neurological lectures...migraine

Treating Migraines

Professor Yasser Metwallywww.yassermetwally.com

World prevalence of migraineWorld prevalence of migraine

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

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)

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 for migraineNo specific tests or clinical markers for migrainePositive 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

Migraine CriteriaMigraine Criteria

5 attacks lasting 45 attacks lasting 4––72 h72 h

2 of the following 42 of the following 4– UnilateralUnilateral– PulsatingPulsating– Moderate or severe intensityModerate or severe intensity– Aggravation by routine physical activityAggravation by routine physical activity

1 of the following1 of the following– Nausea and/or vomitingNausea and/or vomiting– Photophobia and phonophobiaPhotophobia and phonophobia

Not attributable to another disorderNot attributable to another disorder

SULTANS: two from column A, one SULTANS: two from column A, one from column Bfrom column B

evereevere

nini

ateralateral

hrobbinghrobbing

Ctivity worsensCtivity worsens

auseaausea

Lite and sound Lite and sound ensitivityensitivity

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

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

At least five attacks fulfilling these At least five attacks fulfilling these criteria: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 these At least two attacks fulfilling these criteria:criteria:

At least three of the following:At least three of the following:– one or more fully reversibleone or more fully reversible

aura symptomsaura symptoms– gradually developing orgradually developing or

sequential aura symptomssequential aura symptoms– no one aura symptom lastsno one aura symptom lasts

longer 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 diseaseNo evidence of organic disease

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 diseaseNo evidence of organic disease

Clinical features of migraineClinical features of migraine

SleepySleepy

AnorexiaAnorexia nauseanausea Vomiting

Vomiting

yawningyawning

PhonophobiaPhonophobia

PhotophobiaPhotophobia

PhonophobiaPhonophobia

PhotophobiaPhotophobia

OsmophobiaOsmophobia

OsmophobiaOsmophobia

Vomiting

VomitingDeep sleepDeep sleep

HeadacheHeadache

IIIIII IV IVHeadache Resolution Headache Resolution

Blau (1992)Blau (1992)

II II II NormalNormal Prodromes Aura Prodromes Aura

NormalNormal

AppetiteAppetite

Awake/sleepAwake/sleep

Light toleranceLight tolerance

SmellSmell

NoiseNoise

Fluid balanceFluid balance

CravingCraving

TiredTired yawningyawning

HeightenedHeightened

perceptionperception

FluidFluid retentionretention

VVPostdromes NormalPostdromes Normal

Limited

Limited

Light toleranceLight tolerance

NoiseNoise

SmellSmell

Fluid balanceFluid balance

TiredTired

FeelingFeeling

high orhigh or

lowlow

DiuresisDiuresis

AppetiteAppetite

Awake/sleepAwake/sleep

food tolerance food tolerance

NormalNormal

3

Migraine Patients Suffer From Pain and Symptoms

Adapted from Lipton et al. Headache. 2001.

30%

74%

81%

99%

0 20 40 60 80 100

Vomiting

Nausea

Photophobia

Moderate to severe pain

Percentage of patients reporting symptom

77%Phonophobia

5

Migraine Remains Underdiagnosedand Undertreated

Lipton et al. Neurology. 2002.

5%

23%

48%

23%

49%

0

25

50

75

100

MD diagnosis Rx medication only

OTC medication only

Both Rx and OTC

No medication

Per

cen

tag

e o

f p

atie

nts

IMPORTANT DIAGNOSTIC IMPORTANT DIAGNOSTIC CONSIDERATIONSCONSIDERATIONS

Recurring moderate to severe headache is migraine until proven otherwise

Russell MB, et al. Cephalalgia. 1996.Pryse-Phillips WEM, et al. Can Med Assoc J. 1997.

No single criterion necessary nor sufficient for diagnosis

15% of patients have a neurological aura

IHS criteria do not require GI symptoms

Vomiting occurs in < 1/3 of patients

41% of migraine patients report bilateral pain

50% of the time, pain is non-pulsating

Premonitory, aura and postdromal Premonitory, aura and postdromal symptomssymptoms

ProdromeProdrome Occurs in 60% of attacksOccurs in 60% of attacks Alterations inAlterations in

– moodmood– alertnessalertness– appetiteappetite

Originate in hypothalamus Originate in hypothalamus and frontal lobesand frontal lobes

Silberstein and Lipton (1994); Silberstein and Lipton (1994);

Lance (1993); Blau (1992)Lance (1993); Blau (1992)

PostdromePostdrome Occurs in 90% patientsOccurs in 90% patients Symptoms can persist for Symptoms can persist for

several daysseveral days– lethargylethargy– exhaustionexhaustion– impaired concentrationimpaired concentration– irritabilityirritability– sluggishnesssluggishness– diminished appetitediminished appetite– euphoriaeuphoria

AuraAura Occur in MA (20% patients)Occur in MA (20% patients) Visual symptomsVisual symptoms

– blurring, ripplingblurring, rippling– spots or flashesspots or flashes– fortification spectrafortification spectra– scotomascotoma

Sensory symptomsSensory symptoms– numbness/tinglingnumbness/tingling

Motor symptomsMotor symptoms– hemiparesishemiparesis

MIGRAINE WITH AURAMIGRAINE WITH AURA(FORMERLY “CLASSIC” (FORMERLY “CLASSIC”

MIGRAINE)MIGRAINE)

Visual > sensory > motor, language, brainstem

Gradual evolution:

5–20 minutes (<60 minutes)

May or may not be associated with headache

Complex array of symptoms reflecting focal cortical or brainstem dysfunction

International Headache Society. Cephalalgia. 1988;8;(suppl 7):1-96.

MIGRAINE AURAMIGRAINE AURA“Cheiro-oral”“Cheiro-oral”

Fortification SpectrumFortification Spectrum

DIAGNOSIS AND TESTINGDIAGNOSIS AND TESTING

Detailed History and ExaminationDetailed History and Examination

Primary Headache? Preliminary DiagnosisPrimary Headache? Preliminary Diagnosis

NONO

SecondaryHeadacheSecondaryHeadache

DiagnosticTesting

DiagnosticTesting

AtypicalFeatures

YESYES

Alice in WonderlandAlice in Wonderland

REASONS FOR REASONS FOR MISDIAGNOSIS OF MIGRAINE MISDIAGNOSIS OF MIGRAINE

AS TTH OR SINUSAS TTH OR SINUSSinus

Raskin NH. Headache. 2nd ed. 1988; Barbanti P, et.al. Cephalalgia. 2001;Kaniecki R. Cephalalgia. 2001.

Migraine is a referred pain syndrome (V1, C1-C3)

Up to 50% of migraine patients report their headaches are influenced by weather

45% of migraine patients report attack related ‘sinus’ symptoms including lacrimation, rhinorrhea, nasal congestion

Tension-Type Headache

75% of migraine patients report posterior neck pain/tightness/stiffness during attacks

Stress/anxiety frequent migraine trigger

Migraine is bilateral in up to 40% of patients

Differential diagnosis of Differential diagnosis of primary headachesprimary headaches

Dubose Dubose et alet al (1995); Goadsby (1999); Marks and Rapoport (1997) (1995); Goadsby (1999); Marks and Rapoport (1997)

Family historyFamily history YesYes

SexSex More femalesMore females

OnsetOnset Variable Variable

LocationLocation Usually unilateralUsually unilateralin adultsin adults

Character/severityCharacter/severity PulsatilePulsatileThrobbingThrobbing

Frequency/Frequency/ 2–72 h/attack2–72 h/attack durationduration 1 attack/year to1 attack/year to

>8 per month>8 per month

AssociatedAssociated Visual auraVisual aurasymptomssymptoms PhonophobiaPhonophobia

PhotophobiaPhotophobiaPallorPallorNausea/vomitingNausea/vomiting

Clinical featureClinical feature MigraineMigraine

NoNo

More malesMore males

During sleepDuring sleep

Behind/aroundBehind/aroundone eyeone eye

Excruciating/Excruciating/sharpsharpSteadySteady

15–90 min/attack15–90 min/attack1–8 attacks/day1–8 attacks/dayfor 3–16 weeks for 3–16 weeks 1–2 bouts/year1–2 bouts/year

SweatingSweatingFacial flushingFacial flushingNasal congestionNasal congestionPtosisPtosisLacrimationLacrimationConjunctival injectionConjunctival injectionPupillary changesPupillary changes

Cluster headacheCluster headache

YesYes

More femalesMore females

Under stressUnder stress

Bilateral in bandBilateral in bandaround headaround head

DullDullPersistent Tightening/pressingPersistent Tightening/pressing

30 min to 7 days 30 min to 7 days 3–4 attacks/week3–4 attacks/weekto 1–2 attacks/yearto 1–2 attacks/year

Mild photophobiaMild photophobiaMild phonophobiaMild phonophobiaAnorexiaAnorexia

Tension headacheTension headache

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)

Headache ‘red flags’Headache ‘red flags’First or worst headacheFirst or worst headache

Significant change from previous headache patternSignificant change from previous headache pattern

– no longer fulfils IHS criteriano longer fulfils IHS criteria

New onset headache in middle age or laterNew onset headache in middle age or later

New or progressive headache that lasts for daysNew or progressive headache that lasts for days

Precipitation of headache by coughing/sneezing/Precipitation of headache by coughing/sneezing/bending downbending down

Systemic symptoms such as myalgia, fever, malaise, Systemic symptoms such as myalgia, fever, malaise, weight loss, scalp tenderness, jaw claudicationweight loss, scalp tenderness, jaw claudication

Focal symptoms, seizures, confusion, impaired Focal symptoms, seizures, confusion, impaired conciousness, physical examination abnormalitiesconciousness, physical examination abnormalitiesPryse-Phillips Pryse-Phillips et alet al (1997) (1997)

EVALUATION STRATEGIESEVALUATION STRATEGIES

Red Flags”

“Investigate

the

Atypical

and the

SUDDEN ONSET HEADACHESUDDEN ONSET HEADACHE

Primary Secondary

SAH

Pituitary apoplexy

Venous sinus thrombosis

Arterial dissection

Meningoencephalitis

Acute hydrocephalus

Acute hypertension

Spontaneous intracranial hypotension

Idiopathic thunderclap headache (TCH)

Exertional headache

Cough headache

Sexual headache

deBruijn, SF, et al. Lancet. 1996; Lancet. 1998.

LUMBAR PUNCTURELUMBAR PUNCTURE

Headache associated with fever, confusion, meningism, or seizures

Thunderclap headache with negative CT head

Subacute progressive headache

High or low CSF pressure suspected (even if papilledema is absent)

The first unusually severe headache

Evans RE, Rozen TD, Adelman JU. In: Wolff’s Headache And Other Head Pain. 2001.

SENSITIVITY OF CT SCAN IN SENSITIVITY OF CT SCAN IN SUBARACHNOID HEMORRHAGE SUBARACHNOID HEMORRHAGE

(SAH)(SAH)

van Gijn J, van Dongen KJ. Neuroradiology. 1982.Kassell NF et al. J Neurosurg. 1990.

TIME AFTER TIME AFTER HEADACHE HEADACHE

ONSETONSET

PROBABILITYPROBABILITY(%)(%)

DAY 0DAY 0 9595

DAY 3DAY 3 8080

1 WEEK1 WEEK 5050

2 WEEKS2 WEEKS 3030

3 WEEKS3 WEEKS ~0~0

DIAGNOSIS TESTINGDIAGNOSIS TESTINGCT AND MRICT AND MRI

Consensus expert opinion MRI is more sensitive

Role of CT or MRI in patients with nonmigraine headache is unclear

In patients with recurrent migraine, neither CT nor MRI is warranted except in cases where: Recent substantial change in headache pattern History of seizures Focal neurologic symptoms or signs

Report of Quality Standards Subcommittee of AAN. Neurology. 1994.

DIAGNOSTIC TESTING DIAGNOSTIC TESTING ELECTROENCEPHALOGRAPHYELECTROENCEPHALOGRAPHY

EEG may be useful in those patients with Alteration or loss of consciousness Residual focal neurologic defects or

encephalopathy Atypical migrainous aura

EEG is not useful In the routine evaluation of patients with headache

to exclude structural cause

Report of Quality Standards Subcommittee of AAN. Neurology. 1995.

MR AND CONVENTIONAL MR AND CONVENTIONAL ANGIOGRAPHYANGIOGRAPHY

MR Angiography

Acute SAH

Arterial dissection

CNS vasculitis

Angiography

Aneurysm (>5 mm)

Arterial dissection

Venous thrombosis

(MR venography)

AV malformation

Leclerc X et al. Neuroradiology. 1999.

INDICATIONS FOR GADOLINIUM INDICATIONS FOR GADOLINIUM ENHANCED MRIENHANCED MRI

CerebrovascularCerebrovascular– Arterial dissection Arterial dissection

(MRA)(MRA)– Cerebral venous Cerebral venous

sinus thrombosis sinus thrombosis (MRV)(MRV)

– CNS vasculitisCNS vasculitis

TumorsTumors– Posterior fossaPosterior fossa– PituitaryPituitary– LeptomeningesLeptomeninges

Herpes encephalitis

High and low intracranial pressure syndromes

MRA = magnetic resonance angiography.MRV = magnetic resonance venography.

Bousser MG et al; Wall M et al; Mokri B; and Newman C, Solomon S. In: Wolff’s Headache And Other Head Pain. 2001. Tien RD et al. AJR Am J Roentgenol. 1993.

CEREBRAL VENOUS SINUS THROMBOSISCEREBRAL VENOUS SINUS THROMBOSIS

Bousser MG et al. In: Wolff’s Headache And Other Head Pain. 2001.

Sleepers Awake!!

Treatment

STRATEGIES FOR MIGRAINE STRATEGIES FOR MIGRAINE TREATMENTTREATMENT

Preemptive treatmentMigraine triggertime-limited and

predictable

Preemptive treatmentMigraine triggertime-limited and

predictable

PreventiveTreatment

Decrease inmigraine frequency

warranted

PreventiveTreatment

Decrease inmigraine frequency

warranted

Acutetreatment

To stop pain and prevent progression

Acutetreatment

To stop pain and prevent progression

Silberstein SD. Cephalalgia. 1997.

ACUTE MIGRAINE TREATMENTACUTE MIGRAINE TREATMENT

Discuss problems that arise in the acute management of migraine

Evaluate the general principles of treatment

Review the clinical evidence for acute treatment alternatives

Present an approach for selecting and sequencing acute therapies

Objectives

Patient education and behavioral management Nature and mechanism of the disorder Strategies for identifying and avoiding triggers Behavioral strategies

Regular sleep, exercise, meals Stress management, biofeedback Cognitive behavioral therapy

PRINCIPLES OF MIGRAINE PRINCIPLES OF MIGRAINE MANAGEMENTMANAGEMENT

Establish a therapeutic partnership

Pharmacologic management Acute treatment Preventative strategies

NONPHARMACOLOGIC NONPHARMACOLOGIC TREATMENTSTREATMENTS

Insufficient evidence to recommend: GRADE C Acupuncture TENS Cervical manipulation Occlusal adjustment Hyperbaric oxygen Hypnosis

Goslin RE et al. Behavioral and Physical Treatments for Migraine Headache. 1999.

Effective: GRADE A Relaxation training Thermal biofeedback with relaxation training EMG biofeedback Cognitive behavioral therapy

The benefits of behavioral therapy (eg, biofeedback, relaxation) are in addition to preventive drug therapy (eg, propranolol, amitriptyline): GRADE B

Goals of TreatmentGoals of Treatment

Establish diagnosisEstablish diagnosisEducate patientEducate patientDiscuss findingsDiscuss findingsEstablish reasonable expectationsEstablish reasonable expectationsInvolve patient in decisionsInvolve patient in decisionsEncourage Pt to avoid triggersEncourage Pt to avoid triggersChoose the best treatment (tailoring)Choose the best treatment (tailoring)Create treatment planCreate treatment plan

MIGRAINE TRIGGERSMIGRAINE TRIGGERS

Diet

Hormonal changes

Head trauma

Stress and anxiety

Sleep deprivation or excess

Environmental factors

Physical exertion

ACUTE MIGRAINE MEDICATIONSACUTE MIGRAINE MEDICATIONS

Nonspecific NSAIDs Combination analgesics Opioids Neuroleptics/antiemetics Corticosteroids

Specific Ergotamine/DHE Triptans

ACUTE THERAPIES FOR ACUTE THERAPIES FOR MIGRAINEMIGRAINE

Nonspecific Prescription Medications Butorphanol IN Ibuprofen/Naproxen sodium Prochlorperazine IV

GROUP 1a: Substantial empirical evidence and pronounced clinical benefit in

migraine

Silberstein SD. Neurology. 2000.

Migraine-Specific Medications Triptans DHE

SC, IM, IN, IV (plus antiemetic)

GROUP 2: Moderate empirical evidence and clinical benefit

Opioids Others

ACUTE THERAPIES FOR ACUTE THERAPIES FOR MIGRAINEMIGRAINE

Over-the-Counter Analgesics Aspirin Acetaminophen, aspirin, plus caffeine


GROUP 1b: Substantial empirical evidence of clinical benefit in restricted populations

CONSIDERATIONS IN INITIAL CONSIDERATIONS IN INITIAL ACUTE THERAPYACUTE THERAPY

As disability increases, nonspecific treatments less likely to work

In the most severely afflicted 25% of migraine sufferers, an NSAID-metoclopramide combination is successful in only 25% of patients

Try to get the treatment “right” the first time

Match treatment intensity to attack severity (stratified care)

Ask about migraine disability and impact


Trigeminovascular Trigeminovascular model of migrainemodel of migraine

Adapted from Goadsby and Olesen (1996)Adapted from Goadsby and Olesen (1996)

Dura materDura mater

AfferentAfferent

Trigeminal Trigeminal ganglionganglion

Peptide releasingPeptide releasingneuronesneurones

Dura materDura mater

EfferentEfferent

Trigeminal Trigeminal nervenerve

AfferentAfferent

BloodBloodvesselsvessels

EfferentEfferent

CGRP/SPCGRP/SPreleaserelease

DilatationDilatation

CraniumCranium

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

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


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)

ROUTES OF ADMINISTRATIONROUTES OF ADMINISTRATION

Suppositories: antiemetics, ergots, opioids

Oral therapies: most medications

Nasal sprays: sumatriptan, DHE, butorphanol, zolmitriptan

Injectable (SL, IM, IV) sumatriptan, DHE, injectable NSAIDs, opioids, neuroleptics

FORMULATION: ONSETFORMULATION: ONSET

Increasing SpeedIncreasing Speed

ParenteralParenteralOralOral

TabletTablet

SLSL

ININ

PRPR

IM/SCIM/SC IVIV

SumatriptanSumatriptan

Sumatriptan (Glaxo Wellcome) Sumatriptan (Glaxo Wellcome) – 5-HT5-HT1B/1D1B/1D agonist agonist

N

H

NMe2

MeNHSO2

Major advance – good efficacy with Major advance – good efficacy with subcutaneous formulationsubcutaneous formulation

Slow onset (2–4 h p.o.); LogD -1.5Slow onset (2–4 h p.o.); LogD -1.5

Short tShort t1/21/2 (2 h) (2 h)

Ferrari Ferrari et alet al (1995) (1995)

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

24

Incidence of Adverse Events*

*Events experienced by 2% of patients. Incidence following a single dose of study medication.

Relpax® (eletriptan HBr) Prescribing Information. Data on file. Pfizer Inc., New York, NY.

Placebo 20 mg 40 mg 80 mg(n=988) (n=431) (n=1774) (n=1932)

10%5%4%3%Asthenia

4%2%1%1%Chest tightness/pain/pressure

4%3%2%2%Dry mouth

4%3%3%2%Paresthesia

4%3%4%3%Headache

7%6%3%3%Dizziness

7%6%3%4%Somnolence

8%5%4%5%Nausea

Eletriptan

The maximum recommended single dose of eletriptan is 40 mg.

00

2020

4040

6060

8080

100100

00 11 22 33 44

PlaceboPlacebo

Time post dose (h)Time post dose (h)

nn=563=563

Headache responses continue to Headache responses continue to improve over time after eletriptan improve over time after eletriptan

dosingdosingTime course for headache responseTime course for headache response

Pfizer, data on filePfizer, data on file

% Patients with response% Patients with response

20 mg eletriptan20 mg eletriptan

40 mg eletriptan40 mg eletriptan

Study 314Study 314****PP<0.05 vs placebo for all doses<0.05 vs placebo for all doses

80 mg eletriptan80 mg eletriptan****

****

****

ACUTE TREATMENT ACUTE TREATMENT PRINCIPLESPRINCIPLES

Early intervention

Use correct dose and formulation

Use a maximum of 2–3 days/week

Use preventive therapy in selected patients

stratified care

Silberstein SD. Neurology. 2000; Lipton RB, et al. JAMA. 2000.

STEP VS. STRATIFIED CARESTEP VS. STRATIFIED CARE

StartStart

StartStartAA

BB

CC

AA

BB

CC

BASIS OF STRATIFICATIONBASIS OF STRATIFICATION

Symptom profile Prominent nausea and vomiting may require parenteral

therapy

Headache frequency Consider risk of medication overuse

Patient history and preferences Consider adverse events and prior experience

Headache onset and severity Fast onset may benefit from parenteral therapy Disability predicts treatment needs


MIDAS ScoreMIDAS ScoreDays in Last 3 monthsDays in Last 3 months

You’ve missed work or school due to your headaches? You’ve missed work or school due to your headaches? Your productivity at work or school reduced by half or more due to Your productivity at work or school reduced by half or more due to your headaches? your headaches? (Please do not include days you counted in (Please do not include days you counted in question 1 where you missed work or school)question 1 where you missed work or school) You not do household work because of your headaches? You not do household work because of your headaches? Your productivity in household work reduced by half or more Your productivity in household work reduced by half or more because of your headaches?because of your headaches? (Do not include days you counted in (Do not include days you counted in question 3 where you did not do household work)question 3 where you did not do household work) You missed family, social or leisure activities because of your You missed family, social or leisure activities because of your headaches? headaches? A. Had a Headache? If a headache lasted more than one day count A. Had a Headache? If a headache lasted more than one day count each day. each day.

B. On a scale of 1-10 on average how painful were those B. On a scale of 1-10 on average how painful were those headaches? (Where 0 is no pain, 10 is as bas as pain could be??headaches? (Where 0 is no pain, 10 is as bas as pain could be??

GradeDefinitionScoreGradeDefinitionScore

I Minimal or infrequent disability 0-5I Minimal or infrequent disability 0-5

II II Mild or infrequent disability 6-10Mild or infrequent disability 6-10

III III Moderate disability 11-20Moderate disability 11-20

IV IV Severe disability 21+Severe disability 21+

DISABILITY IN STRATEGIES OF DISABILITY IN STRATEGIES OF CARE (DISC) STUDYCARE (DISC) STUDY

Step care across attacks ASA + M Assess response after 3 attacks Escalate treatment to zolmitriptan if ASA + M fails 2/3 or 3/3

Stratification based on disability MIDAS Grade II—ASA + M MIDAS Grade III, IV—Triptan (zolmitriptan)

Step care within attacks ASA + M Assess response at 2 hours

Rescue with zolmitriptan prn

Stratified care produces better headache response less disability time

Disability can be used to predict treatment needs

Compared 3 strategies of migraine management over 6 attacks

Lipton RB et al. JAMA. 2000.

TREAT MIGRAINE WHEN PAIN IS MILDTREAT MIGRAINE WHEN PAIN IS MILD

Retrospective analysis of 3 studies confirmed triptan treatment while pain is mild provided higher pain-free response at 2 h than ergotamine plus caffeine or aspirin plus metoclopramide, and reduced need for redosing

Prospective rizatriptan study of 1919 patients confirms triptan effectiveness at all levels of pain but enhanced benefit if taken while pain is mild

Post-hoc analysis of Spectrum study (26 patients) showed sumatriptan provided more effective relief with less recurrence when taken while pain was still mild

Cady RK et al. Headache. 2000; Cady RK et al. Clin Ther. 2000; Hu XH et al. Headache. 2002.

In patients with migraine, sumatriptan effectively treats all 3 types

TRIPTANS IN THE SPECTRUM TRIPTANS IN THE SPECTRUM OF MIGRAINEOF MIGRAINE

In patients with pure TTH, sumatriptan is not effectiveIn migraine sufferers TTH, has a migraine-like mechanism, whereas pure TTH has a different mechanism

Patients with disabling migraine have different headache types, including migraine, migrainous, and tension-type headache (TTH)

Lipton et al. Headache. 2000; Cady RK et al. Cephalalgia. 1997.

Therefore, sumatriptan can effectively treat TTH in migraine sufferers, probably because it is a form of mild migraine

RECURRENCE & REBOUNDRECURRENCE & REBOUND

Rebound: Recurring headache induced by repetitive and chronic overuse of acute headache medication

Recurrence: Return of episodic headache during the same attack following acute treatment Prevention: Treat early, add NSAID. Use long

duration triptan or DHE

Treatment: Repeat initial acute headache drug; almost always effective

Tfelt-Hansen P et al. Drugs. 2000; Capobianco DJ et al. Headache. 2001.

APPROACH TO DIFFICULT APPROACH TO DIFFICULT HEADACHE PROBLEMSHEADACHE PROBLEMS

Problem Strategy

Headache recurrence Treat earlier, add NSAID, increase dose, change triptans (consider naratriptan or frovatriptan), or switch to DHE

Elderly Use acetaminophen, COX 2 inhibitors, opioids, atypical neuroleptics

Pregnancy Use acetaminophen, opioids, corticosteroids, neuroleptics

Adverse effects Switch triptans, use a different class

Lack of response Treat earlier, increase dose, add metoclopramide or NSAID, change formulation or triptan. Add preventive.

Silberstein SD et al. Wolff’s Headache and Other Head Pain. 2001.

SUMMARY OF ACUTE SUMMARY OF ACUTE MIGRAINE MANAGEMENTMIGRAINE MANAGEMENT

Identify coexistent conditions that influence therapy

Make a specific, credible diagnosis and communicate it

Assess migraine severity and it’s impact on the patient

Determine the patient’s preferences and needs (eg, fast relief, adverse effects tolerance)

Develop a therapeutic partnership with realistic expectations

Create plan based on migraine type and severity, as well as patient’s needs, preferences, and comorbidities

Consider need for preventive treatment

26

Eletriptan Dosing and Administration

• RELPAX should be taken at the onset of a migraine headache.

• RELPAX can be taken with or without food.• RELPAX should not be used within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir.

• Studies have shown that the pharmacokinetics of eletriptan are generally unaffected by age, gender, or menstrual cycle.

Relpax® (eletriptan HBr) Prescribing Information. Pfizer Inc., New York, NY.

7

Eletriptan: Key Clinical Trials

Phase II/III/IIIPhase II/III/III--b b clinical programclinical program8 trials; N=81058 trials; N=8105

Eletriptan8 trials; n=4704

20 mg2 trials; n=434



PlaceboPlacebo8 trials; n=15088 trials; n=1508

Cafergot®

1 trial; n=203Sumatriptan

4 trials; n=1690

25 mg1 trial; n=180



Data on file. Pfizer Inc., New York, NY.

Double-blind, Placebo-controlled, Randomized Trials

The maximum recommended single dose of eletriptan is 40 mg.

16

Efficacy of Eletriptan:Pain-free at 2 Hours

Sumatriptan100 mg(n=799)

Placebo(n=406)

Eletriptan40 mg

(n=782)

0

10

20

30

40

50

5%

27%*

36%*†

Per

cen

tag

e o

f p

atie

nts

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

Adapted from Mathew et al. Headache. 2003.Data on file. Pfizer Inc., New York, NY.

*P<.0001 vs placebo. †P<.001 vs sumatriptan.

Chronic Daily HA

Tension (v. migraine)Tension (v. migraine)

10 attacks lasting 30 min–7 days

2 of the following 4– Bilateral– Not pulsating– Mild or moderate intensity– Not aggravated by routine physical activity

No nausea or vomiting

One or neither photophobia or phonophobia

Not attributable to another disorder

MIGRAINEMIGRAINEADDITIONAL FEATURESADDITIONAL FEATURES

Abatement with sleep

Stereotyped premonitory symptoms

Characteristic triggers

Positive family history

Childhood precursors (motion sickness, episodic vomiting, episodic vertigo)

Osmophobia

Predictable timing around menstruation (or ovulation)

Pryse-Phillips WEM, et al. Can Med Assoc J. 1997.

UNDIAGNOSED MIGRAINE SUFFERERS UNDIAGNOSED MIGRAINE SUFFERERS OFTEN RECEIVE OTHER MEDICAL OFTEN RECEIVE OTHER MEDICAL

DIAGNOSESDIAGNOSES

Lipton RB et al. Headache. 2001.

42%

32%

0% 10% 20% 30% 40% 50%

Sinus HA

Tension-type HA

AURA: MIMICS AND AURA: MIMICS AND SECONDARY CAUSESSECONDARY CAUSES

TIA

Carotid artery dissection

Venous sinus thrombosis

Vasculitis

Tumor

Simple partial seizure

AVM

Bousser MG et al. In: Wolff’s Headache And Other Head Pain. 2001; Campbell JK, Sakai F. In: The Headaches. 2000; Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice. 2002.

LATE-LIFE MIGRAINE LATE-LIFE MIGRAINE ACCOMPANIMENTS VS TIAACCOMPANIMENTS VS TIA

Mild headache in 50%

Progression from one accompaniment to another

Repetition (2 similar attacks)

Duration 15–25 minutes

Characteristic midlife flurry of attacks

Build up of scintillations—“march” of paresthesias

Fisher CM. Can J Neurol Sci. 1980; Silberstein SD, Saper JR, Freitag FG. In: Wolff’s Headache And Other Head Pain. 2001.

MIGRAINE AND STROKEMIGRAINE AND STROKE

Clinical manifestations of underlying disease (MELAS, CADASIL)

Causal

Comorbid

Coexistent

Bousser MG et al. In: Wolff’s Headache And Other Head Pain. 2001.

CADASILCADASIL

CSF XANTHOCHROMIA AFTER SAH SPECTROPHOTOMETRYCSF XANTHOCHROMIA AFTER SAH SPECTROPHOTOMETRY

Vermeulen M et al. J Neurol Neurosurg Psychiatry. 1989.

TIME AFTER TIME AFTER HEMORRHAGEHEMORRHAGE

PROBABILITYPROBABILITY(%)(%)

12 HOURS12 HOURS 100100

1 WEEK1 WEEK 100100

2 WEEKS2 WEEKS 100100

3 WEEKS3 WEEKS >70>70

4 WEEKS4 WEEKS >40>40

Preventive Management of MigrainePreventive Management of Migraine

GUIDELINES: WHEN TO USE GUIDELINES: WHEN TO USE PREVENTIVE MANAGEMENTPREVENTIVE MANAGEMENT

Uncommon migraine conditions

Silberstein SD et al. Wolff’s Headache And Other Head Pain. 2001.

Migraine significantly interferes with patient’s daily routine, despite acute Rx

Acute medications contraindicated, ineffective, intolerable AEs, or overused

Frequent headache (2 attacks per week)

Patient preference

Cost considerations

GOALS OF PREVENTIVE GOALS OF PREVENTIVE TREATMENTTREATMENT

Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.

Decrease attack frequency (by 50%), intensity, and duration

Improve responsiveness to acute Rx

Improve function and decrease disability

Migraine Prevention

GENERAL PRINCIPLES OF GENERAL PRINCIPLES OF PREVENTIVE TREATMENTPREVENTIVE TREATMENT

Evaluate therapy Use headache calendar (diary) Attempt to taper and discontinue treatment when

headaches well controlledSilberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.

Start low and increase dose slowly Use long-acting formulation if compliance an issue

Adequate trial (2–3 months) at an appropriate dosage

Avoid interfering, overused, and contraindicated medications

PREVENTIVE MEDICATIONS:PREVENTIVE MEDICATIONS:DRUG CLASSESDRUG CLASSES

Ca2+-Channel blockers


Anticonvulsants

Antidepressants

-Blockers

NSAIDs

5-HT antagonists

Other Vitamins Minerals Herbs Botulinum

Toxin A

GENERAL PRINCIPLES OF GENERAL PRINCIPLES OF PREVENTIVE TREATMENTPREVENTIVE TREATMENTAssess Coexisting Conditions

Be aware of drug interactions


Select drug to treat both disorders

Do not use migraine drug if contraindicated for other condition

Do not use drug for other condition that exacerbates migraine

Special concern for women of childbearing potential

Comorbidities

Depression “SALSA”

Sleep Disturbance

Anhedonia

Low

Self-esteem

Appetite Change

COMORBID AND COEXISTENT COMORBID AND COEXISTENT CONDITIONSCONDITIONS

Coexistent disorders are commonly present


Therapeutic opportunities Treat two disorders with a single drug

Hypertension or angina—use -blocker Depression—use TCAs or SSRIs Epilepsy or mania—use divalproex or topiramate

Therapeutic limitations Avoid -blockers with depression, asthma, or

hypotension

COMORBID CONDITIONCOMORBID CONDITION

DRUGDRUG EFFICACY*EFFICACY*SIDE SIDE

EFFECTS*EFFECTS*RELATIVE RELATIVE

CONTRAINDICATIONCONTRAINDICATION RELATIVE RELATIVE INDICATIONINDICATION

AnticonvulsantsAnticonvulsants

DivalproexDivalproex 4+4+ 2+2+ Liver disease, bleeding Liver disease, bleeding disordersdisorders

Mania, epilepsy, Mania, epilepsy, impulse controlimpulse control

TopiramateTopiramate 3+3+ 2+2+ Kidney stonesKidney stones Epilepsy, mania, Epilepsy, mania, neuropathic painneuropathic pain

GabapentinGabapentin 2+2+ 2+2+ Epilepsy, neuropathic Epilepsy, neuropathic painpain

AntidepressantsAntidepressants

TCAsTCAs 4+4+ 2+2+ Mania, urinary retention, Mania, urinary retention, heart blockheart block

Other pain disorders, Other pain disorders, depression, anxiety depression, anxiety disorders, insomniadisorders, insomnia

SSRIsSSRIs 2+2+ 1+1+ ManiaMania Depression, OCDDepression, OCD

MAOIsMAOIs 2+2+ 4+4+ Unreliable patientUnreliable patient Refractory depressionRefractory depression

PREVENTIVE TREATMENT:PREVENTIVE TREATMENT:DRUG CHOICEDRUG CHOICE

Silberstein SD et al. Headache in Clinical Practice. 2nd ed. 2002.Gray RN et al. Drug Treatments for the Prevention of Migraine. 1999.

*On a scale of 0 to 4




CONTRAINDICATIONCONTRAINDICATIONRELATIVE RELATIVE

INDICATIONINDICATION

AntiserotoninAntiserotonin

MethysergideMethysergide 4+4+ 4+4+ Angina, PVDAngina, PVD Orthostatic Orthostatic hypotensionhypotension

-Blockers-Blockers 4+4+ 2+2+ Asthma, depression, CHF, Asthma, depression, CHF, Raynaud’s disease, diabetesRaynaud’s disease, diabetes

HTN, anginaHTN, angina

Calcium channel Calcium channel blockersblockers

VerapamilVerapamil 2+2+ 1+1+ Constipation, hypotensionConstipation, hypotension Migraine with Migraine with aura, HTN, aura, HTN, angina, asthmaangina, asthma

PREVENTIVE TREATMENT:DRUG CHOICEPREVENTIVE TREATMENT:DRUG CHOICE






CONTRAINDICATIONCONTRAINDICATIONRELATIVE RELATIVE

INDICATIONINDICATION

NSAIDsNSAIDs

NaproxenNaproxen 2+2+ 2+2+ Ulcer disease, gastritisUlcer disease, gastritis Arthritis, other Arthritis, other pain disorderspain disorders

OtherOther

RiboflavinRiboflavin 2+2+ 1+1+ Preference for Preference for natural productsnatural products

FeverfewFeverfew

Botulinum Botulinum Toxin AToxin A

2+2+

2+2+

2+2+

1+1+ Myasthenia gravisMyasthenia gravis Dystonia orDystonia orSpasticitySpasticity

PREVENTIVE TREATMENT:DRUG CHOICEPREVENTIVE TREATMENT:DRUG CHOICE



PREVENTIVE TREATMENT: PREVENTIVE TREATMENT: USE OF ACUTE MEDICATIONUSE OF ACUTE MEDICATION

Can use acute and preventive treatment together Limit acute drug use to prevent drug-induced

headache Certain drugs require caution or cannot be

used together Acute medications may have more benefit


Preventive treatment does not eliminate all attacks

Breakthrough attacks need treatment

CAUTIONS IN ACUTE CAUTIONS IN ACUTE MEDICATION USEMEDICATION USE

PREVENTIVEPREVENTIVE CAUTIONCAUTION CONTRAINDICATIONCONTRAINDICATION

MethysergideMethysergide Ergots, TriptansErgots, Triptans

MAOIsMAOIs Sumatriptan Sumatriptan (subcutaneous) (subcutaneous) and zolmitriptanand zolmitriptan

Meperidine, Midrin, Meperidine, Midrin, sumatriptan (po, IN) and sumatriptan (po, IN) and rizatriptanrizatriptan

PropranololPropranolol RizatriptanRizatriptan

NSAIDsNSAIDs Other NSAIDs or Other NSAIDs or ASAASA

DivalproexDivalproex ButalbitalButalbital


NONPHARMACOLOGIC NONPHARMACOLOGIC TREATMENT:TREATMENT:

POTENTIAL INDICATIONSPOTENTIAL INDICATIONS

Goslin RE et al. Behavioral and Physical Treatments for Migraine Headache. 1999.

Patient preference

Poor tolerance, response, or contraindications to drug therapy

Pregnancy, planned pregnancy, or nursing

History of overuse

Significant life stress or deficient stress-coping skills

SUMMARY OF PREVENTIONSUMMARY OF PREVENTION

Use preventive medications when needed

Treat long enough

Avoid acute medication overuse

Take coexisting conditions into account

Use drug with the best efficacy for individual patient

neurological lectures...migraine

Health & Medicine

wolffs headache

nonmigraine headache

seizures thunderclap

previous headache pattern

severe headache evans

days precipitation of

lumbar puncture headache

migraine prevalence