II

Emeritus Professor, The Tamilnadu Emeritus Professor, The Tamilnadu Dr.M.G.R. Dr.M.G.R.

MEDICAL University,MEDICAL University,Former HOD, and PROF OF NEUROLOGYFormer HOD, and PROF OF NEUROLOGY

INSTITUTE OF NEUROLOGYINSTITUTE OF NEUROLOGYMADRAS MEDICAL COLLEGE,CHENNAIMADRAS MEDICAL COLLEGE,CHENNAI

03-06-1103-06-11

PROF.A.V.SRINIVASAN, MD, D.M, PhD ,D.Sc (HON) , F.A.A.N, F.I.A.N, PATHOPHYSIOLOGY AND MANAGEMENT

Management of Migraine in this Management of Migraine in this millenniummillennium

Treating Migraines

How Common is Migraine?How Common is Migraine?• 30,000,000 Americans30,000,000 Americans• 20% of women20% of women• 7% of men at any given time7% of men at any given time• Most of us have some migraine Most of us have some migraine

manifestations occasionallymanifestations occasionally

“My Opinions are founded on knowledge but modified by experience”

Recognizing MigraineRecognizing Migraine• Pounding unilateral headachePounding unilateral headache• Preceded by visual or other auraPreceded by visual or other aura• Nausea, vomitingNausea, vomiting• Light and sound sensitivityLight and sound sensitivity

Expert is one who think to his chosen mode of ignorance

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

(MA)(MA)

Headache Classification Committee of IHS (1988)Headache Classification Committee of IHS (1988)

At least five attacks fulfilling At least five attacks fulfilling these criteria:these criteria:• Headache lasting 4–72 h Headache lasting 4–72 h (2–48 h in children)(2–48 h in children)

At least two attacks fulfilling At least two attacks fulfilling these criteria:these criteria:• At least three of the At least three of the following:following:

– one or more fully reversibleone or more fully reversibleaura symptomsaura symptoms

– gradually developing orgradually developing orsequential aura symptomssequential aura symptoms

– no one aura symptom lastsno one aura symptom lastslonger than 1 hlonger than 1 h

– headache shortly follows or headache shortly follows or accompanies auraaccompanies aura

• Accompanied by at least one of:Accompanied by at least one of:– nausea nausea – vomitingvomiting– photophobia and/or photophobia and/or

phonophobiaphonophobia• No evidence of organic No evidence of organic

diseasedisease

• With at least two of:With at least two of:– unilateral locationunilateral location– pulsating qualitypulsating quality– moderate/severe intensitymoderate/severe intensity– aggravated by activityaggravated by activity

• No evidence of organic No evidence of organic diseasedisease

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 historyDiagnosis depends on patient history• No specific tests or clinical markers No specific tests or clinical markers • Positive diagnosis if attack history fulfils IHS Positive diagnosis if attack history fulfils IHS

criteria for migrainecriteria for migraine• Other pointers include:Other pointers include:

– family history of migrainefamily history of migraine– age of onset <45age of onset <45– presence of aurapresence of aura– menstrual associationmenstrual association

• Organic disease must be excludedOrganic disease must be excluded

WORRISOME HEADACHE RED WORRISOME HEADACHE RED FLAGSFLAGS“SNOOP”“SNOOP”

Older: new onset and progressive headache, especially in `

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)

“ He who cannot forgive others destroys the bridge over which he himself must pass” - Annoy

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

FemalesFemalesMalesMales3030

2525

2020

1515

1010

55

002020 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 – LanceVasospasm – Lance• Spreading Wave of Depression – Spreading Wave of Depression –

LeaoLeao• TrigeminocentricTrigeminocentric• AllodyniaAllodynia

If you think you can or you can’t You are always right

VasospasmVasospasm• I. Aura: Arteries SpasmI. Aura: Arteries Spasm

– Visual and focal neurological symtomsVisual and focal neurological symtoms– Pial and Occipital small artery branches Pial and Occipital small artery branches

• II. Headache: Compensatory II. Headache: Compensatory VasodilationVasodilation– Pounding unilateral sick headachePounding unilateral sick headache

• III. Inflammation and muscle spasm: III. Inflammation and muscle spasm: second pain phasesecond pain phase

Phases of MigrainePhases of Migraine• Vague Prodrome: psychic change and Vague Prodrome: psychic change and

cravings e.g. chocolatecravings e.g. chocolate• Aura: Focal symptoms and visionAura: Focal symptoms and vision• Headache: Throbbing unilateral painHeadache: Throbbing unilateral pain• Inflammation: Prolonged phase and TTHInflammation: Prolonged phase and TTH• PostdromePostdrome• Migraine related strokeMigraine related stroke

Experience can be defined as yesterday’s answer to today’s problems

Spreading Wave Spreading Wave • Brainstem controls Cortical ActivityBrainstem controls Cortical Activity• Epileptic like phenomenon that spreads Epileptic like phenomenon that spreads

over Cortexover Cortex• Visual Phenomenon that spreads over Visual Phenomenon that spreads over

surface of brain like shimmering “C”surface of brain like shimmering “C”• Cheiro-oral Jacksonian phenomenaCheiro-oral Jacksonian phenomena• Concurrence of migraine and epilepsyConcurrence of migraine and epilepsy• Why epilepsy drugs work for migraineWhy epilepsy drugs work for migraine

““Men of Genius Admired: Men of Wealth envied: Men of Genius Admired: Men of Wealth envied: women of power feared: But only women of character are women of power feared: But only women of character are trusted”trusted”

-A- Friedman-A- Friedman

Trigeminal TheoryTrigeminal Theory• Serotonin againSerotonin again• Trigeminal Afferents: sensory Trigeminal Afferents: sensory

function of face and meningesfunction of face and meninges• Trigeminal efferents to vesselsTrigeminal efferents to vessels• Cause vessel spasm and sensitivityCause vessel spasm and sensitivity• This theory primarily explains action This theory primarily explains action

of Triptans: 5-HT of Triptans: 5-HT 1b,d1b,d agonists agonists“ “ Maintaining the right attitude is easier than regaining the Maintaining the right attitude is easier than regaining the right mental attitude”right mental attitude”

Migraine attack Trigger

Increased serotonergic and noradrenergic stimulation in the brain stem

Dilation or constriction of cerebral and scalp blood vessels

Stimulation of branches of 5th cranial nerve (Trigeminal)

Thalamus

Cortex

Pain

Chemoreceptor

Hypothalamus - Photophobia

Nausea

Vomiting

J of Pharmacy Practice, Dec 1993; 253-270

““The Wise Man Before He Speaks ,The Wise Man Before He Speaks , Will Consider Well What He Speaks Will Consider Well What He Speaks

Migraine Pathophysiology

Goadsby NEJM 346:257-70,2002

Allodynia TheoryAllodynia Theory• Migraine is a state of hypersensitivityMigraine is a state of hypersensitivity• Light, sounds, smells, touch (head in Light, sounds, smells, touch (head in

headache) headache) • Need for dark roomNeed for dark room• Best preventives decrease sensitivity. Best preventives decrease sensitivity. • Anticonvulsants, tricyclics, beta and Anticonvulsants, tricyclics, beta and

calcium channel blockerscalcium channel blockers

The art of medicine is caring for the heart of the patient

What is Central What is Central Sensitization?Sensitization?• Central Sensitization is a time-Central Sensitization is a time-

dependent physiological eventdependent physiological event• During a migraine attack, neuronal During a migraine attack, neuronal

pathways become sensitized in stagespathways become sensitized in stages– Peripheral neurons are activated early in Peripheral neurons are activated early in

the attack (mild pain phase throbbing)the attack (mild pain phase throbbing)– Central neurons are activated later in the Central neurons are activated later in the

attack (full-blown migraine)attack (full-blown migraine)

Cutaneous allodynia Cutaneous allodynia • Phenomenon later in migraine attackPhenomenon later in migraine attack• Once it develops pts less likely to Once it develops pts less likely to

respond to triptansrespond to triptans• In small sample 15% of pts with and In small sample 15% of pts with and

93% of pts without CA responded to 93% of pts without CA responded to triptan (Burstein et al)triptan (Burstein et al)

Many Ideas grow better when transplanted into another mind than in the one where they sprang UP

O.W. Holmos

• Each of these Theories explains Each of these Theories explains some migraine phenomenasome migraine phenomena

When they tell you to grow up,

they mean stop growing - P. Diccaso

Migraine PhenomenaMigraine Phenomena• Focal and paroxysmal onset of symptomsFocal and paroxysmal onset of symptoms• Specific visual phenomenaSpecific visual phenomena• Spreading numbness and moving visual phenomena Spreading numbness and moving visual phenomena

and sensory distortions.and sensory distortions.• Nausea, vomiting “sick” headacheNausea, vomiting “sick” headache• Pounding unilateral or bilateral painPounding unilateral or bilateral pain• Psychic changesPsychic changes• Light and sound sensitivity even between attacksLight and sound sensitivity even between attacks• Effectiveness of triptansEffectiveness of triptans• Effect of anticonvulantsEffect of anticonvulants• Role of serotoninRole of serotonin

Some DictaSome Dicta• Any paroxysmal headache is likely to Any paroxysmal headache is likely to

be migraine unless proven otherwisebe migraine unless proven otherwise• ““Sinus” headaches and “tension” Sinus” headaches and “tension”

headaches are almost always headaches are almost always migraine headachesmigraine headaches

• First ever severe headache or sudden First ever severe headache or sudden “thunderclap” headaches may be SAH“thunderclap” headaches may be SAH“By Nature All Men/ Women are alike butby Education widely different” - Chinese

Mechanisms for Mechanisms for treatmenttreatment

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: Triptans: – sumatriptan, zolmitriptan, almotriptan, naratriptan, sumatriptan, zolmitriptan, almotriptan, naratriptan,

frovatriptan, elitriptriptan, riaztriptanfrovatriptan, elitriptriptan, riaztriptan• NSAID’sNSAID’s• FioricetFioricet• Midrin (isometheptane, chlorphenoxazone, apapMidrin (isometheptane, chlorphenoxazone, apap• OTC: Caffeine, apap, phenacitin, asaOTC: Caffeine, apap, phenacitin, asa• Ergots: Caffergot, DHE nasal, injectedErgots: Caffergot, DHE nasal, injected• NarcoticsNarcotics• DepaconDepacon

The True Art of Memory is The Art of Attention

- S.Johnson

Plea Plea • Listen to patientsListen to patients• Migraine is mixed up with a lot of thingsMigraine is mixed up with a lot of things

– Emotional factors: ennui, husbands, bosses, Emotional factors: ennui, husbands, bosses, general dissatisfaction with lifegeneral dissatisfaction with life

– Sleep disturbancesSleep disturbances– Hormonal changesHormonal changes

• If you do not address these you will not be If you do not address these you will not be treating your patientstreating your patients

• Don’t just throw drugs at your patientsDon’t just throw drugs at your patients• Be attentive and empatheticBe attentive and empathetic

THE TREATMENTTHE TREATMENTAPPROACH TO APPROACH TO

MIGRAINEMIGRAINE

LONG-TERM TREATMENT GOALS LONG-TERM TREATMENT GOALS FOR THE MIGRAINE SUFFERERFOR THE MIGRAINE SUFFERER• Reducing the attack frequency and Reducing the attack frequency and

severityseverity• Avoiding escalation of headache Avoiding escalation of headache

medicationmedication• Educating and enabling the patient Educating and enabling the patient

to manage the disorderto manage the disorder• Improving the patient’s quality of lifeImproving the patient’s quality of life

A great man is he, who can forgive any sin

MIGRAINE MANAGEMENTMIGRAINE MANAGEMENT• Non-pharmacological treatmentNon-pharmacological treatment

– Identification of triggersIdentification of triggers– MeditationMeditation– Relaxation trainingRelaxation training– PsychotherapyPsychotherapy

• PharmacotherapyPharmacotherapy non-specificnon-specific

– Abortive therapy Abortive therapy specificspecific– Preventive therapyPreventive therapy

Drug Dose RouteAspirin 500-650 mg OralParacetamol 500 mg-4 g Oral

MIGRAINE: MIGRAINE: ABORTIVE ABORTIVE THERAPYTHERAPY

Non-specific treatment

Ibuprofen 200- 300 mg OralDiclofenac 50-100 mg Oral/IMNaproxen 500-750 mg Oral

Expert is one who think to his chosen mode of ignorance

ABORTIVE THERAPY FOR ABORTIVE THERAPY FOR MIGRAINEMIGRAINE

Drug Dose RouteErgot alkaloidsErgotamine 1-2 mg/d; max-6 g/d OralDihydroergotamine 0.75-1 mg SC5-HT receptor agonistsSumatriptan 25-300 mg

6 mgOrallySC

Rizatriptan 10 mg Orally

Specific treatment

Discipline Weighs ounces Regret weighs Tons

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 twoLearn to use one or two• Effective medicinesEffective medicines

“Social Isolation is in itself a pathogenicFactor for disease production”

TRIPTANS:TRIPTANS:TREATMENT CHOICESTREATMENT CHOICES

Are there differences Are there differences between the triptans?between the triptans?

If one triptan fails, will If one triptan fails, will another triptan work?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 RelpaxAdvantagesAdvantagesQuick oral absorptionQuick oral absorptionReliable oral absorptionReliable oral absorptionRelatively long half lifeRelatively long half lifeNumerous Clinical trials where proven Numerous Clinical trials where proven

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

Pain, photosonophobia, nauseaPain, photosonophobia, nausea

Relpax CautionsRelpax Cautions• Available only in oral formAvailable only in oral form• CYP 3A4CYP 3A4

– Do not give within 72 hours of: Ketoconazole, Do not give within 72 hours of: Ketoconazole, Nefazadone, clarithromycin, rotonavir, nelfinavir, others. Nefazadone, clarithromycin, rotonavir, nelfinavir, others. caution with verapamil, erythromycin.caution with verapamil, erythromycin.

• Contraindications (all triptans) Contraindications (all triptans) – Suspected Coronary diseaseSuspected Coronary disease– Basilar or hemiplegic, ophthalmoplegic migraine Basilar or hemiplegic, ophthalmoplegic migraine – Uncontrolled hypertensionUncontrolled hypertension– <18 or >65<18 or >65– Within a day of any other triptanWithin a day of any other triptan– Hypersensitivity to the drugHypersensitivity to the drug

Maintaining the right attitude is easier than regaining the right mental attitude

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

Relpax DosingRelpax Dosing• 40 mg. May repeat X1 in 2 hours40 mg. May repeat X1 in 2 hours• Max dose in 24 hours is 80 mgMax dose in 24 hours is 80 mg• Repeating dose most efficacious if Repeating dose most efficacious if

headache returns headache returns

Opinion is ultimately determined by the feelings and not by the intellect

““Parenteral” triptansParenteral” triptans• Imitrex injections: Very good fast Imitrex injections: Very good fast

reliable onset but peaks quickly with reliable onset but peaks quickly with short half lifeshort half life

• Imitrex and Zomig nasal: absorption Imitrex and Zomig nasal: absorption not reliable, taste not so good but may not reliable, taste not so good but may be tried if a lot of nauseabe tried if a lot of nausea

• Zomig ZMT and Maxalt MLT on tongue: Zomig ZMT and Maxalt MLT on tongue: not strictly parenteral absorbed thru not strictly parenteral absorbed thru gutgut

Truth comes out of error sooner than that of confusion

Triptan worriesTriptan worries• Not released under age 18Not released under age 18• If you even suspect CAD don’t use or get If you even suspect CAD don’t use or get

proper exclusionary tests. proper exclusionary tests. – Man or woman of a certain ageMan or woman of a certain age– Smoker or other risk factorsSmoker or other risk factors

• Cerebrovascular disease or complicated Cerebrovascular disease or complicated migraine - contraindicatedmigraine - contraindicated

• Watch for overuse. These are rescue Watch for overuse. These are rescue medicinesmedicines

Every discovery contains an irrational element or 4 creative intuition

- Karl Popper

Consider CombinationsConsider Combinations• Triptan + NSAIDTriptan + NSAID• Triptan + anti-nauseaTriptan + anti-nausea• Unconventional agentsUnconventional agents• Phenergan, Compazine alone or in Phenergan, Compazine alone or in

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

The secret of walking on water isKnowing where the stones are

Drug Drug Dose (mg)/dDose (mg)/d RouteRoute

DomperidoneDomperidone 10-80 mg10-80 mg OralOral

MetoclopramideMetoclopramide 5-10 mg5-10 mg Oral/IVOral/IV

PromethazinePromethazine 50-125 mg50-125 mg Oral/IMOral/IM

ChlorpromazineChlorpromazine 10-25 mg10-25 mg Oral/IVOral/IV

ANTI-NAUSEANT DRUGS FOR ANTI-NAUSEANT DRUGS FOR MIGRAINE TREATMENTMIGRAINE TREATMENT

Thought is the labour of the intellectReverie is its pleasure

WHY THE NEED FOR PROPHYLAXIS ?WHY THE NEED FOR PROPHYLAXIS ?

• Abortive drugs should not be used more Abortive drugs should not be used more than 2-3 times a weekthan 2-3 times a week

• Long-term prophylaxis improves quality of Long-term prophylaxis improves quality of life by reducing frequency and severity of life by reducing frequency and severity of attacks attacks

• 80% of migraineurs may require 80% of migraineurs may require prophylaxisprophylaxisMemory, the daughter of attention ,

is the teeming mother of knowledge - Martin Tupper

WHEN IS PROPHYLAXIS INDICATED?WHEN IS PROPHYLAXIS INDICATED?According to the US Headache Consortium According to the US Headache Consortium

Guidelines,Guidelines,indications for preventive treatment include:indications for preventive treatment include:• Patients who have very frequent headaches (more than Patients who have very frequent headaches (more than

2 per week)2 per week)• Attack duration is > 48 hoursAttack duration is > 48 hours• Headache severity is extremeHeadache severity is extreme• Migraine attacks are accompanied by prolonged auraMigraine attacks are accompanied by prolonged aura• Unacceptable adverse effects occur with acute migraine Unacceptable adverse effects occur with acute migraine

treatmenttreatment• Contraindication to acute treatmentContraindication to acute treatment• Migraine substantially interferes with the patient’s daily Migraine substantially interferes with the patient’s daily

routine, despite acute treatmentroutine, despite acute treatment• Special circumstances such as hemiplegic migraine or Special circumstances such as hemiplegic migraine or

attacks with a risk of permanent neurologic injuryattacks with a risk of permanent neurologic injury• Patient preferencePatient preference

DrugsDrugs Dose (mg/d)Dose (mg/d)1.1. BetablockersBetablockers

– PropranololPropranolol 40-32040-3202.2. Calcium Channel Calcium Channel

BlockersBlockers– FlunarizineFlunarizine– VerapamilVerapamil

10-2010-20120-480120-480

3.3. TCAsTCAs– AmitriptylineAmitriptyline 10-2010-20

4.4. SSRIsSSRIs– FluoxetineFluoxetine 20-60 20-60

PREVENTIVE THERAPY FOR PREVENTIVE THERAPY FOR MIGRAINEMIGRAINE

Every thing should be made as simple as possible; but not simpler

DrugsDrugs Dose (mg/d)Dose (mg/d)5.5. Anti-convulsantAnti-convulsant

– Sodium valproateSodium valproate 600-1200600-12006.6. Anti-histaminicAnti-histaminic

– CyproheptadineCyproheptadine 4-84-8

PREVENTIVE THERAPY FOR PREVENTIVE THERAPY FOR MIGRAINEMIGRAINE (CONTD.)(CONTD.)

Take time to think; it is the source of powerTake time to read; it is the foundation of wisdomTake time to work; it is the price of success

ROLE OF BETA BLOCKERS IN ROLE OF BETA BLOCKERS IN MIGRAINE PROPHYLAXISMIGRAINE PROPHYLAXIS

• ‘‘Gold standard’ in migraine prophylaxisGold standard’ in migraine prophylaxis• Established efficacy and safety in Established efficacy and safety in

migraine prophylaxismigraine prophylaxis• Especially preferred if hypertension or Especially preferred if hypertension or

anxiety co-existanxiety co-exist

Truth comes out of error sooner than that of confusion

Dedicated to my family Dedicated to my family for making everything worthwhilefor making everything worthwhile

READ not to contradict or confuteNor to Believe and Take for Grantedbut TO WEIGH AND CONSIDER

THANK YOU