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EpisodictoChronicMigraine

TheTransformers

1

DavidW.DodickM.D.

DepartmentofNeurology

MayoClinicinArizona

Disclosure:Reflectsthepast3years

Withinthepast3years,DrDavidW.Dodickservesonadvisoryboards andhas

consultedforAllergan,Alder,Pfizer,Merck,Coherex,Ferring,Neurocore,Neuralieve,

Neuraxon,NuPatheInc.,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.

2

n epas years, r av . o c asrece ve u n n g or rave ,spea ng,or

editorialactivities,fromthefollowing:CogniMed,Scientiae,Intramed,SAGEPublishing,

LippincottWilliamsandWilkins,OxfordUniversityPress,CambridgeUniversityPress,

MillerMedical,AnnenbergforHealthSciences;heservesasEditorinChiefandonthe

editorialboardsofTheNeurologist,LancetNeurology,andPostgraduateMedicine;andhasservedasEditorin ChiefofHeadacheCurrentsandasanAssociateEditorofHeadache;receivespublishingroyaltiesforWolffsHeadache,8thedition(OxfordUniversityPress,2009)andHandbookofHeadache(CambridgeUniversityPress,2010).Withinthepast3years,DrDavidW.Dodickhasreceivedresearchgrantsupportfrom

thefollowing:AdvancedNeurostimulationSystems,BostonScientific,StJudeMedical,

Inc.,Medtronic,NINDS/NIH,MayoClinic.

Objectives:Atthecompletionofthispresentation,

theparticipantwillbeableto:

1. Identifythefactorsthatincreasetheriskforprogression

fromepisodictochronicmigraine

3

.

episodictochronicmigraine

3. Implementatreatmentstrategyforpatientswithchronic

migraine,withorwithoutacutedrugoveruse


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Diagnosis,Epidemiology&RiskFactors

4

ChronicMigraine(CM):FutureofClassification

ICHDII1 medicationoveruse2

combinedcriteriaPracticalclinicalcriteria

Headacheon 15dayspermonthforatleast

3months1Headache 15dayspermonth

andaverage>4hrsperday

AND 5priormigraineattacks1

On 8dayspermonth,headachefulfillscriteria

5

1.HeadacheClassificationCommittee.OlesenJ etal.Cephalalgia 2006;26:742746.2.SilbersteinSD etal.Cephalalgia 2005;25:460465.

formigraine1

2ofthefollowing:a)unilateral;b)

throbbing;

c)moderateorseverepain;d)aggravatedby

physicalactivity

1ofthefollowing:a)nauseaand/or

vomiting;

b)photophobiaandphonophobia

Relievedwithtriptansorergotamine

Currentorpriordiagnosis

ofmigraineand>8days

migraine+ auraorprobable

migraine

AND

Notattributedtoanothercausativedisorder1Withorwithoutmedication

overuse Subclassifiedaswithorwithoutmedicationoveruseheadacheasdiagnosedby8.21,2

TransformingfromEpisodicMigraine(EM)toCM

Everyyear,between2.5and4.6%ofpeoplewithepisodic

migraineexperienceprogressiontochronicmigraine

Patientsmaytransitionsamongthese3migrainestatesin

thedirectionofincreasinganddecreasing frequency

6

Transitionsoccuroverweekstomonths

LiptonRBetal.JAMA 2004;291:493494.LiptonRB.Neurology2009;72(Suppl1):S3S7.MunakataJ etal.Headache 2009;49:498508.

09 headache

days/month15 headache

days/month

1014 headache

days/month

BigalME,etal.CurOpinNeurol.2009;22:269276.


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TheMajorityofChronicMigraineSufferersDo

NotRemit

Over3yearsoffollowup,themajorityofsuffererswithCMremainwith

eitherCMorhighfrequencyepisodicmigraine

7

TransitionRatesin2006and2007

7

LiptonRB.Headache2011;51:7783AMPP=AmericanMigrainePrevalenceandPrevention.

RelativetoCMStatusin2005(Baseline)

Remitted

CM

26%

Persistent

CM

22%

Transitioning

CM

52%

PersistentCMsufferersexperienceanincrease

indisability

60

70

51.0 53.4

64.0

Chronicmigraine

MeanMIDASscoresforpersistentCMandremitted

CMgroupsbyyear

81.LiptonRetal.PosterpresentedatMigraineTrust 2008.2.LiptonRetal.Cephalalgia 2009;29(suppl1):72(abstractPO154).

DatafromtheAmericanMigrainePrevalenceandPrevention(AMPP)Study.

MIDASscore

0

10

20

30

40

50

200720062005

11.4

50.4

12.8

Persistent

Remitted

ComparedtoEM,thosewithCMhave:ComparedtoEM,thosewithCMhave:

Greaterheadacherelateddisabilityandimpact13

Reducedhealthrelatedqualityoflife3,4

Worsesocioeconomicstatus2,5

9

ncrease ea t careresourceut zat on , , ,

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:AmericanAcademyofNeurology61stAnnualMeeting;April25May2,2009;Seattle,WA.6.StewartWFetal.JOccupEnvironMed.2010;52(1):814.7.BuseDetal.JNeurolNeurosurgPsychiatry.2010;81(4):428432.


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CMHasMorePsychiatricandMedicalCMHasMorePsychiatricandMedical

ComorbiditiesthanEMComorbiditiesthanEM

CM(n=655) EM(n=10,609 OR(95%CI)

Ma or

10

Depression30.2% 17.2% 2.1(1.7 2.5)

AnxietyDisorders 30.2% 18.8% 1.9(1.6 2.2)

OtherChronic

PainDisorders31.5% 15.1% 2.6(2.2 3.1)

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

WhichofthefollowinghasNOT beendemonstrated

tobeariskfactorfortheprogressionofmigraine?

1. Migraineattackfrequency

2. Obstructivesleepapnea

11

.

4. Allodynia

5. Depression

Risk Factors for CM?Risk Factors for CM?

MOMO11

AttackfrequencyAttackfrequency22

ObesityObesity

22

HeadinjuryHeadinjury55

SnoringSnoring66

CaffeineCaffeine

77

12

Loweducation;socioLoweducation;socio

economicstatuseconomicstatus33

Stressfullifeevents/Stressfullifeevents/

majorlifechangesmajorlifechanges44

1 . Bi galME,etal. Headache.2008:48:1157682 . Sc he rAI,etal.Pain.2003;106:8189.3 . BuseDC,etal.JNeurolNeurosurgPsychiatry.2010;81:42832.4 . Sc he retal.,Cephalalgia2008; 28:868876.5 . Couc hJ ,etal.Neurology.2007;69:116977.

6. ScherAI,etal.Neurology2003;60:13661368.7 . S ch eretal.,Neurology2004;63:20222027.

8 . A sh in a S ,etal. Headache.2010(abstract).9 . L i ptonRB,etal. AnnNeurol. 2008:63:14858.

DepressionDepression88

AnxietyAnxiety88

AllodyniaAllodynia99


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Severalriskfactorspredictprogression*from

EMtoCM

Everyday life stress

Poor pain coping ability

2 acute headache drugs

13

DatafromtheGermanHeadacheConsortium(GHC).Courtesy ofDr.ZazaKatsarava.

Odds ratio

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

14

OddsRa ti o 9 5%CI pvalue

Headachefrequencyatbaseline

1014days/month vs14days/month8.5 4.416.5 0.001

Frequentdrugintake(>104.6 2.49.0 0.001

RiskFactors:TransitionFromEpisodicMigraine to

ChronicDailyHeadache

14

Chronicbackpain 3.8 1.86.7 0.001

2acuteheadachedrugs 2.6 1.25.8 0.016

Poorpaincopingability 2.4 1.24.8 0.001

Everydaylifestress 1.9 1.03.8 0.003

Depression(CESD) 1.8 0.84.7 NS

DatafromtheGermanHeadacheConsortium(GHC).Courtesy ofDr.ZazaKatsarava.

AcuteMedicationOveruse(MO)

Overuseofacutemedicationiscommoninindividualswithchronic

migraine13

50%80%ofchronicmigrainepatientsseeninheadacheclinicsoveruse

acute

medicationsMedicationoverusemaybedefinedasfollows4:

15days/month:simpleanalgesics,combinationsofdrugs,or10days/month:combinationanalgesics,ergotamines,triptans,

opioids

Avoidanceofmedicationoveruseisimportant2

1.SilbersteinSD etal,eds.HeadacheinClinicalPractice.2nd ed.London:MartinDunitz; 2002:69146.2.LiptonRB etal. Neurology.2003;61;154155.3. WangSJetal.Pain.2001;89:285292.4.HeadacheClassificationCommittee;OlesonJ etal.Cephalalgia. 2006;26:742746.


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Accordingtobestmedicalevidence,whichofthe

followingstatementsregardingthetreatmentof

patientswithchronicmigraineistrue?

1 . Re missi onoccursinthemajorityafterdetoxification

in thoseoverusingacutemedications

2. Preventivemedicationsareeffectiveinthose

overusingacutemedications

3 . Differe ntclassesofacutemedicationsareequally

potentintheirabilitytotransformEMtoCM

4. Preventivemedicationsaremosteffectivewhen

overusedmedicationsarediscontinued

EM=episodicmigraine;CM=chronicmigraine

MedicationOveruseandEstimatedProgression

toCM

ProbabilityofProgression

toChronicMigraine(%) Opiates40

35

30

25

20

15

10

05

0 ProbabilityofProgression

toChronicMigraine(%) Barbiturates40

35

30

25

20

15

10

05

0

17 BigalMEetal.Headache. 2008;48:11571168. Logisticregressionwasusedfor modelingofestimatedprogression

04 59 1014Monthlyheadachedays

0 2 4 6 8 1 0 1 2 14

MonthlyUse(Days)

0 2 4 6 8 1 0 12 14

MonthlyUse(Days)

Triptans4035

30

25

20

15

10

05

0

0 2 4 6 8 1 0 1 2 14

MonthlyUse(Days)

ProbabilityofProgressionto

ChronicMigraine(%)

NSAIDs40

35

30

25

20

15

10

05

0

0 2 4 6 8 10 12 14ProbabilityofProgressionto

ChronicMigraine(%)

MonthlyUse(Days)

Pathophysiology

18


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WhichofthefollowingisNOT likelyafactorinthe

maintenanceofheadacheinchronicmigraine?

1. SensitizationofperipheralTVnociceptor

2. Sensitizationofthe2nd orderTVneuron

3. Sensitizationof3rd orderTVthalamicrelayneurons

19

4. Corticalhyperexcitabilityandneuronalplasticity

5. Altereddescendingmodulationof2nd orderTVneurons

TV=trigeminovascular

ThalamicTVNeuronsHardWiredtoMultipleCortical

Areas:MayAccountfortheMigraineExperienceand

Chronicity

EachTVneuron(Po,LD,LP)projectinto

corticalareasinvolvedinregulationof

affect,motorfunction,visualand

auditoryperception,spatialorientation,

memoryretrieval,andolfaction.

20 NosedaR.etal.JNeurosci2011;31(40):1420414217

Dense,redundantprojectionsto

trigeminalareaofS1

Maydisruptnormalmotorintracortical

inhibitionofothercorticalareas,

thalamicrelayneurons,anddescending

painmodulatingnetworks

TV=trigeminovascular

Migraine:ABrainthatsPrimedforChronicity:

IncreasedIntrinsicBrainActivityandFunctional

ConnectivityinSensoryNetworks

Sensorimotornetwork Visualnetwork

21

Auditorynetwork Saliencenetwork=affectivepainnetwork

Sprengeretal.AHSWashington2011


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Anterior

insulaACC

Basal

gangliaS1

Lateralpre

frontalcortex

NociceptiveMemory:CorticalNeuroplasticity

FacilitatestheDevelopmentofChronicPain

22

Thalamus

RostralACC

Affective Antinociceptive

PAG

Motor

Cerebellum

Sensory

S2

Posterior

insula

Cognitive

Para

hippocampal n=29

YiMandZhangH.JNeurosci2011;31:1334313345

EtoK,etal.JNeurosci2011;31:76317636SlidecourtesyofTillSprenger Riedletal.Neuroimage2011;57:206213

StructuralAlterationsintheChronic

MigraineBrain

23

SignificantGMVreductionsinbilateralinsula,motor/premotor,prefrontal,

cingulatecortex,rightposteriorparietalcortex,andorbitofrontalcortex

KimJHetal.Cephalalgia. 2008;28:598604.

DescendingModulationCircuitsareInvolvedin

Migraine/ChronicMigraine

InterictalHypo

functionofNucleus

24MoultonEA, etal.PLOSone;November2008:3(11):e3799

InterictalDysfunctionofaBrainstemDescending

Modulatory CenterinMigrainePatients

Cuneiformisin

migrainesubjects


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CentralSensitizationinChronicMigraine:Cutaneous

AllodyniaDuringandBetweenAttacks

0

2

4

6

810

48

Painscore Painf ree M ig ra in e

0

2

4

6

8

10

48

Painsco

re Painf re e M ig ra ine

Episodicmigraine ChronicmigraineN=15

25

0

50

100

150

16

20

24

28

32

36

40

44

Heating

Cooling

Thermalpain

thresholds(OC)

Mechanicalpain

threshold(g)

4Hoursafterpainonset

PressurePressure

RBurstein.Unpublishedobservations

0

50

100

150

16

20

24

28

32

36

40

44

Heating

Cooling

Thermalpain

thresholds(OC)

Mechanicalpain

threshold(g)

4Hoursafterpainonset

PressurePressure

Day18

Stress

(1hrofbrightlight)

Day

20 21

TriptanInducedLatentSensitization

APossibleMechanismofMOH/MigraineProgression

CGRP,nNOS

26

Saline

Baseline

Sensory

Thresholds

7Days

Sumatriptanor

SalineInfusion

Vehicle/Vehicle

Vehicle/SNP

Sumatriptan/Vehicle

Sumatriptan/SNP

1 2 3 4 5

0

2

4

6

8

Time (hours)

Withdrawalthreshold(g)

Day18Day

20

DeFeliceM,etal.AnnNeurol. 2010;67:325337

Sodiumnitroprusside

MOH=medicationoveruseheadacheDeFelice M,etal.Brain2010;133:24752488

ManagementofChronicMigraine


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ChronicMigraine:

MultifacetedApproachtoTherapy

Education,

Lifestyle

modifications,behavioral

therapy

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

Chronic

migraine

management

,expectations, and

close follow-up

therapy

RiskFactorManagementRiskFactorManagement

RISKFACTOR TREATMENT/INTERVENTION

Treatmentpatterns Cre ateoptimalpharmacologicplan(utilizeacuteand

preventiveasappropriate),monitorandlimituseofacute

prescriptionandOTCsasappropriate

Attackfr equ enc y Re duc tio n/preventionwithpharmacologicandbehavioral

29

ntervent ons

ObesityObesity Weightloss,Exercise,BehavioralInterventionWeightloss,Exercise,BehavioralIntervention

Stress Stressmanagementwithbiobehavioraltechniques

(biofeedback,cognitivebehavioraltherapy,relaxation

training),Exercise

SnoringSnoring Diagnoseandtreatsleepapnea,WeightlossDiagnoseandtreatsleepapnea,Weightloss

Allodynia Manageattackfrequencyandtreatearly

DepressionDepression Assess,treatwithpharmacologicandbehavioraltherapies,Assess,treatwithpharmacologicandbehavioraltherapies,

refer

when

appropriate

refer

when

appropriate

Anxiety Assess,treatwithpharmacologicandbehavioraltherapies,Assess,treatwithpharmacologicandbehavioraltherapies,

referwhenappropriatereferwhenappropriate

AcuteTreatmentConsiderationsforCM

Limittheuseofacutemedicationtoonaverage,


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PreventiveMedicationsinChronicMigraine:

EvidenceBase

Treatment EvidenceforUseinChronicMigraine

Anticonvulsants:Valproate

Topiramate

Gabapentin

SmallDBPCandcomparatortrialinCM/CDH1,2

ThreeDBPCtrialsinCM3,4

One DBPC trial in CDH5

31

Antidepressants:

Amitriptyline

Fluoxetine

Tizanidine

SmallopenlabeltrialinTM6

SmallDBPCtrialinCDH7

SmallDBPCtrialinCDH8

OnabotulinumtoxinA TwoDBPCtrialsinCM9

1.YurekliVAetal.JHeadachePain.2008;9:3741.2.BartoliniMe t al .ClinNeuropharmacol.2005;28:277279.3.DienerHC etal.Cephalalgia.2007;27:814823.4.SilbersteinSDet al.Headache.2007;47:170180.5.SpiraPJ,BeranRG.Neurology.2003;61:17531759.6.KrymchantowskiAVetal. Headache.2002;45:510514.7.SaperJRetal.Headache.1994;34:497502.8.SaperJRetal.Headache.2002;42:470482.9. DodickDWetal.Headache.

2010;50:921 936.

DBPC=doubleblindplacebocontrolled;TM=transformedmigraine;CDH=chronicdailyheadache;CM=chronicmigraine

ManagingAcuteMedicationOveruse:Responseto

WithdrawalWithoutPreventiveMedication.

Pa

tien

ts(%)

32

Improvementindicateda reductionin headachefrequency.

Diagnosticheadachediaryfilledout ona dailybasis.

1.ZeebergPetal.Neurology. 2006;66:18941898.

2.DienerHCetal.LancetNeurol.2004;3:475483.3.ZidvercTrajkovicJ.Cephalalgia.2007;27:12191225.

Studieshaveshownrelapserateofoveruseaftersuccessfulwithdrawalisnearly40%

duringthefirstyear.2,3

PreventiveTreatmentComparedWithAbrupt

WithdrawalofAcuteMedications

Controls

Abruptwithdrawalonly

Prophylaxisfromthestart

nt

h

30

25uc

tion

in

%)p = 0.01

HagenK etal.Cephalalgia. 2009;29:221232.

Months FollowingWithdrawal

No.

ofHea

dac

he

Days

/M

20

15

10

5

0

0 2 3 4 5 6 7 8 9 10 11 121

Pa

tien

tsEx

hibitinga

50%

Re

d

Hea

dac

he

Days

/Mon

th(

MonthsFollowingWithdrawal


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MonitoringResponsetoTreatment

Maintainheadache

diary

1,2

Useglobalmeasureofimprovement1,2

34

1.DodickDW, SilbersteinSD. PractNeurol. 2007;7:383393.2.FenstermacherNetal.BMJ. 2011;342:540543.

3.KosinskiMetal.QualLifeRes. 2003;12:963974.

functioning1,2(e.g.HIT6;MsQOL)

Summary:ChronicMigraine

Simplify the diagnosis most patients with >15 headache days

per month without secondary cause have chronic migraine

Educate and reassure

35

ssess an a ress rs acors

Multimodal therapy

END

36


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MigraineBrainIsPrimedforAttacks:AlteredInterictal

Excitability,NetworkSynchrony, andFunctionalConnectivity

inSensoryNetworks

37

BoullocheN.,etal.JNeurolNeurosurgPsychiatry201081:978984 Denuelleetal.Neurology2011;76:213218

CentralSensitizationinMigraine

38 Bursteinetal.AnnNeurol2010;68:8191

PreventiveTherapiesUsedby

PatientsWithCM

Chronic

Migraine

(n=520)

Episodic

Migraine

(n=9424)

Chronic

Migraine

(n=520)

Episodic

Migraine

(n=9424)

Antiepileptic Drugs: Antihypertensives:

Divalproex 20% 10% Propranolol 22% 20%

Topiramate 33% 19% Nadolol 3% 3%

Gaba entin % 11% eto rolol 7% 5%

39

Other 7% 6% Atenolol 7% 5%

Antidepressants: Verapamil 9% 5%

Amitriptyline 33% 17% Diltiazem 0.5% 0.2%

Nortriptyline 9% 5% Nutraceuticals/Herbal Therapies:

Duloxetine 7% 2% Feverfew 10% 12%

Venlafaxine 7% 5% Magnesium 11% 10%

Paroxetine 8% 6% Riboflavin 10% 10%

Sertraline 12% 7% Butterbur 1% 1%

Fluoxetine 11% 6%

DatafromtheAmericanMigrainePrevalenceandPrevention(AMPP)study.

BigalMEetal.Neurology. 2008;71;559566.


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CM:GlobalPrevalence*

UnitedStates1

40

: . (SL)1,2

France:2.1% (CDHw/ICHDImigraine)1

Italy:1.6%(CMsubset ofCDH)1

Spain:2.4%(SL)1,2

Germany:2.0%(SL)3

Taiwan:1.7%(SL)

Brazil:5.1%(CDHw/ICHDImigraine)1

*Duetotheheterogeneityofstudies,somevariationindefinitionsofchronicmigraine exists.

CDH=chronicdailyheadache;ICHDI=International ClassificationofHeadacheDisordersI;SL=SilbersteinLipton definitionofchronicmigraine.

1.NatoliJLetal.Cephalalgia.2010;30:599609.

2.SilbersteinSDetal.Neurology.1996;47:871875.3.KatsaravaZ etal.Cephalalgia.2011;31:520529.

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