Treating Migraines Charles Yanofsky M.D.

How Common is Migraine? 30,000,000 Americans 20% of women 7% of men at any given time Most of us have some migraine manifestations occasionally

Recognizing Migraine Pounding unilateral headache Preceded by visual or other aura Nausea, vomiting Light and sound sensitivity

What is migraine? Migraine without aura (MO) Migraine with aura (MA) Headache Classification Committee of IHS (1988) At least five attacks fulfilling these criteria: Headache lasting 4–72 h (2–48 h in children) At least two attacks fulfilling these criteria: At least three of the following: –one or more fully reversible aura symptoms –gradually developing or sequential aura symptoms –no one aura symptom lasts longer than 1 h –headache shortly follows or accompanies aura Accompanied by at least one of: –nausea –vomiting –photophobia and/or phonophobia No evidence of organic disease With at least two of: –unilateral location –pulsating quality –moderate/severe intensity –aggravated by activity No evidence of organic disease

World prevalence of migraine: A disorder of First World 1-year prevalence rates 1-year prevalence rates Population-based studies Population-based studies IHS criteria (or modified) IHS criteria (or modified) USA 12% Chile 7% Japan 8% Italy 16% Denmark 10% France 8% † Switzerland 13% Rasmussen and Olesen (1994); Rasmussen (1995); Lipton et al (1994); Lavados and Tenhamm (1997); Sakai and Igarashi (1997) † Prevalence measured over a few years

Cady (1999); Warshaw et al (1998) Diagnosis of migraine Diagnosis depends on patient history No specific tests or clinical markers Positive diagnosis if attack history fulfils IHS criteria for migraine Other pointers include: –family history of migraine –age of onset <45 –presence of aura –menstrual association Organic disease must be excluded

WORRISOME HEADACHE RED FLAGS “SNOOP” O lder: new onset and progressive headache, especially in middle-age >50 (giant cell arteritis) S ystemic symptoms (fever, weight loss) or S econdary risk factors (HIV, systemic cancer) N eurologic symptoms or abnormal signs (confusion, impaired alertness, or consciousness) O nset: sudden, abrupt, or split-second P revious headache history: first headache or different (change in attack frequency, severity, or clinical features)

Prevalence of migraine by sex and age Females Males Migraine prevalence (%) Age (years) Lipton and Stewart (1993) The American Migraine Study (n=2479 migraine sufferers)

Physiology Vasospasm – Lance Spreading Wave of Depression – Leao Trigeminocentric Allodynia

Vasospasm I. Aura: Arteries Spasm –Visual and focal neurological symtoms –Pial and Occipital small artery branches II. Headache: Compensatory Vasodilation –Pounding unilateral sick headache III. Inflammation and muscle spasm: second pain phase

Phases of Migraine Vague Prodrome: psychic change and cravings e.g. chocolate Aura: Focal symptoms and vision Headache: Throbbing unilateral pain Inflammation: Prolonged phase and TTH Postdrome Migraine related stroke

Spreading Wave Brainstem controls Cortical Activity Epileptic like phenomenon that spreads over Cortex Visual Phenomenon that spreads over surface of brain like shimmering “C” Cheiro-oral Jacksonian phenomena Concurrence of migraine and epilepsy Why epilepsy drugs work for migraine

Trigeminal Theory Serotonin again Trigeminal Afferents: sensory function of face and meninges Trigeminal efferents to vessels Cause vessel spasm and sensitivity This theory primarily explains action of Triptans: 5-HT 1b,d agonists

Migraine Pathophysiology Goadsby NEJM 346 :257-70,2002

Allodynia Theory Migraine is a state of hypersensitivity Light, sounds, smells, touch (head in headache) Need for dark room Best preventives decrease sensitivity. Anticonvulsants, tricyclics, beta and calcium channel blockers

What is Central Sensitization? Central Sensitization is a time- dependent physiological event During a migraine attack, neuronal pathways become sensitized in stages –Peripheral neurons are activated early in the attack (mild pain phase throbbing) –Central neurons are activated later in the attack (full-blown migraine)

Cutaneous allodynia Phenomenon later in migraine attack Once it develops pts less likely to respond to triptans In small sample 15% of pts with and 93% of pts without CA responded to triptan (Burstein et al)

Each of these Theories explains some migraine phenomena

Migraine Phenomena Focal and paroxysmal onset of symptoms Specific visual phenomena Spreading numbness and moving visual phenomena and sensory distortions. Nausea, vomiting “sick” headache Pounding unilateral or bilateral pain Psychic changes Light and sound sensitivity even between attacks Effectiveness of triptans Effect of anticonvulants Role of serotonin

Some Dicta Any paroxysmal headache is likely to be migraine unless proven otherwise “Sinus” headaches and “tension” headaches are almost always migraine headaches First ever severe headache or sudden “thunderclap” headaches may be SAH

Treatment Effective treatment of attack Prevention Address comorbidities

Mechanisms for treatment triptan triptan CONSTRICTION INHIBITION

Acute Attack Triptans: –sumatriptan, zolmitriptan, almotriptan, naratriptan, frovatriptan, elitriptriptan, riaztriptan NSAID’s Fioricet Midrin (isometheptane, chlorphenoxazone, apap OTC: Caffeine, apap, phenacitin, asa Ergots: Caffergot, DHE nasal, injected Narcotics Depacon

TRIPTANS As a class, relative to nonspecific therapies, triptans provide Rapid onset of action High efficacy Favorable side effect profile Adverse events and contraindications Selective 5-HT 1B/1D/1F agonists Silberstein SD. Neurology

Triptans Learn to use one or two Effective medicines

TRIPTANS: TREATMENT CHOICES Are there differences between the triptans? If one triptan fails, will another triptan work? Zolmitriptan Tablet (2.5, 5 mg) Nasal spray (5 mg) Rizatriptan Tablet (5, 10 mg) Naratriptan Tablet (1, 2.5 mg) Question and Answer Almotriptan Tablet (6.25, 12.5 mg ) Frovatriptan Tablet (2.5 mg) Sumatriptan Tablet (25, 50, 100 mg) Injection (6 mg) Nasal spray (5, 20 mg*) * Pediatric efficacy shown Ferrari MD et al. Lancet Eletriptan Tablet (20, 40 mg)

Elitriptan or Relpax Advantages Quick oral absorption Reliable oral absorption Relatively long half life Numerous Clinical trials where proven superior to Imitrex Gets in fast, and stays around Low “rebound” recurrence rate Works for all migraine phenonena Pain, photosonophobia, nausea

Relpax Cautions Available only in oral form CYP 3A4 – Do not give within 72 hours of: Ketoconazole, Nefazadone, clarithromycin, rotonavir, nelfinavir, others. caution with verapamil, erythromycin. Contraindications (all triptans) –Suspected Coronary disease –Basilar or hemiplegic, ophthalmoplegic migraine –Uncontrolled hypertension – 65 –Within a day of any other triptan –Hypersensitivity to the drug

Migraine visual Aura from classic oph textbook

Autoscopy

Relpax Dosing 40 mg. May repeat X1 in 2 hours Max dose in 24 hours is 80 mg Repeating dose most efficacious if headache returns

“Parenteral” triptans Imitrex injections: Very good fast reliable onset but peaks quickly with short half life Imitrex and Zomig nasal: absorption not reliable, taste not so good but may be tried if a lot of nausea Zomig ZMT and Maxalt MLT on tongue: not strictly parenteral absorbed thru gut

Triptan worries Not released under age 18 If you even suspect CAD don’t use or get proper exclusionary tests. –Man or woman of a certain age –Smoker or other risk factors Cerebrovascular disease or complicated migraine - contraindicated Watch for overuse. These are rescue medicines

Consider Combinations Triptan + NSAID Triptan + anti-nausea Unconventional agents Phenergan, Compazine alone or in combination. Zyprexa or atypicals We don’t have enough alternatives

Prophylaxis Anticonvulsants: topiramate, valproate, Keppra, gabapentin Tricyclics –Amitriptylene, nortriptylene, trazodone Beta Blockers –Timolol, propranolol, nadolol Calcium channel blocker – verapamil ACE inhibitors SSRI’s Atypicals

Plea Listen to patients Migraine is mixed up with a lot of things –Emotional factors: ennui, husbands, bosses, general dissatisfaction with life –Sleep disturbances –Hormonal changes If you do not address these you will not be treating your patients Don’t just throw drugs at your patients Be attentive and empathetic