Treating Migraines

Charles Yanofsky M.D.www.susqneuro.com

How Common is Migraine?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 MigraineRecognizing Migraine• Pounding unilateral headache• Preceded by visual or other aura• Nausea, vomiting• Light and sound sensitivity

What is migraine?What is migraine?Migraine without aura (MO) Migraine with aura (MA)

Headache Classification Committee of IHS (1988)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:World prevalence of migraine:A disorder of First WorldA disorder of First World

1-year prevalence rates1-year prevalence rates Population-based studiesPopulation-based studies IHS criteria (or modified)IHS criteria (or modified)

USA 12%USA 12%

Chile 7%Chile 7%

Japan 8%Japan 8%Italy 16%Italy 16%

Denmark 10%Denmark 10%

France 8%France 8%††

Switzerland 13%Switzerland 13%

Rasmussen and Olesen (1994); Rasmussen (1995);Rasmussen and Olesen (1994); Rasmussen (1995);Lipton Lipton et al (et al (1994); Lavados and Tenhamm (1997); 1994); Lavados and Tenhamm (1997);

Sakai and Igarashi (1997)Sakai and Igarashi (1997)††Prevalence measured over a few yearsPrevalence measured over a few years

Cady (1999); Warshaw Cady (1999); Warshaw et alet al (1998) (1998)

Diagnosis of migraineDiagnosis 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 WORRISOME HEADACHE RED FLAGSFLAGS

“SNOOP”“SNOOP”

Older: new onset and progressive headache, especially in middle-age >50 (giant cell arteritis)

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

Previous headache history: first headache or different (change in attack frequency, severity, or clinical features)

Prevalence of migraine by Prevalence of migraine by sex and agesex and age

FemalesFemalesMalesMales3030

2525

2020

1515

1010

55

00

2020 3030 4040 5050 6060 7070 8080 100100

Migraine prevalence (%)Migraine prevalence (%)

Age (years)Age (years)

Lipton and Stewart (1993)Lipton and Stewart (1993)The American Migraine Study (The American Migraine Study (nn=2479 migraine sufferers)=2479 migraine sufferers)

PhysiologyPhysiology• Vasospasm – Lance• Spreading Wave of Depression –

Leao• Trigeminocentric• Allodynia

VasospasmVasospasm• 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 MigrainePhases 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 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 TheoryTrigeminal 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 TheoryAllodynia 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 What is Central Sensitization?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 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 PhenomenaMigraine 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 DictaSome 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

TreatmentTreatment• Effective treatment of attack• Prevention• Address comorbidities

Mechanisms for treatmentMechanisms for treatment

CGRPCGRPNKNKSPSP

5-HT5-HT1F1F5-HT5-HT1D1D

5-HT5-HT1B1B

Blood vesselBlood vessel

Trigeminal Trigeminal nervenerve

Adapted from Goadsby (1997)Adapted from Goadsby (1997)

CGRPCGRP calcitonin genecalcitonin gene related peptiderelated peptide

NKNK neurokinin Aneurokinin A

SPSP substance Psubstance P

triptantriptan

CONSTRICTIONCONSTRICTION

INHIBITIONINHIBITION

Acute AttackAcute 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

TRIPTANSTRIPTANS

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-HT1B/1D/1F agonists

Silberstein SD. Neurology. 2000.

TriptansTriptans• Learn to use one or two• Effective medicines

TRIPTANS:TRIPTANS:TREATMENT CHOICESTREATMENT 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

AlmotriptanTablet (6.25, 12.5 mg)

FrovatriptanTablet (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. 2001.

EletriptanTablet (20, 40 mg)

Elitriptan or RelpaxElitriptan or RelpaxAdvantagesAdvantages

Quick oral absorptionReliable oral absorptionRelatively long half lifeNumerous Clinical trials where proven

superior to ImitrexGets in fast, and stays aroundLow “rebound” recurrence rateWorks for all migraine phenonena

Pain, photosonophobia, nausea

Relpax CautionsRelpax 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 Migraine visual Aura from classic oph textbookclassic oph textbook

22

Efficacy of Eletriptan: Comprehensive Relief at 2 Hours

Relief of Photophobia, %

Headache response, %

Relief of Nausea, %

Relief of Phonophobia, %

Pain-free response, %

Placebo

0

20

40

60

4030

80

2010

40

60

80

80

40

60

80

Adapted from Mathew et al. Headache. 2003.

Sumatriptan was blinded using encapsulation. Encapsulated sumatriptan was bioequivalent to commercial tablets.

60

*†

*†

*†*†

*†

*

*

*

* *

*P<.001 vs placebo. †P<.05 vs sumatriptan.

Sumatriptan 100 mgEletriptan 40 mg

20 20

2040

Autoscopy

Relpax DosingRelpax 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” triptansParenteral” 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 worriesTriptan 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 CombinationsConsider Combinations• Triptan + NSAID• Triptan + anti-nausea• Unconventional agents• Phenergan, Compazine alone or in

combination. Zyprexa or atypicals• We don’t have enough alternatives

ProphylaxisProphylaxis• Anticonvulsants: topiramate, valproate,

Keppra, gabapentin• Tricyclics

– Amitriptylene, nortriptylene, trazodone• Beta Blockers

– Timolol, propranolol, nadolol• Calcium channel blocker – verapamil• ACE inhibitors• SSRI’s• Atypicals

Plea 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