MIGRAINE: PAST,
CURRENT AND FUTURE
Kevin M Kapadia, MD
Meriter Medical Group Neurology
Madison, WI
Objectives
Headache Disorders comprise a large portion of inpatient
and outpatient primary care, pain medicine, and neurologic
care, of which migraine headache disorders are one of the
most common.
• To review the epidemiology, theoretical pathophysiology
and broad clinical presentation of migraine
• To review the current evidence-based treatment therapies
for migraine prevention and abortive therapies
• To become familiar with new targeted therapies being
trialed for migraine
Epidemiology of Migraine
• Most common form of disabling headache for patients
seeking medical treatment.
• >38 million people (between 10% - 15% of US population)
• Onset ages 10 - 45, most commonly recurring during
ages 15 - 55.
• Yet…Underdiagnosed and Undertreated:
• American Migraine Prevalence and Prevention Study:
• ½ of severe migraineurs based on questionnaire never had a formal
diagnosis
• Only 12% were on dedicated preventive management
Acquiring Migraines
• Lifetime Prevalence
• 43% in women
• 18% in men
• Childhood migraines 4-5%; equal in boys and girls
• By Puberty women twice as likely to develop migraines
• Estrogen increases Nitric Oxide (NO) Synthase activity
• Polygenic Inheritance
• Rare Autosomal Dominant monogenic forms
• Head Trauma
Societal Cost of Migraine Headache
• Direct costs (prescriptions, outpatient expenses, ED and
inpatient care) ~$11 billion/year
• Indirect costs (missed work days) >$12 billion/year
• Annual loss of 160 million workdays
Prototypical Case: ‘Julie’
40 yo F episodic migraines for 20 years.
Typical Headache: visual aura of flashing lights followed by
unilateral left sided headache, photosensitivity, and nausea.
• Headaches became more frequent in her 30's.
• Takes OTC medications Tylenol and ibuprofen now to the point
of 8-12 pills per day.
• She reports having a headache starting last Christmas Eve that
lasted for 1 full month.
• On continuous birth control given that she has worsening
headaches around the time of her menses.
Defining Migraine
• Derived from Greek ‘hemi’ and ‘kranion’
• (though up to 40% are bilateral)
• Recurrent primary headache disorder commonly associated
with sensory symptoms (photophobia, phonophobia,
osmophobia, nausea, vomiting, disability) with aura (20%) or
without aura.
• Episodic (<15 headache days per month)
• Chronic (>15 headache days per month)
Migraines of the Past
• 9,000 years ago (cave drawings) to 17th century Europe:
trepanation of skulls to release ‘evil spirits’ to escape.
• 400 BC: Hippocrates: described visual auras and relief after
vomiting ‘to release bad vapors’
• 2nd Century AD: Aretaeus of Cappadocia ‘discoverer of
migraines’ described symptoms of unilateral headache
associated with vomiting and headache-free intervals between
attacks
• Hua T’o: Chinese surgeon Han Dynasty: acupuncture to treat
recurrent migraines of King
More Headache History
• Middle Ages: unorthodox treatments:
• Hot irons
• Blood Letting
• Insertion of Garlic into an incision
• Witchcraft
• Opium and vinegar solutions to skull for ‘directed pain relief’
• 800’s: Persian physician recognized hormonal role of
migraines in women
• Islamic scientist of 900’s recognized the irritation of light
and sound in patients
• 1712: London published Headache 5 major types;
including ‘megrim’: classic migraine with aura.
Primary Headaches:
International Classification of Headache Disorders (ICHD-II/III)
• Migraine:
• Migraine w/o aura and Migraine w/ aura
• Hemiplegic Migraine
• Basilar-Type Migraine
• Menstrual Migraine
• Chronic Migraine
• Non-Migrainous Primary Headache Disorders:
• Tension-type
• Trigeminal Autonomic Cephalgias
• Primary Stabbing Headache
• Hypnic Headache (alarm clock headache)
• Nummular Headache
Laying Down the Blueprints
• 1938: Graham and Wolff: ergotamines effective for
stopping migraine
• 1948: The Wolff’s Headache ‘Headache Bible’ 1st Edition
published:
‘Headache may be equally intense, whether its implications
are malignant or benign, and though there are few
instances in human experience where so much pain may
mean so little in terms of tissue injury, failure to separate
the ominous from the trivial may cost life or create
paralyzing fear.’
Vascular Pathophysiology Dogma
• 1938 Graham and Wolff:
• Headache pain reduced coinciding with reduced amplitude of arterial
pulsations due to IV ergotamine treatments.
Vascular Theory:
• Humoral mediated intracerebral arterial vasoconstriction causing aura
followed by extracerebral vasodilation causing headache.
Cortical Spreading Depression
• 1938 Leao: Cortical Spreading Depression (CSD); wave of
neuronal depolarization followed by suppression of neuronal
activity with corresponding blood flow changes (hyperemia
followed by oligemia) moving across the cerebral cortex at
3mm/min.
• Lashley documented his own visual aura moving across the
occipital lobe at same speed
Auras
• Occur in only 20% of patients with migraines
• ‘Cortical Spreading Depression’
• Manifestations:
• Visual: enlarging scotoma with shimmering edge (fortification
spectra)
• Stars, dots, wavy lines, complex patterns, shapes or visual distortions.
• Sensory: cheiro-oral
• Spreads from hand to shoulder and face and inside mouth or tongue
over minutes
• Less Common:
• Hemiparesis/Hemiplegia, Speech disturbance
Migraine and White Matter Lesions
• Increased prevalence of ‘silent brain lesions’: cerebral
white matter hyperintense lesions in migraine patients;
pooled increased risk of 3.9 (95% CI 2.3–6.7).
• Recent systematic review and meta-analysis showed an
increased risk for lesions in Migraine with Aura
(OR = 1.68; 95% CI 1.07–2.65), no association found for
migraine without aura.
Incidental white matter lesions
Guidetti,D et al. Front Neurol. 2014.
Rare Complication of Migraine
Migrainous Infarction:
• Mostly occurs in the posterior circulation, in younger
women with a history of migraine with aura.
• Large clinical series reported prevalence of migrainous
infarction varies between 0.5 and 1.5% of all ischemic
strokes, ranging up to 10–14% of ischemic strokes in
young patients
Guidetti,D et al. Front Neurol. 2014.
Migraine and Stroke Risk: 9 Study Review
• Relative risk (RR) for ischemic stroke with any type of migraine:
1.73 (95% CI 1.31-2.29).
• Increased risk migraine with aura (RR 2.16, 95% CI 1.53-3.03).
• In contrast, increased risk migraine without aura was not
statistically significant (RR 1.23, 95% CI 0.90-1.69).
• Risk of ischemic stroke was significantly increased for certain
subgroups:
• Women with migraine (RR 2.08, 95% CI 1.13-3.84) but not men (RR
1.37, 95% CI 0.89-2.11)
• Subjects with migraine <45 years of age (RR 2.65, 95% CI 1.41-4.97)
• Smokers who had migraine with aura (RR 9, 95% CI 4.2-19.3)
• Women currently using oral contraceptives who had migraine with
aura (RR 7, 95% CI 1.5-32.7)
Case: Migraines and Stroke Risk
• ‘Julie’ has migraines with aura.
• What is her risk for stroke?
• Oral Contraceptives, women with aura: RR 7.
• Recommendations for smoking cessation, avoid OCPs in women
with migraine with aura.
• Use of Triptans?
• Contraindicated in patients with Cardiovascular Disease, Hemiplegic
Migraine, Basilar Migraine due to theoretical increased risk of stroke.
• Also relative contraindication in pre-menopausal women with migraine
with aura.
Anatomy of Headache Pain
Brain itself does not feel pain.
Dura Mater, Meninges and Blood vessels carry pain fibers to the
cranial nerves, specifically CN V (Trigeminal Nerve).
Migraine Cascade
• Trigeminal Reflex is activated:
• Trigeminal neurons supplying the dural
vessels release calcitonin gene-related
peptide (CGRP), substance P, neurokinin A.
• Vessels dilate and become inflamed, plasma
protein extravasation occurs (sterile neurogenic
inflammation)
• Result is peripheral sensitization of
the first-order neuron innervating the
dural blood vessels (explaining the
pounding pain)
• With prolonged duration: second and
third-order neurons become activated,
resulting in central sensitization.
Therapeutic Goal: Avoid Central
Sensitization
• Central Sensitization occurs and abortives like triptans are
much less likely to be effective.
• Treating the headache early prevents central sensitization
• May also be seen more frequently in chronic migraine
than episodic migraine.
Anatomy of Headache Pain
• Pain from face and head can be
referred to the neck and vice
versa.
• Ipsilateral Greater Occipital
Nerve formed by C2 often is
tender during an attack of
migraine.
• Neural Blockade (occipital nerve
block) may terminate an attack.
• Periaqueductal Gray, Locus
Ceruleus in the midbrain
connects with TNC to inhibit
pathways (target of some
medications)
Migraines and Hormones
• Menstrual migraines, increased headache frequency in
peri-menopausal women
• 25 year old F with migraines around her menstrual cycle.
Infrequent migraines the rest of the month
• What medications to trial?
• Hormonal therapy (if migraines without aura)
• Long-Acting Triptan
• Daily Preventive
Ideal Migraine Acute Treatment
Goal: functional headache-free state in 2 hours with no recurrence in 24
hours.
• No more than 2-3 times per week to avoid medication overuse
• Non-oral formulas should be made available if nausea is severe
High-quality evidence from placebo-controlled randomized trials:
• NSAIDs: aspirin, ibuprofen, naproxen, and diclofenac
• Triptans: sumatriptan
• Combination: sumatriptan and naproxen
• Antiemetic/dopamine receptor antagonists: chlorpromazine,
prochlorperazine, and metoclopramide
Treating the Headache Early
Early treatment reduces overall burden of migraine
Challenges:
• Prodromal symptoms prior to headache:
• Mood change, fatigue, muscle tension, yawning, cognitive
dysfunction
• 50% of patients will delay treatment in order to see if presentation
really represented migraine
• Some avoid medication unless headache is severe
• Some with frequent attacks limit acute medication for fear
of overuse
Hu et al.
Triptans
• Short-acting: sumatriptan (Imitrex), rizatriptan (Maxalt),
eletriptan (Relpax), almotriptan (Axert), zolmitriptan
(Zomig),
• Long-acting: naratriptan (Amerge), and frovatriptan
(Frova)
• Discovered in the 1990’s
• 5-HT1B, 5-HT1D Receptor agonist
• Mechanism of action in migraine unclear
• Vasconstrictor but also inhibits neurogenic inflammation
peripherally
• Prevents Central Sensitization
• Contraindicated in patients with CAD
Dihydroergotamine (DHE)
• Nasal Spray: 1 puff (0.5mg) each nostril repeat in 15
minutes, 2 mg max daily dose
• Injectable: (0.5mg to 1mg) repeat in 1 hour, max of 3mg
daily
• Inpatient Raskin Protocol (IV DHE + antiemetic)
repeatedly for status migranosis.
Acute Medications to Avoid
• Fiorinal (Fioricet): Contains Butalbital (notorious for
rebound headaches)
• Opioids for migraine (Majority of Neurologists do not
prescribe narcotics) Ideal limitation is maximum of 2 days
per week
Medication Overuse Headaches
Regular overuse for more than >3 months of one or more drugs
that can be taken for symptomatic treatment of headache:
• ≥10 days per month for >3 months: ergotamines, triptans,
opioids
• ≥15 days per month for >3 months, of simple analgesics (ie,
acetaminophen, aspirin, or NSAID)
Medication Overuse Headaches: Culprits
Migraine Prevention
• Theories of mechanism of action:
• Enhancement of anti-nociceptive pathways
• Inhibition of central and peripheral sensitization
• Inhibition of cortical spreading depression
• Goals: reduce attack frequency and severity, reduce
associated disability
• Only 12% of patients taking migraine preventive therapy
where up to 40% may be indicated
Evidence-based Medications:
B-Blockers: Metoprolol, propranolol, and timolol
Anti-depressants: Amitriptyline and venlafaxine
Anti-epileptics: Valproate and topiramate
Herbals: Butterbur
Alternatives include calcium channel blockers including
verapamil and flunarizine
Starting Preventive Therapy
• Start low and build slowly (make adjustments every 2 weeks)
• Adequate trial duration 2-3 months
• Headache calendar or diary
• Consider tapering of medication after 6 months is feasible
Anti-Epileptic Drugs
• Valproate: effective
• Contraindicated in pregnancy, nausea, weight gain, alopecia,
transaminitis, pancreatitis, agranulocytosis
• Topiramate: effective
• Titrate slowly from 15-25mg daily up to 100-200mg daily
• Paresthesias, change in taste, cognitive side effects, category D in
pregnancy
• Gabapentin: efficacy unclear
• Generally well-tolerated but somnolence is common
Anti-Hypertensives
First Line:
• B-Blockers: Propranolol and Timolol are FDA approved
Second Line:
• Calcium Channel Antagonists: Verapamil: may be
indicated for those with prolonged aura or vestibular
migraine
• ACE inhibitors and ARBs: Lisinopril, Candesartan
Anti-Depressants
• Tricyclic Antidepressants (amitriptyline)
• Effective at low doses 10-25mg
• Blocks neuronal uptake of both serotonin and norepinephrine;
resulting in anti-nociceptive effects
• Helpful in sleep disruption
Multi-Disciplinary Treatments
• Psychological Approaches:
• Acceptance and Commitment Therapy
• Cognitive-Behavioral Therapy
• Biofeedback techniques
• Exercise:
• 40 minutes, 3 times weekly of aerobic exercise as effective as relaxation
techniques and topiramate
• Neck Pain/Cervicogenic Headaches:
• Isometric neck exercises effective treatment of cervicogenic migraines
(strengthens neck muscles thus less likely to spasm)
• Improvement after 2 weeks of diligent exercise
• Acupuncture: Benefit exceeds placebo (widely practiced and
studied in Germany)
Neurology Continuum, Vol 18 No. 4, 2012
Supplements
• Magnesium oral supplementation (magnesium oxide
400mg daily) or IV infusion 1g
• CoEnzymeQ10 300mg daily
• Riboflavin (Vitamin B2) 400mg daily
• Butterbur (plant derivative) 75mg twice daily
• Feverfew (plant extract) products in US may not have
same quality or consistency
Nonpharmacologic Migraine Prevention
Adequate Hydration
Adequate Restorative Sleep
Managing Stress, Anxiety, Depression
Avoidance of Known Triggers
Aerobic exercise
Biofeedback
Other forms of relaxation training
Cognitive-behavioral therapies
Acupuncture
Transcutaneous electrical nerve stimulation (TENS)
Dietary Changes
• Caffeine: helpful or harmful
2-3 cups of coffee can trigger withdrawal headaches
• Gluten Sensitivity/Celiac Disease association
• Skipping Meals
• Tyramine-rich foods (wines and cheeses)
Common Migraine Headache Triggers
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Caffeine withdrawal
Alcohol (red wine)
Changes in sleep patterns
Bright lights, loud noises, strong odors or perfumes
Exercise or other physical stress or anxiety
Missed meals
Smoking or exposure to cigarette smoke
Weather changes
Foods that contain MSG (monosodium glutamate)
Meats with nitrates and nitrites (bacon, hot dogs, salami, cured meats)
Foods with tyramine, such as aged cheeses, soy products, fava beans,
hard sausages, smoked fish, and red wine
Baked goods, chocolate, nuts, peanut butter, and dairy products
Aspartame (NutraSweet, Equal)
Fruits (avocado, banana, citrus fruit, figs)
Gluten Sensitivity/Celiac Disease
Hormonal changes during the menstrual cycle
Case: ‘Julie’ and Preventives
Past Preventive Medications:
Topiramate: felt 'dopey' memory and balance issues. Effective for
migraine at higher doses but side effects were too much.
Amitriptyline (failed)
Propranolol (gave her headaches)
Magnesium caused GI effects
Chronic Migraine
15 headache days per month for >3 months
with migraine headaches >7 days per
month
3% Annual Risk of transformation from
episodic migraine to chronic migraine
Comorbid Disorders:
63% with chronic fatigue syndrome
36% with fibromyalgia
57% with major depression
Chronic Migraine
• Very Poor Acute Migraine Treatment has a >2 fold risk of
new-onset Chronic Migraine after 1 year.
Lipton, RB et al. Neurology 2015
• PREEMPT2 Trial: OnobotulinumtoxinA (Botox) for Chronic
Migraine
• large mean decrease in frequency of headache days over placebo
at 24 weeks (-8.4 vs -6.6; P < .001) and at all other time points.
• Botox for Chronic Migraine FDA Approved
Dodick, DW et al. Headache 2010
Mechanism of Botox for Chronic Migraine
Aside from reducing wrinkles
(neuromuscular junction blockade)…
Decreases nociceptor pathways:
• C and A delta fibers
• Mechano- and chemo-nociceptors
• Substance P
• Calcitonin Gene Related Peptide (CGRP)
• Glutamate Release
BoTox for Migraines 2013 Moulton-Barrett, R.
Case ‘Julie’
• Initiated on Botox therapy. Responded well, with reduced
headache frequency.
• 4 treatments so far and reports 5 headache days per
month on average. Her headaches typically last 1-2 days.
She takes rizatriptan (Maxalt) as an abortive.
Migraine prevention with a supraorbital
transcutaneous stimulator: A randomized controlled
trial.
Schoenen, Jean; MD, PhD; Vandersmissen, Bart;
Jeangette, Sandrine; Herroelen, Luc; Vandenheede,
Michel; Gerard, Pascale; Magis, Delphine; MD, PhD
Neurology. 80(8):697-704, February 19, 2013.
DOI: 10.1212/WNL.0b013e3182825055
The stimulation electrode placed on the forehead covers
the supratrochlear and supraorbital nervesFigure 1.
Reproduced with permission from STX-Med.
©2013 American Academy of Neurology. Published by LWW_American Academy of Neurology.
2
CEFALY: Transcutaneous Supraorbital
Neurostimulation (tSNS)
• Cefaly Device: FDA Approved 2014
• ‘first transcutaneous electrical nerve stimulation (TENS) device specifically
authorized for use prior to the onset of pain’
• tSNS external self adhesive electrode placed on the forehead Cefaly®
device Belgium
• Bipolar electrode covers origins of the supraorbital nerves (branches of 1st
trigeminal division)
• PREMICE Trial:
• At least once daily 20 minutes for 3 months
Schoenen, J et al. Neurology 2013
Migraine prevention with a supraorbital
transcutaneous stimulator: A randomized controlled
trial.
Schoenen, Jean; MD, PhD; Vandersmissen, Bart;
Jeangette, Sandrine; Herroelen, Luc; Vandenheede,
Michel; Gerard, Pascale; Magis, Delphine; MD, PhD
Neurology. 80(8):697-704, February 19, 2013.
DOI: 10.1212/WNL.0b013e3182825055
Study outcomesFigure 3. (A) Decrease in number of
migraine days over the trial duration compared to run-in
in verum and sham groups. (B) Percentage decrease at
end of trial compared to run-in for the various outcome
measures in verum and sham groups.
©2013 American Academy of Neurology. Published by LWW_American Academy of Neurology.
2
Mechanism of Migraine: Understanding
through Genetics
• Primary Migraine pathology: state of hyper-responsiveness
• Genetic discoveries step to understanding migraine
• Initially considered a cerebrovascular condition, then a
neuro-inflammatory process, and now primarily a neurogenic
disorder.
• Genetic findings revealed ion channels and transporter
mutations, powerful argument for the neurogenic basis of
migraine.
• Modulations of ion channels leading to amelioration of the
migraine “hyper-responsive” brain targets for drug research
Weir and Cader (2011)
Migraine Genetics: Polygenic
Studying of rare monogenic causes:
• Familial Hemiplegic Migraine (FHM) (multiple rare genotypes)
• FHM1: Increased Ca2+ influx into presynaptic terminals, increase of
glutamate
• FHM2: Mutation Na+/K+ ATPase decreased clearance of synaptic
glutamate
• FHM3: Mutation voltage-gated Na+ channels, increased glutamate
Low Brain Magnesium Levels (inhibitory ion for Calcium
channels that inhibit CSD)
All result in hyperexcitable brain
Migraine-Associated Genetics
Recently Identified:
• LRP1 Locus: cell surface receptor for neurons and vasculature:
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vascular smooth muscle
TRPM8 Locus: associated with both migraine w/ and w/o aura.
Also cutaneous allodynia, skin hypersensitivity
MTDH gene: migraine with aura only
MEF2D Locus: survival of newly formed neurons. Dysregulation in
migraine by this transcription factor may cause hyperexcitability
(also associated with epilepsy)
TGFBR2 Locus: transforming growth factor beta receptor 2; cell
proliferation and differentiation and extracellular matrix. Familial
aortic dissection. May explain two fold risk increase for cervical
artery dissection in migraine.
Freilinger et al, 2012.
Investigative Acute Agents
CGRP receptor antagonists
• Randomized Phase III trials CGRP receptor antagonists
telcagepant and olcegepant beneficial for acute migraine
• Telcagepant stopped due to hepatotoxicity
• Olcegepant stopped due to poor oral bioavailability.
Selective Serotonin 1F receptor agonist
• Lasmiditan lacks vasoconstrictor activity, effective in
randomized placebo-controlled trial
• high rate of serious adverse events, particularly at higher doses;
the most common were dizziness, fatigue, vertigo, paresthesia, and
somnolence.
• Ongoing studies to determine lasmiditan tolerability
Alternative Non-Pharmacologic Investigation:
Transcranial Magnetic Stimulation (TMS)
• Efficacy of transcranial magnetic stimulation (TMS)
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demonstrated in randomized controlled trial
164 patients at least one attack of migraine treated during
aura
Pain free at 2 hours post-treatment greater with TMS
compared with sham (39% vs 22%, absolute risk
reduction 17%)
Sustained pain-free response at 24 and 48 hours
No serious adverse events
Debated Invasive Procedures
PFO Closure
• PFO: 25% general population, 50% of patients with migraine with
aura.
• Theory that right to left shunt may circumvent the filtering function
of lung and allow microemboli or other neurotransmitters to affect
the intracranial blood vessels, triggering migraine attacks.
• Recent trial with PFO Closure in migraine with aura patients
showed no benefit.
Migraine Decompression Surgery
Neurologists Don't Buy 'Facelift Treatment' for Migraine
Pauline Anderson July 05, 2013
• "Let's face it: migraine is a very complex disease of the brain; how
could surgery affect the epigenetics of 22 different genes?"
• “Biological plausibility" and "experimental evidence" are "totally
absent" in the studies of the procedure.
Take Away Points
• Be MINDFUL: Cost and Morbidity
• Be WATCHFUL: Underdiagnosed, undertreated: good to
ask during ROS (especially men)
• Be PROACTIVE: Failing to treat early increases risk for
evolution to chronic migraine
• Be CAUTIOUS: Medication overuse headaches
• Be RESOURCEFUL: Multidisciplinary approach to
headache treatment: medical and psycho-social aspects
Thank You!