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Prevention of Migraine
Gerald W. Smetana, M.D., MACP
Division of General Medicine
Beth Israel Deaconess Medical Center
Professor of Medicine
Harvard Medical School
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Goals
• Obtain a headache diary
• Individualized plan to avoid migraine triggers
• Complementary and alternative Rx of migraine
• Acupuncture
• Preventive Rx of migraine for selected patients
• Novel CGRP receptor antagonists
• Refractory preventive Rx options
• Menstrual migraine
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One-Year Prevalence of Common
Headache Disorders
18
41
56
40
2.8
0
10
20
30
40
50
Migraine Episodic Tension-Type Headache Chronic Daily Headache
Female Male
%
Neurology 1996;47:52
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Primary Headache Syndromes
• Migraine without aura
• Migraine with aura
• Migraine with typical aura
• Tension-type headache
• Cluster headache
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Case Vignette: Karen
A 24-year-old primary care patient comes to see you for management of migraines
• What lifestyle changes will help me help my migraines?
• Which acute medication is right for me?
• Should I take preventive medicine?
• Do complementary medicines work?
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Treatment of Migraine: General Principles
• Lifestyle advice to minimize triggers for all patients
• Acute therapy at onset of migraine
• Preventive therapy for patients with frequent and/or disabling migraines
• Consider complementary and physical treatments for patients with poor Rx response or based on patient preference
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Lifestyle Approaches to Migraine: Obtain a
Headache Diary
• Ask patient to keep a headache diary for one month
• Record
– Dates
– Events prior to headache
– Presence of headache
– Type and location of pain
– Menses
– Sleep patterns
– Foods, caffeine, alcohol
– Stress
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Sample Headache DiaryDate 1 2 3
Time headache began
Time headache ended
Menses in past 2 days
Food triggers
Hours of sleep night before
Stressful events
Intensity (1-10 scale)
Preceding symptoms
Type of pain (pressure, stabbing)
Other symptoms (nausea, etc.)
Medication used
Disabled by headache (yes/no)
Relief with treatment (complete, partial, none)
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Patient Education: Avoid Migraine Triggers
• Tailor recommendations based on headache diary
• Regular meal and sleep pattern
• Avoid oversleeping, skipping meals
• Limit caffeine intake < 2 drinks / day
• Avoid offending foods
– Cheese, red wine, MSG, chocolate, alcohol most common offenders
• Regular exercise
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Complementary Physical Treatments for
Headache
Migraine
Probably effective
• Spinal manipulation
• Biofeedback
Possibly effective
• Electromagnetic fields
• TENS and electrical neurotransmitter modulation
Tension-type headache
Probably effective
• Spinal manipulation
Possibly effective
• Therapeutic touch
• Cranial electrotherapy
• TENS
• TENS and electrical neurotransmitter modulation
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Cochrane: Acupuncture is More Effective
than Meds and is Safe
• 22 trials (n=4985)
• Acupuncture vs. placebo:
– 41% vs. 17% (at least 50% reduction)
• Acupuncture vs. sham Rx: sham nearly as effective
– 50% vs. 41% (sham)
• Acupuncture vs. medications for prevention: more effective than meds
– 57% vs. 46%
– Safer than meds (fewer dropouts in trials)
Cochrane Database Syst Rev 2016: Issue 6
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Case Vignette: Linda
• My headaches are terrible
• I can’t work for a day or two each time
• Acute treatments hardly touch my headache
• Can I try preventive Rx?
• Which one is right for me?
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Indications for Preventive Therapy
• More than 2 migraines per week
• Headache related disability for ≥ 3 days per month
• Duration > 48 hours
• Acute migraine treatments are ineffective or overused
• Attacks produce severe disability
• Prolonged aura (> 1 hour), complex aura, or migrainous infarction
• Patient preference
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Principles of Migraine Prevention
• 50% or greater reduction in severity or frequency is a success
• May take 2-3 months to take effect
• Use drugs that benefit a coexisting condition when possible
• Goal is fewer headaches, less absence from work or school, less use of abortive medications
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Beta Blockers
• Most commonly used prophylaxis
• Avoid if history of CHF, asthma, diabetes (relative contraindication), depression
• Propranolol best studied
– 80-240 mg daily
• Timolol, atenolol, metoprolol also effective
• Begin low dose, may need to push to full beta blockade (i.e. HR in 50’s)
• Follow bp, HR
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Divalproex Sodium
• Equivalent efficacy to beta blockers
• Doses of 500-1000 mg daily are effective
• Requires baseline and periodic laboratory monitoring:
– LFTs, platelet count, coagulation studies
• Contraindicated during pregnancy and reproductive age women not using birth control
• Weight gain important side effect
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Topiramate
• Efficacy similar to propranolol
• Side effects are common and may result in discontinuation
– Paresthesias
– Fatigue, poor concentration
– Weight loss
– Acute angle closure glaucoma (rare)
• Limit maximum dose to 50 mg bid
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Cochrane: Odds Ratio for 50% Reduction in
Migraine Frequency with Anticonvulsants
Chronicle, Edward P, Mulleners, Wim M. Anticonvulsant drugs for migraine prophylaxis. Cochrane Database: Revised June 2013
Divalproex Sodium
TopiramateCOPYRIGHT
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Amitriptyline
• Efficacy similar to propranolol in clinical practice
• Side effects are common and may result in discontinuation
– Weight gain
– Dry mouth
– Constipation
• Equally effective in non-depressed patients
• Usual doses 10-50 mg qhs
• Helpful if coexistent chronic pain or insomnia
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TCAs Effective for Both Migraine and Tension Type Headache
Likelihoodof≥50%reductioninheadachec/wplacebo
BMJ 2010;341:c522
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Third Line Approach: Botulinum Toxin
Botulinum toxin pericranial injections
• Ineffective for episodic migraine
• Ineffective for chronic tension-type headache
• Effective for chronic migraine and chronic daily headache
• FDA approved for chronic (not episodic) migraine in 2010 (at least 15 migraine days per month
• Treat every 12 weeks
AAN Guideline: Neurology 2008;70:1707
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Ms. Mai Grène
• 34 year-old woman with disabling migraines 15 days per month
• Intolerant of most preventive Rx’s
• Triptans limited by chest pressure
• NSAIDs cause dyspepsia
• What about this new biologic Rx? Is it right for me?
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Three Potential Theories of Migraine Pathogenesis
1. Vasodilation
2. Cutaneous allodynia
3. Neurogenic inflammation
– Release of neuropeptides from sensory neurons:
– Substance P
– Neurokinin A (NKA)
– Calcitonin gene related peptide (CGRP)
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What is CGRP?
• 37- amino acid neuropeptide
• CGRP containing nerve fibers innervate most organ systems
• Regulates CV system
• Mediates neurogenic inflammation, modulates nociceptive inputs
• CGRP levels rise during acute migraine
• IV injection of CGRP causes migraines
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CGRP Induces Heightened Sensory Perception and Vasodilatation
Annu Rev Pharmacol Toxicol 2015; 55: 533
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Erenumab is a Novel Monoclonal Antibody
Against CGRP Receptor
• Human monoclonal antibody
• Binds to CGRP receptor
• Prevents CGRP induced sensory hypersensitivity and the rise in CGRP activity that occurs during migraine attacksCOPYRIGHT
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STRIVE: RCT of Erenumab vs. Placebo for
Episodic Migraine
• N= 955
• Adults aged 18-65
• Between 4 and 14 migraine days per month
• Randomly assigned to erenumab 70 mg or 140 mg SC monthly, or placebo
• Primary outcome: Change in # migraine days per month
• Secondary outcome: % with at least 50% reduction migraine days, and change in use of acute medications for migraine
NEJM 2017;377:22
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Mean Reduction of 3.2-3.7 Migraine
Days per Month
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One Half of Patients Had at least 50%
Reduction in Migraine Days per Month
50% Reduction
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Adverse Events Less Common than in Placebo
Event Placebo % Erenumab 70
mg %
Erenumab 140
mg %
Any 63 57 56
URI 6 7 5
Arthralgia 2 2 2
Sinusitis 2 2 3
Fatigue 3 2 2
Nausea 2 2 2
Rx d/c 3 2 2
Injection site pain 0.3 3 0.3
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Summary of Results from 3 RCTs (Medical Letter June 2018)
D Migraine
Days/month
≥ 50% Reduction
Days/mo.
Episodic migraine Study 1
Erenumab 70 mg -3.2 43%
Erenumab 140 mg -3.7 50%
Placebo -1.8 27%
Episodic migraine Study 2
Erenumab 70 mg -2.9 40%
Placebo -1.8 30%
Chronic migraine Study 3
Erenumab 70 mg -6.6 40%
Erenumab 140 mg -6.6 42%
Placebo -4.2 24%
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Other Considerations
• No data on safety in pregnancy
• Benefit continued through at least 36 months in a separate study
• Approved dose is 70 mg SC once monthly, self injected
• Can increase to 140 mg SC in selected patients
• 2 other monoclonal Ab to CGRP have since been FDA approved as well: galcanezumab, fremanezumab
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Key Points
• CGRP receptor antagonists are safe and well tolerated
• Need longer term data to establish if ?CV risk
• Single monthly injection, safe at home
• Reduces migraine days by one half
• Cost comparable to Botulinum toxin and easier to administer
• A major advance for patients who are disabled by migraines and tolerate existing Rx options poorly
• Safe and appropriate to Rx in primary care settings
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Other Preventive Therapies
• Verapamil
– Particularly for exertional migraine or migraines in men
• Venlafaxine probably effective
– Suggest use if amitriptyline fails or not tolerated
• Short term daily triptans
– Effective for menstrual migraine
• ACE inhibitors
– Lisinopril effective in a single study
• ARBs
– Candesartan may be effective
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American Academy of Neurology 2012:
Evidence Based Preventive Treatment
Level A
Established efficacy
Anti-epileptic drugs
Topiramate
Divalproex sodium
Beta blockers
Propranolol
Metoprolol
Timolol
Level B
Probably effective
Antidepressants
Amitriptyline
Venlafaxine
Beta blockers
Atenolol
Nadolol
Triptans
Naratriptan
ZolmitriptanNeurology 2012;78:1137
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2012 Evidence Based Preventive Treatment
Level C
Possibly effective
ACEi
Lisinopril
ARB
Candesartan
Alpha blocker
Clonidine
Anti-epileptic drugs
Carbamazepine
Level U (abbreviated list)
Conflicting or inadequate data
Acetazolamide
Warfarin
Fluoxetine
Gabapentin
Nifedipine
Verapamil
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Summary: Preventive Migraine Rx
Drug Efficacy Side effects Relative contraindications
β-Blockers• Metoprolol• Propranolol
4+ 2+ Asthma, depression, CHF
Antidepressants
• Amitriptyline 3+ 3+ Mania, BPH, heart block
• Venlafaxine 2+ 1+ Mania
Anticonvulsants
• Divalproex 4+ 2+ Liver dz, bleeding disorders
• Topiramate 4+ 2+ Kidney stones
NSAIDs 2+ 2+ Ulcer disease, gastritis
CGRP Antagonists 4+ 1+ None
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Complementary Migraine Prevention:
Positive Results but Small Studies
– Coenzyme Q 100 mg tid• Effective in two small trials
• Magnesium citrate 300 mg daily• Effective in 3 of 4 small trials to date• Data limited
• Riboflavin 200 mg bid • >50% response rate in 2 small trials
• Extract of feverfew plant• Effective in 4 of 6 studies (n=561) included in a
systematic review*• Small sample sizes with effect magnitude uncertain
*Cochrane 2015, April 20
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Evidence Based Complementary Treatments
for Migraine Prevention
Level A
Established efficacy
(None)
Level B
Probably effective
• Magnesium
• MIG-99 (feverfew)
• Riboflavin
Level C
Possibly effective
• Co-Q10
AAN Guideline: Neurology 2012;78:1346
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Butterbur No Longer Recommended
• Butterbur (Petasites) had been recommended by the AAN 2012 guideline
• However, many proprietary products contain pyrrolizidine alkaloids which are potentially hepatotoxic
• Carcinogenic in animal studies
• Potency of active drug also varies in products
• AAN and UpToDate no longer recommend Butterbur due to safety concerns
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Cost of Commonly Used Dose of
Migraine Prevention Drugs
Drug 30 Day AWP Cost
(USD)
Propranolol 60 mg qd $12
Divalproex Sodium 250 mg bid $7
Topiramate 50 mg bid $6
Amitriptyline 50 mg qhs $9
Botulinum toxin $400
Erenumab 70 mg SC monthly $575
Medical Letter November 2018
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Preventive Therapy of Migraines:
My Recommendations
First Line Rx Second Line Rx Third Line Rx
Propranolol
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Preventive Therapy of Migraines:
My Recommendations
First Line Rx Second Line Rx Third Line Rx
Propranolol Topiramate
Divalproex Sodium
Amitriptyline
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Preventive Therapy of Migraines:
My Recommendations
First Line Rx Second Line Rx Third Line Rx
Propranolol Topiramate CGRP Receptor Antagonist
Divalproex Sodium Verapamil
Amitriptyline Magnesium
Riboflavin
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Relationship Between Sex Hormones
and Migraine
• No gender difference in prevalence among prepubertal children
• Migraine often begins at menarche
• Migraines often disappear during pregnancy
• May decrease or increase at menopause
• 60% of women with migraine note relationship to menstrual cycle, usually just before or during menses
• Postulated to relate to fall in estrogen levels
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Effects of Oral Contraceptive Use on Migraine Pattern
• May increase (30%) or decrease (10%) frequency or severity of migraines
• No relationship to tension-type headaches
• Migraines often occur during drug free week of OCP cycle
• Migraines may occur for the first time after beginning OCP’s
• Do not use OCP’s for patients with aura or typical aura
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Three Strategies for Drug Treatment of Menstrual Migraine
Acute Rx
Long term prevention
Short term prevention
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Acute Treatment of
Menstrual Migraine
• First line
– Non-pharmacologic approaches
– NSAIDS
– Aspirin, acetaminophen, and caffeine (AAC)
• Second line
– Triptans
• If severe and refractory
– Corticosteroids
– Intravenous DHE
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Short Term Preventive Rx of
Menstrual Migraine
• For 1 week / month around time of menses beginning 2-4 days before menses
– Daily NSAIDs (first line Rx)
– Oral triptan once or twice daily
– Magnesium 120 mg tid
– Any standard prophylactic medication
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Long Term Preventive Rx of
Menstrual Migraine• For women who do not respond adequately to short
term prevention
• Use any of the commonly used preventive meds:
– Propranolol
– Divalproex sodium
– Topiramate
• For refractory migraines, after referral to specialist, consider
– Premenstrual estradiol patches
– Danazol, tamoxifen, or bromocriptine
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American Headache Society
Choosing Wisely
1
• Don’t perform neuroimaging studies in patients with stable headaches that meet criteria for migraine.
2
• Don’t perform computed tomography (CT) imaging for headache when magnetic resonance imaging (MRI) is available, except in emergency settings.
3• Don’t recommend surgical deactivation of migraine trigger points
outside of a clinical trial.
4• Don’t prescribe opioid or butalbital-containing medications as
first-line treatment for recurrent headache disorders.
5• Don’t recommend prolonged or frequent use of over-the-counter
(OTC) pain medications for headache.
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Summary
• Preventive medications for migraine
– Propranolol
– Divalproex sodium
– TCAs
– Topiramate
– Botulinum toxin
– CGRP receptor antagonists
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Summary
• Complementary physical strategies for migraine
– Acupuncture (preferred)
– Spinal manipulation
– Biofeedback
– Cognitive behavioral therapy
• Complementary oral medications
– Magnesium
– Riboflavin
– Feverfew
– Co-Enzyme QCOPYRIGHT