Migraine headache

ACRONYMS AND DEFINITIONS

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 overall U.S. adult population, 18% of women and 6% of men report at least one migraine attack in the last year. The prevalence of migraine headaches increases until the age of 40 years reaching a peak of around 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]
In children, the prevalence of migraine headache is 1% – 3% for 3 to 7 years old, 4% – 11% for 7 to 11 year olds, and 8% – 23% by age 15 years. The average age of onset is 7.2 years in boys and 10.9 years in girls [10,11,22]

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 stimulate arterial dilation in the meninges, and at the same time, activate perivascular trigeminal nerves. Trigeminal nerve activation leads to brain stem stimulation.
Brain stem stimulation ascends to the thalamus and the cortex causing heightened sensitivity to pain and stimulation
The auras that precede some migraines are thought to occur from a slow wave of oligemia (reduced blood flow) that crosses the cerebral cortex [1,8]

DIAGNOSTIC CRITERIA

Overview

Migraine headaches are typically divided into two classes - Migraine without aura and Migraine with aura
The International Headache Society publishes the most widely accepted criteria for migraine headaches. The criteria are detailed below.

^✝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)

TRIGGERS

Reference [9]
MIGRAINE TRIGGERS
Food triggers 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 triggers Too much or too little sleep Skipped meals Stress or post-stress Menstruation Fatigue Physical activity
Environmental triggers Loud noises Weather changes Perfumes or fumes High altitude Exposure to glare or flickering lights

MIGRAINE AND ATRIAL HEART DEFECTS

Patent foramen ovale (PFO)

The foramen ovale is a hole between the atria that allows right-to-left shunting of blood in utero. After birth, when blood circulation assumes its normal physiology, the foramen ovale closes by the age of one year in most individuals.
In up to 35% of the population, the foramen ovale does not completely close, and it becomes what is called a "patent foramen ovale"
Some observational studies have found that patients with a PFO are at higher risk of migraine headaches, particularly migraine with aura. Other studies have not found a significant association.
Proposed mechanisms of the link include: shunting of migraine triggering agents from right-to-left that normally would have been removed in the lungs; sudden hypoxemia from periodic right-to-left shunting
Observational studies have found that PFO closure improves migraine in some patients
A randomized, controlled trial (the MIST trial) was performed that compared PFO closure with sham closure in patients with intractable migraines with aura. The study found no significant effect of PFO closure on the primary outcome of migraine cessation. [PMID 18316488]
Based on the available evidence, there is no conclusive evidence that PFO increases the risk of migraine or that PFO closure reduces migraine [18,19]

Atrial septal defects (ASD)

Atrial septal defects occur when the septum between the atria of the heart fails to develop correctly leaving a defect (hole) between the atria. Atrial septal defects typically cause left-to-right shunting of blood.
Much like patent foramen ovale, ASDs have been associated with migraine headaches in observational studies. ASD closure has also been shown to improve migraine symptoms in some patients.
Paradoxically, ASD closure has been associated with new-onset migraines in patients who never had migraine headaches. In some studies, up to 17% of patients who never had a migraine experienced new-onset migraine headaches within 2 months of having an ASD closed. [19, 20]
A randomized controlled trial published in the JAMA in 2015 found that the addition of clopidogrel (75 mg/day for 3 months) to aspirin following ASD closure significantly reduced the number of days with migraine (0.4 vs 1.4) and the incidence of new-onset migraine (9.5% vs 21.8%) in the 3 months after closure. [PMID 26551304]

ACUTE TREATMENT

Adults

The American Academy of Neurology issued migraine treatment guidelines in 2000. The American Academy of Family Physicians and the American College of Physicians (AAFP/ACP) issued joint guidelines in 2002. The guidelines are very similar, and the AAFP/ACP guidelines are presented below.
Since the publication of these guidelines, several new classes of drugs (e.g. CGRP receptor antagonists, 5-HT1F agonists) have become available. No guidelines have been published since the advent of these medications, so they are not addressed.

See **migraine headache medications** for a review of triptans and ergotamines

Use a non-oral route if nausea and vomiting are intense

Reference [9]
AAFP/ACP Adult Migraine Treatment Recommendations
First-line therapies Aspirin Ibuprofen (Motrin®, Advil®) Naproxen sodium (Aleve®) Acetaminophen + aspirin + caffeine (Excedrin® migraine)
Second-line therapies Migranal® Oral naratriptan (Amerge®) Subcutaneous or oral sumatriptan (Imitrex®) Oral rizatriptan (Maxalt®) Oral zolmitriptan (Zomig®)

Children and adolescents

The AAN published guidelines for the treatment of acute migraine in children in 2019. Those guidelines along with information from trials and other sources are presented in the table below.

Reference [10,11,21]
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 it has been studied in children as young as 8 years old. In one study, sumatriptan was given to children aged 8 - 17 years with patients weighing 20 - 39 kg receiving 10 mg and patients weighing ≥ 40 kg receiving 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 it has been studied in children as young as 8 years old. In one study, sumatriptan was given to children aged 8 - 17 years with patients weighing 20 - 39 kg receiving 10 mg and patients weighing ≥ 40 kg receiving 20 mg. [PMID 15037686] In two other studies, sumatriptan nasal spray was given to children aged 12 - 17 years at doses of 5, 10, and 20 mg. [PMID 11061765, PMID 16492230]

Pregnancy

There are no consensus guidelines for treating migraines in pregnancy. Further complicating the matter, drug safety data is largely from observational studies.
In general, 60 - 70% of women see an improvement in their migraine headache symptoms during pregnancy. Up to 20% see their migraines disappear. [12]
The tables below summarizes the current available safety information for migraine medications in pregnancy and nursing

Reference [12,13,14,15]

AAP - American Academy of Pediatrics
Migraine Medications in Pregnancy
Medication	Comment
Acetaminophen	Preferred agent if effective Considered safe in all trimesters
Aspirin	Considered safe in first and second trimesters Avoid in third trimester
Ibuprofen Naproxen	Considered safe in first and second trimesters Avoid in third trimester
Caffeine	Considered safe in all trimesters
Triptans	Sumatriptan (Imitrex®) has the largest amount of available data. Based on observational studies, it appears to be safe in pregnancy. Rizatriptan (Maxalt®) and naratriptan (Amerge®) also appear to be safe, but there is less data for these two triptans. See migraine headache medications for a review of triptans
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

Adults

Medication recommendations from the AAN and the AHS are presented in the table below along with criteria for preventive therapy from the AAFP and ACP
Since the guidelines were published, several new classes of migraine medications have become available (e.g. CGRP inhibitors). No guidelines have been published since the advent of these medications, so they are not addressed.

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 [9,16,17]
Medications that are proven effective in preventing migraines in adults
Medication	Dosing
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 a day 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 a day 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	Biologicals approved to treat migraine See migraine headache medications for more

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 ≥ 50% reduction in headache frequency. In almost all trials, medications were not superior to placebo. Topiramate is the only FDA-approved medication for migraine prevention in children, and it is approved for children aged 12 - 17 years.
Given the lack of proven efficacy, the guidelines recommend that providers discuss treatment options with patients and family, but they do not recommend one medication over another. The table below lists some common medications that have been studied in pediatric migraine prevention trials. The AAN guidelines do not give specific criteria for starting preventive therapy, but criteria that are generally used in trials include ≥ 4 headache days a month and/or 3 - 4 migraine attacks per month for at least 3 months.

Medications for preventing migraines in children and adolescents
Medication	Dosing and study
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 In one trial, topiramate was found to be no better than placebo in preventing migraines in 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 In one trial, amitriptyline was found to be no better than placebo in preventing migraines in 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 migraines that are related to menstruation. They typically occur within 5 days (-2 to +3) of the onset of menses.
Several triptans have been shown to be effective in preventing menstrual migraine when taken daily for short periods around the onset of menses

Reference [7]
Medications for preventing menstrual migraine
Medication	Dosing and study
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

In general, 60 - 70% of women see an improvement in their migraine headache symptoms during pregnancy. Up to 20% see their migraines disappear. [12]
Medications that have been used in pregnancy and nursing are presented in the tables below

Reference [12,13,14,15]

AAP - American Academy of Pediatrics
Preventive therapies in pregnancy
Propranolol 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

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.

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.

Ubrogepant vs Placebo in 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

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.

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.

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.

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.

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

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