Disorders A Systematic Review and MetaAnalysis文档格式.docx

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AcomprehensiveliteraturereviewwasconductedinordertoidentifypublishedstudiesassessingtheeffectsofmodafinilonfatigueandEDSassociatedwithneurologicaldisorders.PrimaryoutcomesincludedfatigueandEDS.Secondaryoutcomesincludeddepressionandadverseeffects.

Findings

Tenrandomizedcontrolledtrialswereidentifiedincluding4studiesofParkinson’sdisease（PD）,3ofmultiplesclerosis（MS）,2oftraumaticbraininjury（TBI）and1ofpost-poliosyndrome（PPS）.Atotalof535patientswereenrolled.OurresultssuggestedatherapeuticeffectofmodafinilonfatigueinTBI（MD-0.8295%CI-1.54--0.11 

p=0.02,I2=0%）,whileabeneficialeffectofmodafinilonfatiguewasnotconfirmedinthepooledstudiesofPDorMS.TreatmentresultsdemonstratedaclearbeneficialeffectofmodafinilonEDSinpatientswithPD（MD-2.4595%CI-4.00--0.91 

p=0.002I2=14%）,butnotwithMSandTBI.NodifferencewasseenbetweenmodafinilandplacebotreatmentsinpatientswithPPS.Modafinilseemedtohavenotherapeuticeffectondepression.Adverseeventsweresimilarbetweenmodafinilandplacebogroupsexceptthatmorepatientswerefoundwithinsomniaandnauseainmodafinilgroup.

Conclusions

ExistingtrialsofmodafinilforfatigueandEDSassociatedwithPD,MS,TBIandPPSprovidedinconsistentresults.Themajorityofthestudieshadsmallsamplesizes.Modafinilisnotyetsufficienttoberecommendedforthesemedicalconditionsuntilsoliddataareavailable.

Figures

12

Citation:

ShengP,HouL,WangX,WangX,HuangC,etal.（2013）EfficacyofModafinilonFatigueandExcessiveDaytimeSleepinessAssociatedwithNeurologicalDisorders:

ASystematicReviewandMeta-Analysis.PLoSONE8（12）:

e81802.doi:

10.1371/journal.pone.0081802

Editor:

FriedemannPaul,Charité

UniversityMedicineBerlin,Germany

Received:

June3,2013;

Accepted:

October16,2013;

Published:

December3,2013

Copyright:

©

2013Shengetal.Thisisanopen-accessarticledistributedunderthetermsofthe 

CreativeCommonsAttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.

Funding:

Dr.YanDongissupportedbyNaturalScienceFoundationfromScienceandTechnologyCommissionofShanghaiMunicipality（11ZR1448700）andResearchFoundationforReturnedScholarsfromMinistryofEducationofChina.Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.

Competinginterests:

Theauthorshavedeclaredthatnocompetinginterestsexist.

Introduction

Excessivedaytimesleepiness（EDS）andfatiguearefrequentlyencounteredsymptomsinneurologicalpractice,whichmayarisefromavarietyofdisorderssuchasParkinson’sdisease（PD）,multiplesclerosis（MS）,Alzheimer’sdisease（AD）,depression,strokeandtraumaticbraininjury（TBI）[1-13].EDSisdefinedasnotbeingabletokeepalertorawakeindaytimehoursandmightfallasleepininappropriatesituations.Differentdefinitionshavebeenproposedforfatigue.Forexample,inMS,fatiguehasbeendefinedas“Asubjectivelackofphysicaland/ormentalenergythatisperceivedbytheindividualorcaregivertointerferewithusualanddesiredactivities”[14].Ingeneral,fatigueisconsideredasasubjectivefeelingoftiredness,weakness,orlackofenergy[15].FatigueandEDSnotonlyseverelyimpairproductivityandperformance,butmayalsohavedetrimentaleffectsonsocialfunctioningandoverallqualityoflife.ThemechanismsoffatigueandEDSremainpoorlydefined,whichseemtobemultifactorial,arisingfromprimarydiseasesrelatedfactorsandothersecondaryones.Recentlygrowingevidenceindicatesthatsleepdisturbances,whicharecommoninMSpatients,maybeanimportantcontributingfactorandtreatmentofsleepdisturbancescanimprovefatigueandEDSinpatientswithMS[16-20].TherapiesforfatigueandEDSshouldaddresscausalmechanismsifpossible.Unfortunately,thepotentialmechanismsoffatigueandEDSinclinicalpracticeareoftenhardtobeunderstoodandmanyfactorsmaybeinvolved.Hence,bothpharmacologicalandnon-pharmacologicaltherapieshavebeenappliedinthemanagementoffatigueandEDS[21-24].

Modafinilisanovelwake-promotingagentthatispharmacologicallydifferentfromthoseofamphetamineandmethylphenidate,thetwoclassicalpsychostimulants.Itsexactmodeofactionremainsunclear.Modafinilmaypromotewakefulnessthroughactivationofnoradrenergicanddopaminergicsystems,probablythroughinteractionwiththehypocretin/orexinsystem[25,26].ModafinilamelioratesEDSinallthreedisorders，i.e.narcolepsy,shiftworksleepdisorder（SWSD）andobstructivesleepapnea（OSA）,andhasbeenapprovedbytheFDA[27,28].Ofnote,theEuropeanMedicinesAgencyhasrecentlyrecommendedtheuseofModafinilberestrictedtothetreatmentofnarcolepsyduetoseverepsychiatricsideeffectsandskinreactions[29].Furthermore,modafinilhasbeenusedininvestigationaltreatmentofEDSandfatigueassociatedwithPD,MS,AD,stroke,TBIandpost-poliosyndrome（PPS）[30-46].However,existingtrialsofmodafinilfortheseneurologicaldisordersprovidedinconsistentresults.AlthoughtherehavebeensomeclinicaltrialsontheeffectofmodafinilonfatigueandEDSassociatedwithpsychiatricdisorders,suchasattentiondeficithyperactivitydisorder,depression,schizophreniaandcocaineaddiction,theyarebeyondthescopeofthepresentstudy.

Thecurrentstudyemployedmeta-analysistointegratetheavailableliteratureonthetreatmentofmodafinilonfatigueandEDSassociatedwithneurologicaldisordersandassessedtheefficacyofmodafinilonfatigueandEDSanditssafetyinpatientswithneurologicaldiseaseswitharigorousmethodologicalqualityassessment.

SelectionofStudies

AcomprehensiveliteraturereviewbasedonOvidMedline,EMBASE,theCochraneandPSYCHInfodatabaseswasconductedtoidentifypublishedstudiesontheeffectofmodafinilonfatigueandEDSassociatedwithneurologicaldisorders.SearchtermsusedwerelistedinsupplementS1.ThesearchwaslimitedtoarticleswritteninEnglishandpublishedinpeer-reviewedjournalsfromJanuary1980toDecember2012.Studiesmustinvolvehumansubjectsandprimarydatamustbepresented.Referencelistsfromtherelevantstudiesweresearchedforadditionalliterature.

Inclusioncriteria

Originalstudieswereconsideredforinclusioninthemeta-analysisiftheymetwiththefollowingcriteria:

（1）theywererandomizedcontrolledtrials（RCT）;

（2）patientsover18yearsoldwithneurologicaldiseasessuchasPD,AD,MS,stroke,TBI,PPSandbraintumorwereinvestigated;

（3）theefficacyofmodafinilonfatigueandEDSwasexamined;

（4）resultsweresufficienttoallowcalculationofeffectsizes.

Dataextractionandqualityassessment

Twoauthors（PSandLJH）independentlyreviewedthefullmanuscriptsofeligiblestudies.Datawereextractedinstandardizeddata-collectionforms.Extracteddataincludedfirstauthor’sname,yearofpublication,samplesize,patients’characteristics（meanage,gender）,durationoftreatment,dosage,typeofdisease,durationofdisease,outcomes,baselinefindings,country,studydesignandJadadscore.Anydiscrepancywasresolvedbydiscussionwithathirdauthor（XH）.SelectedRCTswerecriticallyappraisedusingtheJadadscale,whichassessesthemethodologyofthestudysuchasrandomization（2points）,blinding（2points）andattritioninformation（1point）[47].

Studyoutcomes

Primaryoutcomesincludedself-reportedfatigue,whichisthenmeasuredbysingleitemscaleandquestionnaireinstruments,aswellassubjectiveEDSmeasuredbyEpworthSleepinessScaleandobjectiveEDSmeasuredbyMultipleSleepLatencyTest（MSLT）orMaintenanceofWakefulnessTest（MWT）.Secondaryoutcomesincludeddepressionandadverseeffects.

Statisticalanalysis

Fordichotomousdata,theimpactoftheinterventionwasexpressedasrelativerisk（RR）with95%confidenceintervals（CI）usingtheMantel-Haenszelmethod.Forcontinuousdata,thedifferenceinchangefrombaselinetofollow-upbetweeninterventionandcontrolgroupswasexpressedasmeandifferenceswith95%CI（ifthesamescalewasusedinallstudies）orstandardizedmeandifferenceswith95%CI（whendifferentscaleswereused）usinginversevariancemethodotherwise.HeterogeneityoftreatmenteffectsbetweenstudieswasstatisticallyexploredbytheI2 

statistic,inwhich0%–40%indicatesunimportantheterogeneity,30%–60%indicatesmoderateheterogeneity,50%–90%indicatessubstantialheterogeneity,and75%–100%indicatesconsiderableheterogeneity[48].Thesensitivityanalyseswerecarriedoutbyexcludingstudiessuccessively.Allreported 

P 

valuesweretwo-sided,and 

Pvalueslessthan0.05weredeemedasstatisticallysignificant.ThepublicationbiaswasstatisticallyexaminedusingtheEgger’sregressionmodel,calculatedbyStata12.0（StataCorporation,CollegeStation,TX,USA）.

Results

Studycharacteristics

Atotalof427citationswereidentifiedfromtheelectronicsearchesand3throughothersources,ofwhich338wereexcludedafterapreliminaryreview.Theremaining92studieswe