Why do I get migraines? What triggers them? Herbert G. Markley, M.D. New England Regional Headache Center Worcester, MA

Reprinted from Cell. 87, Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner P, Hoffman SMG, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJB, Hofker MH, Ferrari MD, Frants RR. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A , Copyright 1996, with permission from Elsevier Science. Neuronal Hyperexcitability: Genetic Evidence Mutations in neuronal ion channels: gene for neuronal/ vascular calcium channel CACNA1A4 locus S4 S4S4 S4 FHM Cytoplasm N FHM + Cerebellar ataxia

Migraine is More Common than Asthma & Diabetes Combined Data from the Centers for Disease Control and Prevention, US Census Bureau, and the Arthritis Foundation. Disease Prevalence in the US Population

The Migraine Attack Postdrome Prodrome AssociatedFeatures Headache Aura Time Intensity of Symptoms or Phases

The Migraine Attack Postdrome Prodrome AssociatedFeatures Headache Aura Time Intensity of Symptoms or Phases Prodrome Mood changes Fatigue Cognitive Change Muscle Pain Food Craving Aura Fully reversible Neurological changes: Visual Somatosensory Early Headache Dull headache Nasal congestion Muscle pain “Tension Headache of Migraine” Mild Moderate Evolving Headache Localization of headache Associated symptoms begin to appear Severe Advanced Headache Unilateral Throbbing Nausea Photophobia Phonophobia Postdrome Fatigue Cognitive changes Muscle pain

Anatomical pathophysiology of migraine Anatomical pathophysiology of migraine Goadsby, Lipton, Ferrari. N Engl J Med;346: PAIN CSD NAUSEA PHOTOPHOBIA + SONOPHOBIA NEUROGENIC INFLAMMATION

Lipton, Diamond et al, 2000 Migraine Prevalence by Age and Gender Migraine Prevalence % Age (years) Adapted from Lipton RB, Stewart WF. Neurology Males Females

Female Life Events that Influence Migraine Menarche Menses Oral Contraception Pregnancy Lactation Menopause Hormone Replacement Therapy

Migraine and Menarche Females suffer from migraine at a 3:1 ratio to males Beginning with puberty, migraine is more common in girls Menstrually associated migraine begins at menarche in 33% of women 60-70% of female sufferers experience migraine in association with menses Silberstein SD. Neurology. 1991; 41: MacGregor EA. Neruologic Clinics. 1997; 15(1): Benedetto, C et al. Cephalalgia. 1997; 20: 32-34

Menstrual Migraine: Definitions Menstrually-associated Migraine (MAM): –Women who experience attacks that occur both perimenstrually and at other times of the month –60-70% of female migraineurs report a menstrual relationship to their headaches Menstrual Migraine (MM): –Women who experience attacks that occur only perimenstrually –In female migraineurs, true menstrual migraine occurs in only 7-14% Benedetto, C et al. Cephalalgia. 1997; 20: 32-34

Migraine Vulnerability During the Menstrual Cycle Can occur before, during, and after menstruation –Migraine may be part of premenstrual syndrome (PMS), now a part of the DSM- IIIR criteria for Late Luteal Phase Dysphoric Disorder (LLPDD) –Greatest likelihood of menstrual migraine on Day -1 to Day +4, but can vary –Decrease in estrogen levels in the late luteal phase is a likely trigger for migraine Silberstein SD. Neurology. 1991; 41:

Hormone Levels During Menstrual Cycle Adapted from Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. 2 nd Ed. New York, NY: Martin Dunitz; 2002:102 Follicular phaseLuteal phase Endocrine cycle LH FSH E2 P Ovulation HORMONAL FLUCTUATIONS DURING THE MENSTRUAL CYCLE

Estradiol Treated Cycle Somerville BW, Neurology, 1972;22: Days From Onset of Menstruation Estradiol Treated Cycle Normal Cycle Migraine-unilateral, duration 8 hours. Nausea. Migraine-unilateral duration 12 hours. Nausea. Estradiol valerate 10 mg Plasma Estradiol (ng/100 ml)

Other Migraine Triggers Vasoactive foods –Chocolate (phenylethylamine) –Caffeine or its withdrawal (caffeine is a phosphodiesterase inhibitor) –Smoked meats, fish (nitrites, dilate arteries) –Alcohol, esp. beer, red wine (direct vasodilator, congeners with vasoactive effects) –Monosodium glutamate (excitatory neurotransmitter) –Cold foods (ice cream headache more common in migraine patients)

Other Migraine Triggers Strong odors – fragrances, gasoline Certain foods Weather changes Exercise

Management of migraine The four basic modalities

Four basic modalities Avoidance of trigger factors Non-pharmacological techniques Acute (rescue) therapy of individual attacks Preventive medicine

Avoidance techniques: identify and avoid factors which trigger migraine Oral contraceptives –May precipitate migraine, also increase risk of stroke in women with migraine –Migraine associated with use of these agents sometimes resolves completely when they are discontinued Other precipitating factors: seek and eliminate –Foods: chocolate, cheddar cheese, alcohol (red wine) –Alterations in sleep schedule, stress, vacation –Weather changes, missing meals or strong odors –“Phobic approach” works well in children with food sensitivities, but adults may find stringent dietary and activity restrictions too confining

Abortive treatment of individual attacks Used alone if acute attacks occur less than eight times per month Treatment oftener with abortive drugs may produce drug toxicity, drug dependence, both

Outpatient abortive therapy for migraine Triptans Ergot compounds Analgesics –NSAIDs –Combination analgesics –Opioid analgesics Additional doses of daily prophylactic Rx Adjunctive Rx

The Seven Triptans Short-acting (2-4 hours): Sumatriptan (Imitrex) –Oral: 25, 50, 100 mg tabs –Nasal spray: 5, 20 mg –SC injection 6 mg Zolmitriptan (Zomig) –Oral: 2.5, 5 mg –ZMT tablet: 2.5, 5 mg –Nasal spray: 5 mg Rizatriptan (Maxalt) –Oral: 5, 10 mg –MLT 10 mg Almotriptan (Axert) –Oral: 6.25, 12.5 mg Eletriptan –Oral: 40, 80 mg Long-acting (4-26 hours): Frovatriptan –Oral: 2.5 mg Naratriptan (Amerge): –Oral: 1, 2.5 mg tablets

Abortive Tx with NSAIDs Indomethacin suppositories 50 mg Indomethacin capsules 50 – 150 mg Naproxen 1000 – 1500 mg Ibuprofen 600 mg + caffeine 200 mg

Combination analgesics Butalbital ± caffeine compounds –With acetaminophen (generic, Fioricet, Esgic) –With ASA (Fiorinal) –Hazard: analgesic rebound headache Isometheptene mucate/chloralphenazone –Midrin, Duradrin, generics –Less analgesic rebound

Abortive opioids Opioids –Oxycodone, hydrocodone, codeine,Tramadol, Butorphanol NS –Overuse: dependence, analgesic rebound HA

Abortive Rx with ergots Ergotamine tartrate heavily used in Europe –Availability in U.S. spotty –Caffeine-ergotamine (Cafergot, others) recently withdrawn or unavailable –Drug is safe & effective, many AEs Dihydroergotamine –Migranal NS Less effective than advertised due to packaging Canadian dosing device easier, more effective –DHE-45 sc, im

The Analgesic Rebound Effect Overuse of analgesics (pain relievers) produces increased number and intensity of headaches –Rebound effect seen if analgesics taken more than four days per week –Rebound effect seen if more than six combination analgesic doses taken per week –Chronic daily headaches may be end-result of years of analgesic overuse Overuse of analgesics also blocks prophylactic effect of daily preventive headache medication Mechanism: probably serotonin depletion (2000)

Prophylactic management Migraine interferes with ADL despite abortive Rx Chronic recurring headaches > twice/week Severe/disabling attacks even if less often Abortive Rx limited by AEs or contraindications Patient preference or lifestyle “Complicated migraine” variants –Hemiplegic migraine –Basilar migraine –Migraine with prolonged aura –Migrainous infarction

Prophylactic management: strategy Patients should be told to take the medication every day whether they have headache or not Start with low dose, increase slowly for minimum 2 month trial Use daily headache diary Reduce dose after 6 months if well-controlled Avoid pregnancy

Migraine Prevention Classes of preventive drugs: –Anticonvulsants –Antidepressants –Beta-blockers –Calcium channel blockers

Prophylaxis with NSAIDs Indomethacin 50 – 225 mg/day –Most effective –Most gastric aes –Many different effects: pain, CSF pressure Naproxen 500 – 1000 mg/day Other NSAIDs

Prophylaxis with beta-blockers Drugs –Propranolol 40 mg – 240 mg/day –Nadolol 20 – 160 mg/day –Metoprolol 25 – 100 mg/day –Atenolol 25 – 50 mg/day

Migraine Ca-channel blockers Verapamil SR 240 – 480 mg/day –More effective for cluster headache –Cluster dose up to 1 gram/day Amlodipine (Norvasc) 5 – 10 mg/day Nimodipine Flunarizine –Most effective – available in Europe, Canada

TCAs useful in migraine Amitriptyline 25 – 250 mg/day Nortriptyline 25 – 200 mg/day Imipramine 75 – 300 mg/day Desipramine mg/day Trazodone 50 – 400 mg/day

SSRIs and novel antidepressants Prozac 20 – 80 mg/day Paxil 20 – 60 mg/day Zoloft – ineffective in several trials Serzone 200 – 450 mg/day Effexor XR 37.5 – 225 mg/day Wellbutrin 75 – 300 mg/day

Ergot derivatives useful Methysergide (Sansert) 4 – 8 mg/day –FDA approved for migraine prophylaxis –Not available: not manufactured Methylergonovine (Methergine) 0.6–1.6 mg/day –Oxytocic to uterus primed by pregnancy –Demethylated derivative of methergine –Much less vasoconstriction

The Headache Patient's Bill of Rights The right to be taken seriously The right to a complete medical evaluation, including complete history and neurological examination The right to neurodiagnostic testing: CT/MRI scans The right of referral to a specialist: neurologist or a Headache Clinic The right to receive specific headache therapy, instead of non-prescription drugs, narcotics, or combination analgesics which may increase the headache problem