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EpisodictoChronicMigraine TheTransformers
DavidW.DodickM.D. DepartmentofNeurology MayoClinicinArizona

Disclosure:Reflectsthepast3years
Withinthepast3years,DrDavidW.Dodickservesonadvisory boardsandhas consultedforAllergan,Alder,Pfizer,Merck,Coherex, Ferring,Neurocore, Neuralieve, Neuraxon,NuPathe Inc.,MAP,SmithKlineBeecham,BostonScientific, Medtronic, Inc., Nautilus,EliLilly&Company,Novartis,Colucid, GlaxoSmithKline, Autonomic Technologies,MAPPharmaceuticals, Inc.,Zogenix,Inc.,ImpaxLaboratories, Inc.,Bristol MyersSquibb,NevroCorporation, Atlas,Arteaus,AlderPharmaceuticals. Withinthepast3years, years DrDavidW. W Dodickhasreceived fundingfortravel, travel speaking, speaking or editorialactivities,fromthefollowing:CogniMed,Scientiae, Intramed,SAGEPublishing, LippincottWilliamsandWilkins,Oxford UniversityPress,Cambridge UniversityPress, MillerMedical,Annenberg forHealthSciences;heservesasEditorinChiefandonthe editorialboardsofTheNeurologist, Lancet Neurology, andPostgraduate Medicine;and hasservedasEditorin ChiefofHeadache Currents andasanAssociate Editorof Headache;receivespublishingroyaltiesforWolffsHeadache, 8thedition(Oxford UniversityPress,2009)andHandbook ofHeadache (CambridgeUniversityPress,2010). Withinthepast3years,DrDavidW.Dodickhasreceived research grant supportfrom thefollowing:Advanced Neurostimulation Systems,BostonScientific, StJudeMedical, Inc.,Medtronic, NINDS/NIH,MayoClinic.

Objectives:Atthecompletionofthispresentation, theparticipantwillbeableto:

1. Identifythefactorsthatincreasetheriskforprogression fromepisodictochronicmigraine 2 Discusstheneurobiologyunderlyingtheprogressionfrom 2. episodictochronicmigraine 3. Implementatreatmentstrategyforpatientswithchronic migraine,withorwithoutacutedrugoveruse

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Diagnosis,Epidemiology&RiskFactors

ChronicMigraine(CM):FutureofClassification
ICHDII1 medicationoveruse2 combinedcriteria
Headacheon15dayspermonthforatleast

Practicalclinicalcriteria Headache15dayspermonth andaverage>4hrsperday AND

3months1
5priormigraineattacks1 On8days y p permonth, ,headachefulfillscriteria

formigraine1
2ofthefollowing:a)unilateral;b)

throbbing; c)moderateorseverepain;d)aggravatedby physicalactivity 1ofthefollowing:a)nauseaand/or vomiting; b)photophobiaandphonophobia Relievedwithtriptansorergotamine

Notattributedtoanothercausative disorder1 Subclassifiedaswithorwithoutmedication

Currentorpriordiagnosis ofmigraineand>8days migraine+ auraorprobable migraine AND

Withorwithoutmedication overuse

overuseheadacheasdiagnosedby8.21,2
5

1.HeadacheClassification Committee.OlesenJetal.Cephalalgia 2006;26:742746. 2.SilbersteinSDetal.Cephalalgia 2005;25:460465.

TransformingfromEpisodicMigraine(EM)toCM
Everyyear,between2.5and4.6%ofpeoplewithepisodic

migraineexperienceprogressiontochronicmigraine Patientsmaytransitionsamongthese3migrainestatesin thedirectionofincreasinganddecreasingfrequency Transitionsoccuroverweekstomonths

09 headache days/month

1014 headache days/month

15 headache days/month

LiptonRBetal.JAMA 2004;291:493494. LiptonRB.Neurology2009;72(Suppl 1):S3S7. MunakataJetal.Headache 2009;49:498508. BigalME,etal.CurOpinNeurol.2009;22:269276.

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TheMajorityofChronicMigraineSufferersDo NotRemit
Over3yearsoffollowup,themajorityofsuffererswithCMremainwith

eitherCMorhighfrequencyepisodicmigraine

TransitionRatesin2006and2007 RelativetoCMStatusin2005(Baseline)

Remitted CM

26%
Persistent CM

Transitioning CM

52%

22%

AMPP=AmericanMigrainePrevalenceandPrevention.
7

LiptonRB.Headache2011;51:7783

PersistentCMsufferersexperienceanincrease indisability

70 60
MIDASscore

MeanMIDASscoresforpersistentCMandremitted CMgroupsbyyear 64.0 51.0 50.4 53.4 Chronicmigraine Persistent Remitted

50 40 30 20 10 0 2005 11.4 2006 12.8 2007

DatafromtheAmericanMigrainePrevalenceandPrevention(AMPP)Study.

1.LiptonRetal.PosterpresentedatMigraineTrust2008. 2.LiptonRetal.Cephalalgia 2009;29(suppl1):72(abstractPO154).

ComparedtoEM,thosewithCMhave:
Greaterheadacherelateddisabilityandimpact13 Reducedhealthrelatedqualityoflife3,4 Worsesocioeconomicstatus2,5
2356 Increased I dh healthcare lth resourceutilization tili ti 2,3,5,6

Higherdirectandindirectcosts2,3,5,6 Higherratesofmedicalandpsychiatriccomorbidities2,7

1.BigalMEetal.Headache. 2003;3(4):336342. 2.BigalMEetal.Neurology.2008;71(8):559566. 3.BlumenfeldAMetal. Cephalalgia.2011;31(3):301315. 4.MeleticheDM.Headache.2001;41(6):573578. 5.LiptonRetal.Presentedat:American AcademyofNeurology61st AnnualMeeting;April25May2,2009; Seattle,WA.6.StewartWFetal.JOccupEnvironMed. 2010;52(1):814. 7.BuseDetal.JNeurolNeurosurgPsychiatry.2010;81(4):428432.

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CMHasMorePsychiatricandMedical ComorbiditiesthanEM
CM (n=655) Major Depression AnxietyDisorders OtherChronic PainDisorders EM (n=10,609 OR (95%CI)

30.2%

17.2%

2.1(1.7 ( 2.5) )

30.2% 31.5%

18.8% 15.1%

1.9(1.6 2.2) 2.6(2.2 3.1)

BuseDC,etal.JNeurolNeurosurgPsychiatry.2010;81:42832.
10

WhichofthefollowinghasNOT beendemonstrated tobeariskfactorfortheprogressionofmigraine?

1. Migraineattackfrequency 2. Obstructivesleepapnea 3 Headinjury 3. 4. Allodynia 5. Depression

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Risk Factors for CM? MO1 Attackfrequency2 Obesity2 Loweducation;socio economicstatus3 Stressfullifeevents/ majorlifechanges4
1. 2. 3. 4. 5. BigalME,etal. Headache.2008:48:115768 ScherAI,etal.Pain.2003;106:8189. BuseDC,etal.JNeurolNeurosurg Psychiatry.2010;81:42832. Scheretal.,Cephalalgia2008;28:868876. CouchJ,etal.Neurology.2007;69:116977.

Headinjury5 Snoring6 Caffeine7 Depression8 Anxiety8 Allodynia9

6.ScherAI,etal.Neurology2003; 60:13661368. 7. Scheretal.,Neurology 2004;63:20222027. 8. AshinaS,etal. Headache.2010(abstract). 9. LiptonRB,etal. AnnNeurol.2008:63:14858.

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Severalriskfactorspredictprogression*from EMtoCM
Everyday life stress Poor pain coping ability 2 acute headache drugs Chronic back pain Frequent drug intake (>10 d/mo) Headache frequency at baseline (10 14 d/mo vs 1 4 d/mo) 0 1 2 3 4 5 6 7 8 9 10

Odds ratio

DatafromtheGermanHeadacheConsortium (GHC).CourtesyofDr.ZazaKatsarava.
13

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RiskFactors:TransitionFromEpisodicMigraine to ChronicDailyHeadache
OddsRatio Headachefrequency atbaseline 1014days/month vs14days/month Frequentdrugintake(>10 days/month) Chronicback pain 2acute headache drugs Poorpaincoping ability Everydaylifestress Depression(CESD) 8.5 4.6 3.8 2.6 2.4 1.9 1.8 95%CI 4.416.5 2.49.0 1.86.7 1.25.8 1.24.8 1.03.8 0.84.7 pvalue 0.001 0.001 0.001 0.016 0.001 0.003 NS

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DatafromtheGermanHeadacheConsortium (GHC).CourtesyofDr.ZazaKatsarava.

AcuteMedicationOveruse(MO)
Overuseofacutemedicationiscommoninindividualswithchronic

migraine13
50%80%ofchronicmigrainepatientsseeninheadacheclinicsoveruse

acutemedications
Medicationoverusemaybedefinedasfollows4: 15days/month:simpleanalgesics,combinationsofdrugs,or 10days/month:combinationanalgesics,ergotamines,triptans,

opioids
Avoidanceofmedicationoveruseisimportant2

1.SilbersteinSDetal,eds.HeadacheinClinicalPractice.2nd ed.London: MartinDunitz; 2002:69146. 2.LiptonRBetal. Neurology.2003;61;154155. 3. Wang SJetal.Pain.2001;89:285292. 4.HeadacheClassification Committee;OlesonJetal.Cephalalgia. 2006;26:742746.

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Accordingtobestmedicalevidence,whichofthe followingstatementsregardingthetreatmentof patientswithchronicmigraineistrue?

1. 2. 3. 4. Remissionoccursinthemajorityafterdetoxification inthoseoverusingacutemedications Preventivemedicationsareeffectiveinthose overusingacutemedications Differentclassesofacutemedicationsareequally potentintheirabilitytotransformEMtoCM Preventivemedicationsaremosteffectivewhen overusedmedicationsarediscontinued
EM=episodicmigraine;CM=chronicmigraine

MedicationOveruseandEstimatedProgression toCM
ProbabilityofProgression toChronicMigraine(%)
40 35 30 25 20 15 10 05 0 0 2

ProbabilityofProgression toChronicMigraine(%)

Opiates

40 35 30 25 20 15 10 05 0 0 2

Barbiturates

4 6 8 10 MonthlyUse(Days)

12

14

4 6 8 10 MonthlyUse(Days)

12

14

ProbabilityofProgressionto ChronicMigraine(%)

40 35 30 25 20 15 10 05 0 0 2

Triptans

ProbabilityofProgressionto ChronicMigraine(%)

40 35 30 25 20 15 10 05 0 0 2

NSAIDs

4 6 8 10 MonthlyUse(Days)

12

14

4 6 8 10 MonthlyUse(Days)

12

14

Monthlyheadachedays

04

59

1014

17

Logisticregressionwasusedformodeling ofestimatedprogression

BigalMEetal.Headache. 2008;48:11571168.

Pathophysiology

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WhichofthefollowingisNOT likelyafactorinthe maintenanceofheadacheinchronicmigraine?

1. SensitizationofperipheralTVnociceptor 2. Sensitizationofthe2nd orderTVneuron 3. Sensitizationof3rd orderTVthalamicrelayneurons 4. Corticalhyperexcitabilityandneuronalplasticity 5. Altereddescendingmodulationof2nd orderTVneurons

TV=trigeminovascular
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ThalamicTVNeuronsHardWiredtoMultipleCortical Areas:MayAccountfortheMigraineExperienceand Chronicity

EachTVneuron(Po,LD,LP)projectinto corticalareasinvolvedinregulationof affect,motorfunction,visualand auditoryperception,spatialorientation, memoryretrieval,andolfaction. Dense,redundant projectionsto trigeminalareaofS1 Maydisruptnormalmotorintracortical inhibitionofothercorticalareas, thalamicrelayneurons,anddescending painmodulatingnetworks

20

TV=trigeminovascular

NosedaR.etal.JNeurosci2011;31(40):14204 14217

Migraine:ABrainthatsPrimedforChronicity: IncreasedIntrinsicBrainActivityandFunctional ConnectivityinSensoryNetworks

Sensorimotornetwork Visualnetwork

Auditorynetwork

Saliencenetwork =affective painnetwork

21

Sprengeretal.AHSWashington2011

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NociceptiveMemory:CorticalNeuroplasticity FacilitatestheDevelopmentofChronicPain
S1 Lateralpre frontalcortex Basal ganglia Anterior insula Posterior insula S2 PAG Sensory
22 Slidecourtesy ofTillSprenger

ACC

RostralACC

Thalamus Cerebellum Cognitive Para hippocampal Motor

n=29
Antinociceptive

Affective

Riedletal.Neuroimage2011;57:206213

YiMandZhangH.JNeurosci2011;31:1334313345 EtoK,etal.JNeurosci2011; 31:76317636

StructuralAlterationsintheChronic MigraineBrain

SignificantGMVreductionsinbilateralinsula,motor/premotor,prefrontal,

cingulatecortex,rightposteriorparietalcortex,andorbitofrontal cortex

23

KimJHetal.Cephalalgia. 2008;28:598604.

DescendingModulationCircuitsareInvolvedin Migraine/ChronicMigraine

InterictalHypo functionofNucleus Cuneiformisin migrainesubjects

InterictalDysfunction ofaBrainstemDescending Modulatory Center inMigrainePatients

24

MoultonEA,etal.PLOSone;November 2008:3(11):e3799

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CentralSensitizationinChronicMigraine:Cutaneous AllodyniaDuringandBetweenAttacks
Episodicmigraine
Pain score
10 8 6 4 2 0 48 44 40 36 32 28 24 20 16 150 100 50 0 Pressure 4 Heating Cooling

ChronicmigraineN=15
Pain score
10 8 6 4 2 0 48 44 40 36 32 28 24 20 16 150 100 50 0 Pressure 4 Heating Cooling

Painfree

Migraine

Painfree

Migraine

Mechanical pain threshold (g)

Hoursafterpainonset
25

Mechanical pain threshold (g)

Thermal pain O thresholds ( C)

Thermal pain O thresholds ( C)

Hoursafterpainonset RBurstein.Unpublishedobservations

TriptanInducedLatentSensitization APossibleMechanismofMOH/MigraineProgression
CGRP,nNOS
Stress (1hrofbrightlight) Day Day18 20 21
Withdrawalthreshold (g)

7Days Sumatriptanor SalineInfusion

Baseline Sensory Thresholds

Saline
Day18 Day 20

4 Vehicle/Vehicle Vehicle/SNP Sumatriptan/Vehicle Sumatriptan/SNP 1 2 3 4 5

0 Time(hours)

Sodiumnitroprusside
DeFeliceM,etal.Brain2010;133:24752488
26

MOH=medicationoveruseheadache

DeFeliceM,etal.AnnNeurol.2010;67:325337

Managementof fChronic h Migraine

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ChronicMigraine: MultifacetedApproachtoTherapy
Lifestyle modifications, behavioral therapy Education, support, managing support expectations, and close follow-up Pharmacologic therapy

Chronic migraine management

Dodick DW. N Engl J Med. 2006;354:158-165.

RiskFactorManagement
RISKFACTOR Treatmentpatterns TREATMENT/INTERVENTION Createoptimalpharmacologic plan(utilizeacute and preventiveasappropriate), monitor andlimituseofacute prescriptionandOTCsasappropriate Reduction/prevention withpharmacologic andbehavioral interventions i i Weightloss,Exercise,Behavioral Intervention Stressmanagement withbiobehavioral techniques (biofeedback,cognitive behavioral therapy, relaxation training),Exercise Diagnoseandtreat sleepapnea,Weight loss Manageattack frequency andtreat early Assess,treat withpharmacologic andbehavioral therapies, referwhenappropriate Assess,treat withpharmacologic andbehavioral therapies, referwhenappropriate

Attackfrequency Obesity Stress

Snoring Allodynia Depression Anxiety

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AcuteTreatmentConsiderationsforCM

Limittheuseofacutemedicationtoonaverage,<3

days/week1,2
Avoidopioids,barbiturates,andergots*ifpossiblein

patientswithfrequent p q attacks1,3
Asinepisodicmigraine,triptans,NSAIDsandDHEareuseful

formanypatientswithchronicmigraine2,4

1.DienerHCetal.LancetNeurol.2004;3:475483. 2.SilbersteinSDetal,eds.HeadacheinClinicalPractice.2nd ed.London: MartinDunitz; 2002:69111. 3.BigalMEetal.Headache.2008;48:11571168. 4.Dodick DW.NEnglJMed. 2006;354:158165.

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PreventiveMedicationsinChronicMigraine: EvidenceBase
Treatment Anticonvulsants: Valproate Topiramate Gabapentin p Antidepressants: Amitriptyline Fluoxetine Tizanidine OnabotulinumtoxinA EvidenceforUseinChronicMigraine SmallDBPCandcomparatortrialinCM/CDH1,2 ThreeDBPCtrialsinCM3,4 OneDBPCtrialinCDH5 SmallopenlabeltrialinTM6 SmallDBPCtrialinCDH7 SmallDBPCtrialinCDH8 TwoDBPCtrialsinCM9

DBPC=doubleblind placebocontrolled;TM=transformedmigraine;CDH=chronicdailyheadache;CM=chronicmigraine
1.YurekliVAetal.JHeadachePain.2008;9:3741.2.BartoliniMetal.ClinNeuropharmacol.2005;28:277279. 3.DienerHCetal.Cephalalgia.2007;27:814823.4.Silberstein SDetal.Headache.2007;47:170180. 5.SpiraPJ,BeranRG.Neurology.2003;61:17531759. 6.Krymchantowski AVetal.Headache. 2002;45:510514. 7.SaperJRetal.Headache. 1994;34:497502. 8.SaperJRetal. Headache. 2002;42:470482.9. Dodick DWetal.Headache. 2010;50:921936.

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ManagingAcuteMedicationOveruse:Responseto WithdrawalWithoutPreventiveMedication.

Improvementindicatedareduction inheadachefrequency. Diagnosticheadachediaryfilledoutonadailybasis. 1.ZeebergPetal.Neurology. 2006;66:18941898. 2.DienerHCetal.LancetNeurol.2004;3:475483. 3.ZidvercTrajkovic J.Cephalalgia.2007;27:12191225.

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PreventiveTreatmentComparedWithAbrupt WithdrawalofAcuteMedications
Controls Abruptwithdrawalonly Prophylaxisfromthestart
30

Patients (%)

Studieshaveshownrelapserate ofoveruseaftersuccessfulwithdrawal isnearly40% duringthefirstyear.2,3

Patients Exhibiting a 50% Reduction in %) Headache Days/Month (%

No. of Headache Days/Mo onth

25 20 15 10 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12

p = 0.01

MonthsFollowingWithdrawal

MonthsFollowingWithdrawal

HagenKetal.Cephalalgia. 2009;29:221232.

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MonitoringResponsetoTreatment

Maintainheadachediary1,2 Useglobalmeasureofimprovement1,2 Assessforheadacheimpactonpatient functioning1,2(e.g.HIT6;MsQOL)

1.Dodick DW,SilbersteinSD.PractNeurol. 2007;7:383393. 2.Fenstermacher Netal.BMJ. 2011;342:540543. 3.Kosinski Metal.QualLifeRes. 2003;12:963974.

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Summary:ChronicMigraine
Simplify the diagnosis most patients with >15 headache days

per month without secondary cause have chronic migraine

Educate and reassure Assess A and d address dd risk i kf factors t Multimodal therapy

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END

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MigraineBrainIsPrimedforAttacks:AlteredInterictal Excitability,NetworkSynchrony,andFunctionalConnectivity inSensoryNetworks

BoullocheN.,etal.JNeurolNeurosurg Psychiatry 201081:978984

Denuelleetal.Neurology2011;76:213218

37

CentralSensitizationinMigraine

38

Bursteinetal.AnnNeurol2010;68:8191

PreventiveTherapiesUsedby PatientsWithCM
Chronic Migraine (n=520) Antiepileptic Drugs: Divalproex Topiramate Gabapentin Other Antidepressants: Amitriptyline Nortriptyline Duloxetine Venlafaxine Paroxetine Sertraline Fluoxetine 33% 9% 7% 7% 8% 12% 11% 17% 5% 2% 5% 6% 7% 6% 20% 33% 22% 7% 10% 19% 11% 6% Episodic Migraine (n=9424) Antihypertensives: Propranolol Nadolol Metoprolol Atenolol Verapamil Diltiazem 22% 3% 7% 7% 9% 0.5% 20% 3% 5% 5% 5% 0.2% Chronic Migraine (n=520) Episodic Migraine (n=9424)

Nutraceuticals/Herbal Therapies: Feverfew Magnesium Riboflavin Butterbur 10% 11% 10% 1% 12% 10% 10% 1%

DatafromtheAmericanMigrainePrevalenceandPrevention (AMPP)study. BigalMEetal.Neurology. 2008;71;559566.

39

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CM:GlobalPrevalence*

UnitedStates 12 CM 1.3% CM: 1 3%(S ( L) )1,2

Taiwan:1.7%(SL)

Brazil:5.1%
(CDHw/ICHDI migraine)1

France:2.1% (CDH w/ICHDI migraine)1 Italy:1.6%(CMsubset ofCDH)1 Spain:2.4%(SL)1,2 Germany:2.0%(SL)3

*Duetotheheterogeneityofstudies, somevariationindefinitions ofchronic migraineexists. CDH=chronic dailyheadache;ICHDI=InternationalClassificationofHeadacheDisordersI;SL=SilbersteinLipton definitionofchronic migraine. 1.NatoliJLetal.Cephalalgia.2010;30:599609. 2.SilbersteinSDetal.Neurology.1996;47:871875. 3.KatsaravaZetal.Cephalalgia.2011;31:520529.

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