Charles Yanofsky M.D.PA Neurological Assocs.

The Dark Side:Pitfalls of therapy

Migraine

www.pneuro.com

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

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)

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

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 Without AuraMigraine Without Aura

Diagnostic CriteriaDiagnostic Criteria– A. At least 5 attacks fulfilling criteria B-DA. At least 5 attacks fulfilling criteria B-D– B. HA attacks lasting 4-72 hoursB. HA attacks lasting 4-72 hours– C. HA has at least 2 of following:C. HA has at least 2 of following:

1. Unilateral location1. Unilateral location

2. pulsatile quality2. pulsatile quality

3. moderate to severe pain3. moderate to severe pain

4. aggravation by routine physical activity4. aggravation by routine physical activity

– D. During attack at least one of foll’gD. During attack at least one of foll’g1. Nausea and/or vomitting1. Nausea and/or vomitting

2. photophobia and/or phonophobia2. photophobia and/or phonophobia

Migraine Pathophysiology

Goadsby NEJM 346:257-70,2002

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

What is Central Sensitization?What is Central Sensitization?

Central Sensitization is a time-dependent Central Sensitization is a time-dependent physiological eventphysiological 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 the Peripheral neurons are activated early in the

attack (mild pain phase throbbing)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)

TriptansTriptans

Major Advance in treatment of migrainesMajor Advance in treatment of migraines

Useful for Occasional Highly paroxysmal Useful for Occasional Highly paroxysmal headachesheadaches

Oral administration: Newer agents may be Oral administration: Newer agents may be more effective than Imitrex (sumatriptan)more effective than Imitrex (sumatriptan)

Imitrex: Nasal and SQ form availableImitrex: Nasal and SQ form available

Triptans: Partial answerTriptans: Partial answer

serotonin

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.

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)

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

40 mg8 trials; n=2797

80 mg6 trials; n=1473

PlaceboPlacebo8 trials; n=15088 trials; n=1508

Cafergot®

1 trial; n=203Sumatriptan

4 trials; n=1690

25 mg1 trial; n=180

50 mg2 trials; n=362

100 mg3 trials; n=1148

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

Double-blind, Placebo-controlled, Randomized Trials

The maximum recommended single dose of eletriptan is 40 mg.

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

Individual eletriptan–sumatriptan comparison trials: Individual eletriptan–sumatriptan comparison trials: Headache response at 2 hHeadache response at 2 h

100100

8080

6060

4040

2020

00

% Patients with response% Patients with response

nn=605=605

Sumatriptan Sumatriptan Goadsby et al (2000)Goadsby et al (2000)

80 mg80 mg((nn=118)=118)

77%77%**††

40 mg40 mg((nn=117)=117)

65%65%**

PlaceboPlacebo((nn=126)=126)

24%24%

Mild or no painMild or no pain

Eletriptan Eletriptan

20 mg20 mg((nn=129)=129)

54%54%**

**PP<0.01 vs placebo<0.01 vs placebo††PP<0.05 vs sumatriptan<0.05 vs sumatriptan

Study 314Study 314

100 mg100 mg((nn=115)=115)

55%55%

Pain-freePain-free

29% 37%23%6%* * *†

19%

**

*

Elitriptan in Pts poorly tolerance or Elitriptan in Pts poorly tolerance or response to Sumatriptanresponse to Sumatriptan

446 pts, 40 or 80 mg v placebo446 pts, 40 or 80 mg v placebo

2 hr ha response up to 70% for 80mg, 2 hr ha response up to 70% for 80mg, 59% for 40 mg59% for 40 mg

2 hr pain free 35% E40, 42% E802 hr pain free 35% E40, 42% E80Farkkila et al, Cephalalgia 2003,23,463-471Farkkila et al, Cephalalgia 2003,23,463-471

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.

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.

Pharmacokinetic parameters for Pharmacokinetic parameters for eletriptan and sumatriptaneletriptan and sumatriptan

EletriptanEletriptan1,21,2 SumatriptanSumatriptan33

Oral absorption (TOral absorption (Tmaxmax)) Consistent, 1.5 hConsistent, 1.5 h†† Variable, 0.75–5 hVariable, 0.75–5 h

Half-life (tHalf-life (t1/21/2)) 5 h5 h 2 h2 h

1 Milton 1 Milton et al (et al (1997)1997)2 Pfizer data on file2 Pfizer data on file3 Lacey 3 Lacey et alet al (1995) (1995)4 Dixon 4 Dixon et alet al (1994) (1994)5 Johnson 5 Johnson et alet al (1997) (1997)††TTmaxmax increases to 2.8 h during migraine attacks increases to 2.8 h during migraine attacks55

Intersubject variabilityIntersubject variability 37%37% 60%60%

Oral bioavailabilityOral bioavailability 50%50% 14%14%

Renal clearanceRenal clearance 10%10% 20%20%

Metabolic pathwayMetabolic pathway P450P450 MAOMAO44

Relpax (Eletriptan) AdvantagesRelpax (Eletriptan) Advantages

Favorable pain free, 1 Favorable pain free, 1 and 2 hour efficacy vs. and 2 hour efficacy vs. SumatriptanSumatriptan

Longer half life, quick Longer half life, quick absorptionabsorption– Peak 1.5-2 hrs, T1/2=4 Peak 1.5-2 hrs, T1/2=4

hrs, 50% oral absorptionhrs, 50% oral absorption

Cerebro (vs. Cardio) Cerebro (vs. Cardio) SelectiveSelective– Avid binder to relevant Avid binder to relevant

receptorsreceptors

Eletriptan (Relpax™)

Relpax CautionsRelpax Cautions

Available only in oral formAvailable only in oral formCYP 3A4CYP 3A4– Do not give within 72 hours of: Ketoconazole, Do not give within 72 hours of: Ketoconazole,

Nefazadone, clarithromycin, rotonavir, nelfinavir, Nefazadone, clarithromycin, rotonavir, nelfinavir, others. caution with verapamil, erythromycin.others. 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

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

Refractory Migraine

After Triptans

Why we fail (and what to do about Why we fail (and what to do about it)it)

Misdiagnosis – exclusion, inclusionMisdiagnosis – exclusion, inclusion

Unrealistic expectationsUnrealistic expectations

Chronic Daily headache and reboundChronic Daily headache and rebound

Logic and PersistenceLogic and Persistence

Ignoring psychological factorsIgnoring psychological factors

Missing Red FlagsMissing Red Flags

Sinus Headache and Tension Sinus Headache and Tension Headaches are almost always Headaches are almost always

migraine headachesmigraine headaches

Tension headache Tension headache pharmacologically is Migrainepharmacologically is Migraine

““Sinus” Headache FallacySinus” Headache Fallacy

Paroxysmal headaches are migraine until Paroxysmal headaches are migraine until proved otherwise.proved otherwise.

Most “Sinus headaches” are migrainesMost “Sinus headaches” are migraines

Sinus headaches are rare in comparison to Sinus headaches are rare in comparison to migraine.migraine.

Patients commonly present years or decades Patients commonly present years or decades after failed treatment for sinus headachesafter failed treatment for sinus headaches

ENT’s among our most frequent referrers for ENT’s among our most frequent referrers for head painhead pain

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

ExpectationsExpectations

Two thirds of patients will have a 50% reduction Two thirds of patients will have a 50% reduction of headachesof headaches

Migraine is a Chronic DiseaseMigraine is a Chronic Disease

No Preventive therapy will eliminate all No Preventive therapy will eliminate all headachesheadaches

Patients should expect “breakthrough headache”Patients should expect “breakthrough headache”

Give patient some means of escapeGive patient some means of escape

You can’t kill every headache with medicineYou can’t kill every headache with medicine

““Rules of the game” have to be explainedRules of the game” have to be explained

Morphed MigraineMorphed Migraine

Conversion from headache attacks to Conversion from headache attacks to chronic headache.chronic headache.Paroxysmal headache becomes chronic Paroxysmal headache becomes chronic headacheheadachePatients describe multiple headache typesPatients describe multiple headache types– All of them are migraine variantsAll of them are migraine variants

Migraine natural history:Migraine natural history:– Asthma becomes COPDAsthma becomes COPD– RR MS becomes secondary progressive MSRR MS becomes secondary progressive MS

Chronic Daily HAChronic Daily HA

Treating Morphed MigraineTreating Morphed Migraine

Cut prn medsCut prn meds– Tough to convince pts to give up prn medsTough to convince pts to give up prn meds

Emphasize preventive medsEmphasize preventive medsTreat psychosocial comorbiditiesTreat psychosocial comorbidities– Psychotherapy, counselingPsychotherapy, counseling– MedicineMedicine

Ancillary modalitiesAncillary modalities– Relaxation, biofeedback, exercise, healthtful Relaxation, biofeedback, exercise, healthtful

habitshabits

ComorbiditiesComorbidities

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 headacheSignificant change from previous headache Significant change from previous headache patternpatternNew onset headache in middle age or laterNew onset headache in middle age or laterNew progressive headache lasting for daysNew progressive headache lasting for daysPrecipitation by cough, sneeze, bending downPrecipitation by cough, sneeze, bending downSystemic symptoms: fever, myalgia, malaise, wt Systemic symptoms: fever, myalgia, malaise, wt loss, scalp tenderness, jaw claudicationloss, scalp tenderness, jaw claudicationFocal symptoms or altered sensorium, seizuresFocal symptoms or altered sensorium, seizures

Pryce-Phillips et al, 1997Pryce-Phillips et al, 1997

Children red flagsChildren red flags

AM headacheAM headache

Posterior HeadachePosterior Headache

Vomiting without nauseaVomiting without nausea

PapilledemaPapilledema

Focal signs or ataxiaFocal signs or ataxia

Consider tumor or pseudotumorConsider tumor or pseudotumor

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.

But the vast majority of these But the vast majority of these headaches turn out to be headaches turn out to be

migraines!!migraines!!

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

Headache CrisisHeadache Crisis

Rule out serious CauseRule out serious Cause

DHE + Reglan i.v.DHE + Reglan i.v.

Toradol i.v. + ReglanToradol i.v. + Reglan

DepaconDepacon™ i.v. 1000 mg.™ i.v. 1000 mg.

DecadronDecadron

Morphine infusionMorphine infusion

Consider outpatient Actiq™-saves trip to ERConsider outpatient Actiq™-saves trip to ER– DependenceDependence

Medication Impersistence

Treatment

Changing MedsChanging Meds

Most preventives req’r 1-2 month trialMost preventives req’r 1-2 month trial

Long lists of meds Long lists of meds

Inadequate trialInadequate trial

Inadequate dosageInadequate dosage

““I want relief now!!”I want relief now!!”

2 headache (for PRN’s), 2 month (for 2 headache (for PRN’s), 2 month (for prophylaxis) ruleprophylaxis) rule

Inadequate trialsInadequate trialsPick a medication Pick a medication – Good track record Type IA evidenceGood track record Type IA evidence– Treat comorbiditiesTreat comorbidities

Sleep disturbanceSleep disturbance

DepressionDepression

HypertensionHypertension

Use it long enough for reasonable trialUse it long enough for reasonable trial– 2 months – No medicine works immediately 2 months – No medicine works immediately – Headache calendarHeadache calendar– Give patient an “out’ for breakthru headacheGive patient an “out’ for breakthru headache

Ignoring psychological factorsIgnoring psychological factors

Underlying migraine diathesis (history)Underlying migraine diathesis (history)Very frequent gnawing headache Very frequent gnawing headache ororScreamingly urgent headache frequentlyScreamingly urgent headache frequentlyState of being overwhelmedState of being overwhelmedSub-optimal life strategiesSub-optimal life strategies– Ennui vs. pointless moto-perpetuo patternEnnui vs. pointless moto-perpetuo pattern

When When ΨΨ paramount paramount

Don’t abandon patientDon’t abandon patientGive her an “out”Give her an “out”Continue to treat headachesContinue to treat headachesGet Help!!Get Help!!Don’t just keep trying medicines and throwing Don’t just keep trying medicines and throwing SSRI’s at patientSSRI’s at patient““Therapy” in guise in non-drug treatmentTherapy” in guise in non-drug treatment– Exercise, getting away, regularization of sleep, diet, Exercise, getting away, regularization of sleep, diet,

CounselingCounseling

Surprisingly, some few patients respond Surprisingly, some few patients respond dramatically, sadly, most don’tdramatically, sadly, most don’t

HA prophylaxisHA prophylaxis

Anti-convulsants are “in”Anti-convulsants are “in”– Topamax, Depakote ER and i.v., Zonegran, Topamax, Depakote ER and i.v., Zonegran,

Neurontin, KeppraNeurontin, Keppra

Tricyclics, not SSRI’s for headache and Tricyclics, not SSRI’s for headache and sleep, depression comorbiditysleep, depression comorbidity

ACE inhibitors: PrinivilACE inhibitors: Prinivil™™, Atacand, Atacand™™

BotoxBotox™™, Myobloc, Myobloc™™

Our Armamentarium expandsOur Armamentarium expands

Botox (from B. Todd Troost, m.d.)Botox (from B. Todd Troost, m.d.)

Conquering Headache

That’s the Tale of the Comet

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