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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

Migraine without aura (MO)

At least five attacks fulfilling these criteria: Headache lasting 472 h (248 h in children) With at least two of:
unilateral location pulsating quality moderate/severe intensity aggravated by activity

What is migraine?
Migraine with aura (MA)
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

No evidence of organic disease

Headache Classification Committee of IHS (1988)

World prevalence of migraine: A disorder of First World

Denmark 10% France 8% Switzerland 13%

USA 12% Italy 16%

Japan 8%

Chile 7%

 1-year prevalence rates  Population-based studies Population IHS criteria (or modified)
Rasmussen and Olesen (1994); Rasmussen (1995); Lipton et al (1994); Lavados and Tenhamm (1997); (1994); Sakai and Igarashi (1997)

Prevalence measured over a few years

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
Cady (1999); Warshaw et al (1998)

Organic disease must be excluded


Systemic symptoms (fever, weight loss) or Secondary risk factors (HIV, systemic cancer) Neurologic symptoms or abnormal signs (confusion,
impaired alertness, or consciousness)

Onset: sudden, abrupt, or split-second Older: new onset and progressive headache, especially
in middle-age >50 (giant cell arteritis)

Previous headache history: first headache or different

(change in attack frequency, severity, or clinical features)

Prevalence of migraine by sex and age

Migraine prevalence (%) 30 25 20 15 10 5 0 20 30 40 50 60 Age (years) 70 80 100 Females Males

The American Migraine Study (n=2479 migraine sufferers) (n

Lipton and Stewart (1993)

Vasospasm Lance Spreading Wave of Depression Leao Trigeminocentric Allodynia

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 timedependent 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

Effective treatment of attack Prevention Address comorbidities

Mechanisms for treatment

Trigeminal nerve INHIBITION 5-HT1D 5-HT1F

CGRP triptan NK SP


calcitonin gene related peptide neurokinin A substance P



Adapted from Goadsby (1997)

Acute Attack
sumatriptan, zolmitriptan, almotriptan, naratriptan, frovatriptan, elitriptriptan, riaztriptan

NSAIDs Fioricet Midrin (isometheptane, chlorphenoxazone, apap OTC: Caffeine, apap, phenacitin, asa Ergots: Caffergot, DHE nasal, injected Narcotics Depacon

Selective 5-HT1B/1D/1F agonists As a class, relative to nonspecific therapies, triptans provide

onset of action  High efficacy  Favorable side effect profile

Adverse events and contraindications

Silberstein SD. Neurology. 2000.

Learn to use one or two Effective medicines




Tablet (25, 50, 100 mg) Injection (6 mg) Nasal spray (5, 20 mg*)

(6.25, 12.5 mg)


(2.5 mg)



Tablet (2.5, 5 mg) Nasal spray (5 mg)

(20, 40 mg)


Question and Answer

Tablet (1, 2.5 mg)

Are there differences between the triptans? If one triptan fails, will another triptan work?


Tablet (5, 10 mg)

* Pediatric efficacy shown

Ferrari MD et al. Lancet. 2001.

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 <18 or >65 Within a day of any other triptan Hypersensitivity to the drug

Migraine visual Aura from classic oph textbook

Eff cacy f Eletr ta : C re e s ve Relief at 2 H

Hea ac e res

lace Sumatriptan 100 mg Eletriptan 40 mg


60 *

ain-free res

nse, *


Relief f Na sea,
* * 80

30 20 10

20 0 20 20 20 40


Relief f

ia, *


40 60

* 60

* *
er a ab e

Relief f


Su a r p an wa b nded u ng en ap u a on

n ap u a ed u a r p an wa b oequ a en o o A a te fr

*P<.001 vs lace

. P<.05 vs s


at ew et al. Headache. 2003.


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 dont 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 dont have enough alternatives

Anticonvulsants: topiramate, valproate, Keppra, gabapentin Tricyclics
Amitriptylene, nortriptylene, trazodone

Beta Blockers
Timolol, propranolol, nadolol

Calcium channel blocker verapamil ACE inhibitors SSRIs Atypicals

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 Dont just throw drugs at your patients Be attentive and empathetic