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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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