Disorders A Systematic Review and MetaAnalysis文档格式.docx
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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
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