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®)


  • 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]


  • 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]
Medications that are proven effective in preventing migraines in adults
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
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

  • Reference [9,16,17]
Medications that are probably effective in preventing migraines in adults
Amitriptyline
Venlafaxine (Effexor XR®)
Atenolol (Tenormin®)
Nadolol (Corgard®)


Medications for preventing migraines in children and adolescents
Medication Dosing and study
Valproic acid (Depakote®)
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


  • 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]


  • 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)



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

Duration: 72 hours
Outcome Las 200 mg Las 100 mg Las 50 mg Placebo Comparisons
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

Duration: 48 hours
Outcome Rimegepant Placebo Comparisons
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

Duration: 24 hours
Outcome Placebo Ubr 50 mg Ubr 100 mg Comparisons
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.



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 Amitriptyline Topiramate Placebo 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 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

Duration: 6 months
Outcome Placebo Ere 70 Ere 140 Comparisons
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

Duration: 12 weeks
Outcome Erenumab Placebo Comparisons
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

Duration: 12 weeks
Outcome Frem every 3 mon Frem monthly Placebo Comparisons
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

Duration: 12 weeks
Outcome Frem once Frem monthly Placebo Comparisons
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

Duration: 12 weeks
Outcome Rimegepant Placebo Comparisons
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.