migraine headache (e.g., unilateral, accompanied by nausea, vomiting, or photophobia)

Medication overuse headache

Diagnostic criteria for medication overuse headache include all of the following:

A. Pre-existing headache disorder: The patient must have a pre-existing primary headache disorder, most commonly migraine or tension-type headache
B. Headache frequency: Headache occurs on ≥ 15 days per month
C. Regular overuse of acute headache medication: Regular overuse for more than 3 months of one or more acute headache medications:

Triptans, opioids, ergots, combination analgesics: on ≥ 10 days per month
Simple analgesics (e.g., aspirin, ibuprofen, acetaminophen): on ≥ 15 days per month

D. Not better accounted for by another headache syndrome diagnosis: The headache is not better explained by another headache disorder. [23]

TRIGGERS

Food

Alcohol
Caffeine
Chocolate
Monosodium glutamate - found in tomatoes, Parmesan cheese, potatoes, mushrooms, and certain cuisines (Korean, Japanese and Chinese)
Tyramine-containing foods - found in most cheeses, chocolate, alcoholic beverages, aged or smoked meats, and other fermented foods
Nitrate-containing foods - found in certain vegetables (celery, cress, chervil, lettuce, red beetroot, spinach)

Physiologic

Too much or too little sleep
Skipped meals
Stress or post-stress
Menstruation
Fatigue
Physical activity

Environmental

Loud noises
Weather changes
Perfumes or fumes
High altitude
Exposure to glare or flickering lights [9]

MIGRAINE AND ATRIAL HEART DEFECTS

Patent foramen ovale (PFO)

The foramen ovale is an opening between the left and right atria that allows blood to flow from the right atrium to the left atrium before birth. After birth, the foramen closes within a year in most individuals; however, in up to 35% of people, it does not close completely and is called a "patent foramen ovale" or PFO for short.
Some observational studies have found a higher risk of migraine headaches, particularly with aura, in patients with a PFO. Proposed theories for the association include (1) right-to-left shunting of migraine-triggering agents that would normally be filtered by the lungs and (2) sudden hypoxemia from periodic right-to-left shunting. [18,19]
STUDY
A 2008 trial (N=147) comparing PFO closure to a sham procedure in patients with intractable migraines with aura found no significant effect of PFO closure on the primary outcome of migraine cessation. [PMID 18316488]

Atrial septal defects (ASD)

Atrial septal defects (ASD) occur when the septum between the right and left atria fails to develop correctly, leaving a defect between the chambers. Atrial septal defects typically cause left-to-right blood shunting. Like PFOs, ASDs have been associated with migraine headaches in observational studies. However, ASD closure has been paradoxically associated with new-onset migraines in patients with no migraine history, with up to 17% of patients experiencing new-onset migraine within 2 months of ASD closure. [19, 20]
STUDY
A 2015 trial (N=171) found that the addition of clopidogrel (75 mg/day for 3 months) to aspirin following ASD closure significantly reduced the incidence of new-onset migraine (9.5% vs 21.8%) and monthly migraine days (0.4 vs 1.4) in the 3 months following closure. [PMID 26551304]

ACUTE TREATMENT

See migraine headache medications

Reference [25]
ACP 2025 Acute Episodic Migraine Treatment Recommendations for Nonpregnant Adults
All patients Highlight the importance of lifestyle modifications with patients, including staying well hydrated, maintaining regular meals, securing sufficient and consistent sleep, engaging in regular physical activity (preferably moderate to intense aerobic exercise), managing stress with relaxation techniques or mindfulness practices, and, where applicable, pursuing weight loss for those who are overweight or obese. Also, explore modifiable migraine triggers or contributing factors during a detailed history.
Mild migraine Consider treating mild episodic migraine headache with an NSAID, acetaminophen, or a combination of the two
Moderate to severe migraine First-line therapy NSAID or acetaminophen. Ensure that the patient is receiving an adequate dose. Consider switching to a different NSAID if one is not working. Second-line therapy For patients who do not respond to NSAIDs or acetaminophen, add a triptan. Consider switching to a different triptan if one is not working. Third-line therapy For patients who do not tolerate or have an inadequate response to NSAIDs/acetaminophen with a triptan, consider CGRP receptor antagonists (rimegepant, ubrogepant, or zavegepant) or ergot alkaloid (dihydroergotamine) Fourth-line therapy For patients who do not tolerate or have an inadequate response to the above therapies, consider using lasmiditan (Reyvow) Other Counsel patients to begin treatment of migraine headache as soon as possible after its onset, using combination therapy (such as a triptan with an NSAID or acetaminophen) to improve efficacy Do not use opioids or butalbital for the treatment of acute episodic migraine Make sure patients are aware of medication overuse headache Consider using a nonoral triptan and an antiemetic in people having severe nausea or vomiting

Reference [10,11,21]
AAN 2019 Migraine Treatment Recommendations in Children and Adolescents
Children (4 - 11 years old) First-line Preferred: Ibuprofen 7.5 - 10 mg/kg/dose every 6 - 8 hours. Do not exceed 400 mg/dose. Do not exceed 40 mg/kg/day. Alternative: Acetaminophen 10 - 15 mg/kg/dose every 4 - 6 hours. Do not exceed 5 doses in 24 hours. Do not exceed 4000 mg/day Second line (one of the following) Maxalt® (rizatriptan) - rizatriptan is FDA-approved for children 6 - 17 years Imitrex® nasal spray (sumatriptan) - sumatriptan nasal spray is not FDA-approved in children but has been studied in patients as young as 8 years old. In one study, sumatriptan was given to children aged 8 to 17, with the following weight-based dosing: 44 lbs (20 kg) - 85 lbs (39 kg): 10 mg ≥ 88 lbs (40 kg): 20 mg [PMID 15037686]
Adolescents (≥ 12 years old) First-line Preferred: Ibuprofen 200 - 400 mg every 4 - 6 hours. Do not exceed 1200 mg in 24 hours. Alternative: Acetaminophen 650 mg every 4 - 6 hours. Do not exceed 3250 mg in 24 hours. Second line (one of the following) Maxalt® (rizatriptan) - rizatriptan is FDA-approved for children 6 - 17 years Axert® (almotriptan) - almotriptan is FDA-approved for children aged 12 - 17 years Zomig® nasal spray (zolmitriptan) - zolmitriptan nasal spray is FDA-approved in children gte 12 years old Imitrex® nasal spray (sumatriptan) - sumatriptan nasal spray is not FDA-approved in children but has been studied in patients as young as 8 years old. In one study, sumatriptan was given to children aged 8 to 17, with the following weight-based dosing: 44 lbs (20 kg) - 85 lbs (39 kg): 10 mg ≥ 88 lbs (40 kg): 20 mg [PMID 15037686] In two other studies, sumatriptan nasal spray was given to children aged 12 - 17 at doses of 5, 10, and 20 mg. [PMID 11061765, PMID 16492230]

Pregnancy

Pregnancy tends to improve migraine headaches, with 60 to 70% of women seeing an improvement and up to 20% becoming migraine-free. There are no consensus guidelines on treating migraines in pregnancy, but a review of pregnancy and nursing safety data for common therapies is provided in the tables below. [12]

Reference [12,13,14,15]

AAP - American Academy of Pediatrics
Migraine Headache Medications in Pregnancy
Acetaminophen Preferred agent if effective Considered safe in all trimesters
Aspirin Considered safe in first and second trimesters Avoid in third trimester
Ibuprofen and Naproxen Considered safe in first and second trimesters Avoid in third trimester
Caffeine Considered safe in all trimesters
Triptans Sumatriptan (Imitrex®) has the most data and appears to be safe based on observational studies. Rizatriptan (Maxalt®) and naratriptan (Amerge®) also appear to be safe but have less data. See migraine headache medications.
Ergotamines DO NOT USE

Reference [12,13,14,15]

AAP - American Academy of Pediatrics
Migraine Medications in Nursing
Medication	Comment
Acetaminophen	Considered safe (AAP)
Aspirin	Associated with Reye's syndrome Use caution (AAP)
Ibuprofen Naproxen	Considered safe (AAP)
Caffeine	Considered safe (AAP)
Triptans	Sumatriptan - considered safe (AAP) Naratriptan - probably safe Rizatriptan - probably safe
Ergotamines	DO NOT USE

PREVENTIVE TREATMENT

Overview

Preventive therapy criteria from the AAFP and ACP are presented below, along with the ACP 2025 preventive treatment recommendations. A review of available therapies from the AAN and AHS, dividing medications into proven effective and probably effective categories, is also provided.

Preventive therapy criteria

In general, preventive medication is recommended for patients who meet any of the following criteria:

Two or more attacks per month that produce disability that lasts 3 or more days per month
Contraindication to, or failure of, acute treatments
Use of abortive medication more than twice per week
The presence of uncommon migraine conditions, including hemiplegic migraine, migraine with prolonged aura, or migrainous infarction [9]

Reference [24]
ACP 2025 Adult Episodic Migraine Headache Prevention Recommendations
STEP 1 ACP suggests clinicians initiate monotherapy to prevent episodic migraine headache in nonpregnant adults in outpatient settings by choosing one of the following pharmacologic treatments (conditional recommendation; low-certainty evidence): A beta-adrenergic blocker, either metoprolol or propranolol The antiseizure medication valproate The serotonin and norepinephrine reuptake inhibitor venlafaxine The tricyclic antidepressant amitriptyline ➤If headaches are not controlled, proceed to STEP 2
STEP 2 ACP suggests clinicians use monotherapy with a calcitonin gene-related peptide (CGRP) antagonist-gepant (atogepant or rimegepant) or a CGRP monoclonal antibody (eptinezumab, erenumab, fremanezumab, or galcanezumab) to prevent episodic migraine headache in nonpregnant adults in outpatient settings who do not tolerate or inadequately respond to a trial or trials of a beta-adrenergic blocker (metoprolol or propranolol), the antiseizure medication valproate, the serotonin and norepinephrine reuptake inhibitor venlafaxine, or the tricyclic antidepressant amitriptyline (conditional recommendation; low-certainty evidence). ➤If headaches are not controlled, proceed to STEP 3
STEP 3 ACP suggests clinicians use monotherapy with the antiseizure medication topiramate to prevent episodic migraine headache in nonpregnant adults in outpatient settings who do not tolerate or inadequately respond to a first trial or trials of a beta-adrenergic blocker (metoprolol or propranolol), the antiseizure medication valproate, the serotonin and norepinephrine reuptake inhibitor venlafaxine, or the tricyclic antidepressant amitriptyline and a further trial with a calcitonin gene-related peptide (CGRP) antagonist-gepant (atogepant or rimegepant) or a CGRP monoclonal antibody (eptinezumab, erenumab, fremanezumab, or galcanezumab) (conditional recommendation; low-certainty evidence). Clinicians should use an informed decision-making approach and discuss benefits; harms; costs; patients’ values and preferences, including financial burden and mode of administration; contraindications; pregnancy and reproductive status in females; clinical comorbidities; and availability when selecting a pharmacologic treatment to prevent episodic migraine.

Reference [9,16,17]
Medications proven effective at preventing migraines in adults
Valproic acid (Depakote®) Dosing: 500 - 1000 mg/day See valproic acid for more
Topiramate (Topamax®) Starting: 25 mg in the evening Target dose: 50 mg twice daily Increase daily dose by 25 mg at weekly intervals See topiramate for more
Propranolol (Inderal®) Standard-release Starting: 80 mg/day Maintenance: 160 - 240 mg/day Give in 2 - 3 divided doses Extended-release Starting: 80 mg once daily Maintenance: 160 - 240 mg once daily See beta blockers for more
Metoprolol (Toprol®) Dosing: 150 - 200 mg/day Titrate dose over several weeks See beta blockers for more
Timolol Starting: 10 mg twice daily Maintenance: 10 - 30 mg/day Maximum: 30 mg/day 20 mg/day dose may be given as single daily dose See beta blockers for more
Petasites (butterbur plant extract) Dosing: 50 - 75 mg twice a day Petasites is a herbal extract from the butterbur plant Found effective in these two studies - PMID 15623680, PMID 11020030
CGRP inhibitors See migraine headache medications

Reference [9,16,17]
Medications that are probably effective in preventing migraines in adults
Amitriptyline Dosing: 25 - 150 mg/day See amitriptyline for more
Venlafaxine (Effexor XR®) Dosing: 75 - 150 mg/day See venlafaxine for more
Atenolol (Tenormin®) Dosing: 50 - 100 mg/day See beta blockers for more
Nadolol (Corgard®) Dosing: 40 - 80 mg/day See beta blockers for more

Children and adolescents

The AAN published recommendations on preventive migraine therapy in children in 2019. The guidelines state that the efficacy of current therapies is suspect because, in trials, up to 61% of children who received placebo reported a greater than 50% reduction in headache frequency. In almost all trials, medications were not superior to placebo. Topiramate is the only FDA-approved migraine prevention medication in children, with an indication in pediatric patients aged 12 to 17.
Given the lack of proven efficacy, the guidelines do not recommend one therapy over another; instead, they recommend providers discuss treatment options with patients and family. They also do not give specific criteria for preventive therapy. In trials, criteria included 4 or more headache days a month and/or 3 - 4 migraine attacks per month for at least 3 months. The table below lists some common medications that have been studied in pediatric migraine prevention trials.

Medications for preventing migraines in children and adolescents
Valproic acid (Depakote®) 7 - 16 years old: 15 - 45 mg/kg/day. Based on [PMID 10971664] See valproic acid for more
Topiramate (Topamax®) ≥ 12 years old Starting: 25 mg in the evening Target: 50 mg twice daily Increase daily dose by 25 mg at weekly intervals A 2017 trial found that topiramate was no better than placebo at preventing migraines in pediatric patients 8 - 17 year olds (see migraine prevention trial below) 6 - 15 years old Starting: 15 mg/day Target: titrate to a target of 2 - 3 mg/kg/day (max 200 mg/day) over an 8-week period. Based on [PMID 16324162] See topiramate for more
Amitriptyline 9 - 15 years old: Titrate slowly to a target of 1 mg/kg/day. Based on [PMID 10940092] See amitriptyline for more A 2017 trial found that amitriptyline was no better than placebo at preventing migraines in pediatric patients 8 - 17 year olds (see migraine prevention trial below)
Cyproheptadine 2 - 6 years: 2 mg two to three times a day (max 12 mg/day) 7 - 14 years: 4 mg two to three times a day (max 16 mg/day) Dosing from manufacturer's package insert
Propranolol 6 - 12 years old: 3 mg/kg/day. Based on [PMID 3822681]

Menstrual migraine

Menstrual migraines are migraine headaches that typically occur in the two days before or three days after the onset of menses. The triptans in the table below have been shown to be effective in preventing menstrual migraines in studies.

Reference [7]
Medications for preventing menstrual migraine
Frovatriptan (Frova®) Dosing: 2.5 mg once or twice daily for 6 days starting 2 days before anticipated headache. Based on [PMID 15277618]
Naratriptan (Amerge®) Dosing: 1 mg twice daily for 5 days starting 2 days before anticipated onset of menses. Based on [PMID 11264684]
Zolmitriptan (Zomig®) Dosing: 2.5 mg two to three times daily for 7 days starting 2 days before anticipated onset of menses. Based on [PMID 18788838]

Pregnancy and nursing

Pregnancy tends to improve migraine headaches, with 60 to 70% of women seeing an improvement and up to 20% becoming migraine-free. Preventive therapies that have data in pregnancy and nursing are reviewed in the tables below. [12]

Reference [12,13,14,15]
Preventive therapies in pregnancy
Propranolol and metoprolol Preferred agents Use lowest effective dose Stop 2 - 3 days before delivery to reduce risk of fetal bradycardia and reduction in uterine contractions
Amitriptyline Considered safe at lower doses (10 - 50 mg/day) When possible, taper 3 - 4 weeks before delivery
Aspirin Low-dose aspirin (75 mg/day) is considered safe in the first and second trimester Do not use in third trimester

Reference [12,13,14,15]

AAP - American Academy of Pediatrics
Preventive therapies in nursing
Propranolol	Considered safe (AAP)
Metoprolol	Considered safe (AAP)
Amitriptyline	Effect unknown but may be of concern (AAP)
Aspirin	Associated with Reye's syndrome Use caution (AAP)

STUDIES | ACUTE TREATMENT

RCT

Lasmiditan vs Placebo for Acute Migraine, Brain (2019) [PubMed abstract]

The trial enrolled 3005 patients with > 1 year history of disabling migraine with or without aura

Main inclusion criteria

≥ 1 year history of disabling migraine
Meet IHS diagnostic criteria
MIDAS score ≥ 11
Onset before age 50 years
3 - 8 migraines a month

Main exclusion criteria

≥ 15 headache days/month
Epilepsy
Vestibular migraine
Diabetes with complications
≥ 3 doses/month of opiate or barbiturate

Baseline characteristics

Average age 43 years
Female sex - 84%
Average migraines/month - 5.3
Average years with migraines - 18
Migraine with aura - 36%
MBS: Photophobia - 50% | Phonophobia - 21% | Nausea - 21%

Randomized treatment groups

Group 1 (528 patients): Lasmiditan 200 mg
Group 2 (532 patients): Lasmiditan 100 mg
Group 3 (556 patients): Lasmiditan 50 mg
Group 4 (540 patients): Placebo
Patients were instructed to take their assigned medication within 4 hours of next migraine attack
The study had another arm that looked at a second dose of study drug in patients who did not respond to the first dose. Results from that arm were not reported in this publication.
Of the 3005 enrolled patients, only 2156 patients treated a headache within 4 hours of onset and were included in the final analysis

Primary outcomes: Proportion of patients who were headache pain-free and most bothersome symptom (MBS) free at 2 hours after the first dose

Results

Outcome	Las 200 mg	Las 100 mg	Las 50 mg	Placebo	Comparisons
Duration: 72 hours
Headache pain-free	38.8%	31.4%	28.6%	21.3%	1 and 2 vs 4 p <0.001 \| 3 vs 4 p=0.003
MBS-free	48.7%	44.2%	40.8%	33.5%	1 and 2 vs 4 p <0.001 \| 3 vs 4 p=0.009
Dizziness	18%	18.1%	8.6%	2.5%	N/A
Somnolence	6.5%	4.6%	5.4%	2.0%	N/A
Paresthesia	6.6%	5.8%	2.4%	0.9%	N/A

Findings: Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.

RCT

Rimegepant vs Placebo for Acute Migraine Headache, Lancet (2019) [PubMed abstract]

The study enrolled 1466 patients with ≥ 1-year history of migraine headache with or without aura

Main inclusion criteria

≥ 1-year history of migraine
Meet IHS diagnostic criteria
Migraine onset before age 50 years
2 - 8 severe migraines/month
< 15 headache days/month

Main exclusion criteria

Alcohol or drug abuse

Baseline characteristics

Average age 40 years
Female sex - 85%
Migraine with aura - 30%
Average # of moderate-severe attacks/month - 4.6
MBS: Photophobia - 57% | Nausea - 23% | Phonophobia - 19%

Randomized treatment groups

Group 1 (669 patients): Rimegepant 75 mg one time with moderate-severe migraine headache
Group 2 (682 patients): Placebo
Subjects were allowed to take other rescue medications (e.g. NSAIDs, antinausea) if necessary 2 hours post-dose

Primary outcomes: Freedom from pain and freedom from the most bothersome symptom (MBS) associated with migraine at 2 hours post-dose

Results

Outcome	Rimegepant	Placebo	Comparisons
Duration: 48 hours
Freedom from pain	21%	11%	p<0.0001
Freedom from MBS	35%	27%	p=0.0009
Nausea	2%	<1%	N/A
Adverse events were minimal and similar between groups

Findings: In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns.

RCT

Ubrogepant vs Placebo for Acute Migraine Headache, NEJM (2019) [PubMed abstract]

The trial enrolled 1667 patients with ≥ 1-year history of migraine headache with or without aura

Main inclusion criteria

≥ 1-year history of migraine
Meet IHS diagnostic criteria
Migraine onset before age 50 years
2 - 8 moderate-severe migraines/month

Main exclusion criteria

≥ 15 headache days/month
Previous CGRP-based treatment
Significant CVD
Significant liver disease

Baseline characteristics

Average age 41 years
Female sex - 88%
Use of preventive med - 23%
MBS: Photophobia - 56% | Phonophobia - 22% | Nausea - 21%

Randomized treatment groups

Group 1 (456 patients): Placebo
Group 2 (423 patients): Ubrogepant 50 mg with moderate-severe migraine headache
Group 2 (448 patients): Ubrogepant 100 mg with moderate-severe migraine headache
The study had another arm that looked at a second dose of study drug in patients who did not respond to the first dose. Results from that arm were not reported in this publication.
Of the 1667 enrolled patients, only 1327 patients correctly followed the protocol and were included in the final analysis

Primary outcomes: Freedom from pain at 2 hours after the initial dose of ubrogepant or placebo and absence of the most bothersome symptom (MBS) associated with migraine at 2 hours

Results

Outcome	Placebo	Ubr 50 mg	Ubr 100 mg	Comparisons
Duration: 24 hours
Pain-free at 2 hours	11.8%	19.2%	21.2%	2 vs 1 p=0.002 \| 3 vs 1 p<0.001
MBS-free at 2 hours	27.8%	38.6%	37.7%	2 or 3 vs 1 p=0.002
Pain relief at 2 hours	49.1%	60.7%	61.4%	2 or 3 vs 1 p=0.002
Nausea	1.6%	1.7%	4.1%	N/A
Somnolence	0.8%	0.6%	2.5%	N/A
Dry mouth	0.4%	0.6%	2.1%	N/A

Findings: A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine.

STUDIES | PREVENTIVE

RCT

Amitriptyline vs Topiramate vs Placebo for Prevention of Pediatric Migraine, NEJM (2017) [PubMed abstract]

The trial enrolled children 8 to 17 years old with ≥ 4 migraines/month

Main inclusion criteria

Females or males 8 - 17 years
Migraine with or without aura or chronic migraine
≥ 4 migraine days a month

Main exclusion criteria

Current use of preventive migraine med
Previously failed amitriptyline or topiramate
Prolonged QT interval (≥ 450 msec)

Baseline characteristics

Average age - 14 years
Average # of headache days/month - 11
Female sex - 69%

Randomized treatment groups

Group 1 (144 patients): Amitriptyline target dose of 1 mg/kg/day given in 2 divided doses
Group 2 (145 patients): Topiramate target dose of 2 mg/kg/day given in 2 divided doses
Group 3 (72 patients): Placebo
Doses were increased every 2 weeks over 8 weeks
The trial had a 28-day baseline period before randomization

Primary outcome: Relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial

Results

Outcome	Amitriptyline	Topiramate	Placebo	Comparisons
Duration: 24 weeks
Primary outcome	52%	55%	61%	1 vs 3: p=0.26 \| 2 vs 3: p=0.48
Reduction in headache days/month	6.7	6.7	5.9	1 vs 3: p=0.36 \| 2 vs 3: p=0.41

Findings: There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events.

RCT

Erenumab vs Placebo for Prevention of Episodic Migraine, NEJM (2017) [PubMed abstract]

The trial enrolled 955 patients with episodic migraine headache

Main inclusion criteria

History of migraine with or without aura for at least 12 months before screening
4 - 15 migraine days per month

Main exclusion criteria

Older than 50 years of age at migraine onset
History of hemiplegic migraine or cluster headache
Prior nonresponse to more than two migraine-preventive treatment categories
Taking ≥ 2 migraine preventive medications

Baseline characteristics

Average age - 41 years
Female sex - 85%
Taking preventive migraine medication at baseline - 3%
Average migraine days per month - 8.3
Failed previous preventive treatment - 40%

Randomized treatment groups

Group 1 (316 patients) - Placebo injection
Group 2 (312 patients) - Erenumab 70 mg SQ once monthly
Group 3 (318 patients) - Erenumab 140 mg SQ once monthly
Abortive medications including triptans and ergotamines were allowed for acute treatment
The trial had a 4-week run-in phase before patients were randomized to the 6-month double-blind treatment phase

Primary outcome: Change in mean number of migraine days per month from baseline to the final 3 months (months 4 through 6) of the double-blind treatment phase

Results

Outcome	Placebo	Ere 70	Ere 140	Comparisons
Duration: 6 months
Primary outcome	-1.8	-3.2	-3.7	Group 2 or 3 vs 1 p<0.001
Reduction of ≥ 50% in migraine days/month	27%	43%	50%	Group 2 or 3 vs 1 p<0.001
Change in days/month using acute migraine meds	-0.2	-1.1	-1.6	Group 2 or 3 vs 1 p<0.001
Adverse event rates were similar between the two treatment groups and placebo

Findings: Erenumab administered subcutaneously at a monthly dose of 70 mg or 140 mg significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine-specific medication over a period of 6 months. The long-term safety and durability of the effect of erenumab require further study.

RCT

LIBERTY Study - Erenumab vs Placebo for Prevention of Treatment-Resistant Migraines, Lancet (2018) [PubMed abstract]

The trial enrolled 246 patients with episodic migraine who had failed previous treatment

Main inclusion criteria

History of episodic migraine with or without aura for at least 12 months
Failed previous treatment (in terms of either efficacy or tolerability, or both) with 2 - 4 migraine preventive therapies. Preventive therapies included propranolol, metoprolol, topiramate, flunarizine, valproate, amitriptyline, venlafaxine, lisinopril, candesartan, or other locally approved preventives.

Main exclusion criteria

Older than 50 years at migraine onset
Active chronic pain syndrome

Baseline characteristics

Average age - 44 years
Female - 80%
Average monthly migraine days - 9.2
Previous unsuccessful treatments: Topiramate - 85%, Propranolol - 45%, Amitriptyline - 45%, Metoprolol - 38%, Valproate - 28%

Randomized treatment groups

Group 1 (121 patients): Erenumab 140 mg SQ once monthly
Group 2 (125 patients): Placebo

Primary outcome: Proportion of patients who achieved at least a 50% reduction from their individual baseline in the number of monthly migraine days during the third month of the double-blind treatment phase (ie, weeks 9–12)

Results

Outcome	Erenumab	Placebo	Comparisons
Duration: 12 weeks
Primary outcome (≥ 50% reduction)	30%	14%	OR 2.7 95%CI [1.4 - 5.2], p=0.002
Primary outcome (≥ 75% reduction)	12%	4%	OR 3.2 95%CI [1.1 - 9.0], p=0.025
Primary outcome (100% reduction)	6%	0%	N/A
Reduction in monthly migraine days (weeks 9 - 12)	1.8 days	0.2 days	Diff 1.6 95%CI [0.5 - 2.7], p=0.004
Adverse events were similar between the two groups

Findings: Compared with placebo, erenumab was efficacious in patients with episodic migraine who previously did not respond to or tolerate between two and four previous migraine preventive treatments. Erenumab might be an option for patients with difficult-to-treat migraine who have high unmet needs and few treatment options.

RCT

Fremanezumab vs Placebo for Prevention of Migraine, NEJM (2017) [PubMed abstract]

The trial enrolled 1130 patients with episodic migraine

Main inclusion criteria

Age 18 to 70 years with migraine onset at ≤ 50 years of age
History of migraine for ≥ 12 months prior to screening
Headache occurring on ≥ 15 days each month
Using ≤ 1 preventive medication

Main exclusion criteria

Patients using opioids or barbiturates
Taking preventive treatment and previously failed ≥ 2 previous preventive treatments
Unremitting headaches (headaches for > 80% of awake time)

Baseline characteristics

Average age - 41 years
Female - 87%
Average monthly headache days - 13
Taking preventive medication - 21%
Previous use of topiramate - 30%

Randomized treatment groups

Group 1 (376 patients): Fremanezumab 675 mg once every 3 months
Group 2 (379 patients): Fremanezumab 675 mg one time followed by 225 mg at weeks 4 and 8
Group 3 (375 patients): Placebo

Primary outcome: Mean change from baseline in the average number of headache days (defined as days in which headache pain lasted ≥4 consecutive hours and had a peak severity of at least a moderate level or days in which acute migraine–specific medication [triptans or ergots] was used to treat a headache of any severity or duration) per month during the 12 weeks after the first dose

Results

Outcome	Frem every 3 mon	Frem monthly	Placebo	Comparisons
Duration: 12 weeks
Primary outcome	-4.3	-4.6	-2.5	1 or 2 vs 3 p<0.001
Change in days/month using acute migraine meds	-3.7	-4.2	-1.9	1 or 2 vs 3 p<0.001
≥ 50% reduction in mean HA days/month	38%	41%	18%	N/A
Injection site reactions were slightly more common in the fremanezumab groups - 47% vs 40% Other adverse events were similar between fremanezumab and placebo

Findings: Fremanezumab as a preventive treatment for chronic migraine resulted in a lower frequency of headache than placebo in this 12-week trial. Injection-site reactions to the drug were common. The long-term durability and safety of fremanezumab require further study.

RCT

FOCUS trial - Fremanezumab vs Placebo for Treatment-Resistant Migraines, Lancet (2019) [PubMed abstract]

The FOCUS trial enrolled 838 patients with episodic (6 - 14 headaches/month) or chronic migraines (≥ 15 headaches/month) who had failed 2 - 4 preventive therapies

Main inclusion criteria

Migraine diagnosis before age of 50 years
Migraines for ≥ 12 months prior
Episodic or chronic migraines with or without aura
Failure of 2 - 4 preventive meds in last 10 years

Main exclusion criteria

Current use of preventive med
Previous CGRP use
Significant cardiovascular disease

Baseline characteristics

Average age 46 years
Female - 84%
Episodic migraine - 40% | Chronic migraine - 60%
Average years since diagnosis - 24
Average migraine days/month - 14
Average days of acute headache med/month - 12.6
Number of failed meds: 2 - 50% | 3 - 32% | 4 - 18%

Randomized treatment groups

Group 1 (276 patients): Fremanezumab 675 mg SQ one time followed by monthly placebo
Group 2 (283 patients): Fremanezumab 225 mg (episodic) or 675 mg (chronic) SQ one time followed by 225 mg every month
Group 3 (279 patients): Placebo
Anticonvulsants (70%), beta blockers (56%), and tricyclic antidepressants (46%) were the most common classes of migraine preventive medications that patients had failed previously
There was a 28-day run-in period before randomization where participants recorded their headache frequency
Acute migraine treatments were continued as needed

Primary outcome: Mean change from baseline (28-day run-in period) in the monthly average number of migraine days during the entire 12 weeks after the first dose of study drug. A migraine day was defined as a calendar day with ≥ 4 consecutive hours of a migraine with or without aura as per ICHD-3 diagnostic criteria, or a headache of any duration treated with migraine-specific acute medications (triptans or ergot compounds).

Results

Outcome	Frem once	Frem monthly	Placebo	Comparisons
Duration: 12 weeks
Primary outcome	-3.7	-4.1	-0.6	1 or 2 vs 3 p<0.0001
≥ 50% reduction in monthly migraine days	34%	34%	9%	1 or 2 vs 3 p<0.0001
% change in days/month with headache	-34.9%	-36.8%	-8.5%	N/A
Effects were similar between patients with episodic and chronic migraines There was no significant difference in adverse events

Findings: Fremanezumab was effective and well tolerated in patients with difficult-to-treat migraine who had previously not responded to up to four classes of migraine preventive medications

RCT

Rimegepant vs Placebo for Migraine Prevention, Lancet (2021) [PubMed abstract]

The trial enrolled 1591 adults with at least a 1-year history of migraine headache

Main inclusion criteria

Age ≥ 18 years
≥ 1-year history of migraine with aura, migraine without aura, or chronic migraine
4 - 18 moderate-to-severe migraines per month
Age of onset < 50 years

Main exclusion criteria

History of nonresponse to > 2 preventive drug categories
Alcohol or drug abuse
Basilar migraine or hemiplegic migraine
Chronic pain syndrome (e.g. fibromyalgia)

Baseline characteristics

Average age 41 years
Female sex - 83%
Average migraine days/month - 10.1
Migraine with aura - 40%
Average age of migraine onset - 18 years

Randomized treatment groups

Group 1 (370 patients): Rimegepant 75 mg every other day
Group 2 (371 patients): Placebo
The study had a 4-week run-in observation period where all subjects documented their daily migraines and treatments used
Participants were allowed to take one preventive migraine drug, excluding CGRP receptor antagonists and CGRP monoclonal antibodies, provided that the dose was stable for at least 3 months before the 4-week observation period and did not change during the observation period or the double-blind treatment phase
Rescue medications that were permitted during the trial included triptans, NSAIDs, paracetamol, aspirin, caffeine, baclofen, antiemetics, and muscle relaxants

Primary outcome: Change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9–12)

Results

Outcome	Rimegepant	Placebo	Comparisons
Duration: 12 weeks
Primary outcome	-4.3	-3.5	p=0.0099
> 50% reduction in migraine days	49%	41%	p=0.044
Rescue medication days	3.7	4	p=0.39
Adverse events were similar between the groups

Findings: Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted.

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MIGRAINE HEADACHE

Acronyms