MIGRAINE HEADACHE












  • * 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)


  • 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





  • 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®)


Migraine treatment recommendations in children and adolescents
Children (4 - 12 years old)
  • First-line - Ibuprofen 7.5 - 10 mg/kg/dose every 6 - 8 hours. Do not exceed 400 mg/dose. Do not exceed 40 mg/kg/day.
  • Second-line - Acetaminophen 10 - 15 mg/kg/dose every 4 - 6 hours. Do not exceed 5 doses in 24 hours. Do not exceed 4000 mg/day
  • Third-line - triptans
    • Maxalt® (rizatriptan) - rizatriptan is FDA-approved for children 6 - 17 years
    • Imitrex® nasal spray (sumatriptan) - sumatriptan nasal spray has been studied in children as young as 8 years old
      • PMID 15037686 - sumatriptan nasal spray was given as a single dose in children 8 - 17 years old
        Dosing was as follows: 20 - 39 kg - 10 mg; ≥ 40 kg - 20 mg
Adolescents (> 12 years old)
  • First-line - Ibuprofen 200 - 400 mg every 4 - 6 hours. Do not exceed 1200 mg in 24 hours.
  • Second-line - Acetaminophen 650 mg every 4 - 6 hours. Do not exceed 3250 mg in 24 hours.
  • Third-line - triptans
    • Maxalt® (rizatriptan) - rizatriptan is FDA-approved for children 6 - 17 years
    • Axert® (almotriptan) - almotriptan is FDA-approved for adolescents 12 - 17 years
    • Imitrex® nasal spray (sumatriptan) - sumatriptan nasal spray has been studied in adolescents
      • PMID 15037686 - sumatriptan nasal spray was given as a single dose in children 8 - 17 years old.
        Dosing was as follows: 20 - 39 kg - 10 mg; ≥ 40 kg - 20 mg
      • PMID 11061765 - sumatriptan nasal spray was given as a single dose in children 12 - 17 years old.
        Dosing was 5, 10, and 20 mg.
      • PMID 16492230 - sumatriptan nasal spray was given as a single dose in children 12 - 17 years old.
        Dosing was 5 and 20 mg.



  • 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



  • Reference [9,16,17]
Criteria for starting preventive therapy
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]
Medications that are proven effective in preventing migraine
Medication Dosing
Valproic acid (Depakote®)
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
  • See beta blockers for more
Extended-release
  • Starting: 80 mg once daily
  • Maintenance: 160 - 240 mg once daily
Metoprolol (Toprol®)
  • 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)
  • 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
Medications that are probably effective in preventing migraine
Amitriptyline
Venlafaxine (Effexor XR®)
Atenolol (Tenormin®)
Nadolol (Corgard®)


  • Reference [7]
Medications for preventing migraines in children and adolescents
Medication Dosing and study
Valproic acid (Depakote®)
Topiramate (Topamax®)
  • Starting dose was 15 mg/day. Dose was titrated over an 8 week period to a target of 2 - 3 mg/kg/day. (ages 6 - 15)
  • Dosing based on PMID 16324162
  • See topiramate for more
Amitriptyline
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 is from package insert
  • Dosing based on PMID 15012660
Propranolol


Medications for preventing menstrual migraine
Medication Dosing and study
Frovatriptan (Frova®)
  • 2.5 mg once or twice daily for 6 days starting 2 days before anticipated headache
  • Dosing based on PMID 15277618
Naratriptan (Amerge®)
  • 1 mg twice daily for 5 days starting 2 days before anticipated onset of menses
  • Dosing based on PMID 11264684
Zolmitriptan (Zomig®)
  • 2.5 mg two to three times daily for 7 days starting 2 days before anticipated onset of menses
  • Dosing based on PMID 18788838


  • 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
Metoprolol
  • 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)



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

Duration: 24 weeks
Outcome Group 1 Group 2 Group 3 Comparisons
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 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

Duration: 6 months
Outcome Group 1 Group 2 Group 3 Comparisons
Primary outcome (decrease in migraine days/month) 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
Reduction in days/month of use of acute migraine–specific medications 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 Migraines that Failed 2 - 4 Previous Preventive Treatments, 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

Duration: 12 weeks
Outcome Group 1 Group 2 1 vs 2
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 Migraine Prevention, 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

Duration: 12 weeks
Outcome Group 1 Group 2 Group 3 Comparisons
Primary outcome -4.3 -4.6 -2.5 1 or 2 vs 3, p<0.001
Change in days/month of use of acute migraine–specific medications -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.