updateofasystematicreview EErnst²andMHPittler DepartmentofComplementaryMedicineSchoolofPostgraduateMedicineandHealthSciencesUniversityof Exeter25VictoriaParkRoadExeterEX24NTUK PublicHealthNutri ID: 954962
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Theefficacyandsafetyoffeverfew(TanacetumpartheniumL.):an updateofasystematicreview* EErnst²andMHPittler DepartmentofComplementaryMedicine,SchoolofPostgraduateMedicineandHealthSciences,Universityof Exeter,25VictoriaParkRoad,ExeterEX24NT,UK PublicHealthNutrition:3(4A),509±514*Apreviousversionofasimilarpaperwasfirstpublishedin1998(VoglerBK,PittlerMH,ErnstE.Feverfewasapreventivetreatmentformigraine:asystematicreview.Cephalalgia:704±8).Correspondingauthor:Emaile.ernst@exeter.ac.uk2000NutritionSociety K W W S V G R L R U J 6 3 X E O L V K H G R Q O L Q H E \ & D P E U L G J H 8 Q L Y H U V L W \ 3 U H V V Table1Double-blind,placebo-controlledRCTsoffeverfewformigrainepreventionFirstauthor[reference]Jadadscore(max:5)DesignPatientsentered/samplesize(age;years)MedicationLengthofmedication(months)MainoutcomemeasuresResultCommentsJohnsonetal.al.4Twoparallel17/17(n.r.)Twocapsules(25mg)ofpowderedfeverfewperday6FrequencyofheadacheIncidenceofnauseaandFrequencyofheadacheincreasedsignificantlyinpatientsreceivingplacebocomparedwithbaselineSignificantinter-groupdifferencesinfavouroffeverfewtheincidenceofnausea,vomitingAllpatientshadtakenfeverfewdailyfortheprevious3±4yearsSmallsamplesizeetal.al.4Crossover72/59(24±72)Onecapsule(meanweight:82mg)ofpowderedfeverfewperday4Frequency,durationandseverityofheadacheIncidenceofnauseaand24%reductioninattackfrequencySignificantreduction002ofnauseaandvomitingNochangeindurationandseverityofheadacheInhomogeneouspatientssamplewithrespecttoformeruseoffeverfewOne-monthplaceboNowash-outperiodSubgroupanalysisinclassical/commonmigraineKuritzkyetal.al.*Crossover20/n.r.(18±60)100mgfeverfewperday2EffectoffeverfewonserotoninuptakeandplateletactivityNoeffectReportedonlyasabstractSmallsamplesizeNomentionofdetailsoffeverfewpreparations,furtheroutcomemeasuresorwithdrawalsetal.al.5Crossover50/44(18±64)Onecapsule(143mg)ofgranulatedfeverfewperday4SeverityofheadacheattacksNumberofworkdayslostNosignificanteffectineitheroutcomemeasureDifferentdrugpreparationOnemonthplaceborun-inperiodNowash-outperiodsPalevitchetal.al.3Crossover57/57(9±65)Twocapsules(50mg)ofpowderedfeverfewperday1PainintensitySeverityofnausea,vomitingSensitivitytonoiseandlightSignificantreductionineachoutcomemeasureBothgroupsweretreatedwithfeverfewinthepreliminaryperiodfor60daysNowash-outperiodNomentionofthepatients'migrainehistory,inclusioncriteriaorwithdrawalsPfaffenrathetal.al.*Fourparallel147/49A.2.08B.6.25C.18.75mgextract3D.placebo3FrequencyofmigraineSignificantreductionDose±responserelationshipobservedn.r.,notreported.*Cannotbecalculated(abstractonly).EErnstandMHPittler K W W S V G R L R U J 6 3 X E O L V K H G R Q O L Q H E \ & D P E U L G J H 8 Q L Y H U V L W \ 3 U H V V searchtermswerefeverfew,TanacetumpartheniumChrysanthemumparthenium,Mutterkraut(theGermancommonname),headacheandmigraine.Amanualsearchwasperfo
rmedusingthebibliographiesofarticleslocatedthroughthecomputersearchandthroughscanningourownfiles.Inaddition,leadingmanufacturersoffeverfewpreparationswerecontactedandaskedtocontributepublishedandunpublishedmaterial.Onlydouble-blind,placebo-controlledRCTsoffeverfewformigraineprophylaxiswereincluded.Studieswereexcludedifnotperformedonfeverfewmono-preparations.Therewerenorestrictionsregardingpublicationlanguage.Datawereextractedindependentlybytworeviewersfollowingastandardized,predefinedprocedure.Methodo-logicalqualitywasassessedusingtheJadadscore.Ameta-analysiswasconsideredbutprovedtobeinfeasibleduetothelackofacommonoutcomemeasureacrossthestudies.Sixclinicalstudiesmettheaboveinclusion/exclusioncriteria(Table1).Alltrialsscoredatleast2of5pointsontheJadadscore.Fourstudiesreportingpositiveresultsfavouringfeverfewscored3±4pointsonthequalityscale5±7,9.Oneofthetwonegativetrialsscored5points(Table1).etal.conductedatrialincluding17patientswhohadconsumedrawfeverfewleaveseverydayfortheprevious3±4years.Patientswererandomizedtoreceiveeithertwocapsulesoffreeze-driedfeverfewleavesdaily(50mg)oridenticalplacebofor24weeks.Duringthetrialperiodallpatientsgradedseverityandfrequencyofheadache,visualdisturbance,incidenceofnauseaandvomitingondiarycards.Asignificantincreaseofmeanattackfrequencypermonthwasobservedintheplacebogroupcomparedwithbaselinemeasurementswhilethisparameterremainedconstantinpatientsreceiv-ingfeverfew.Fiveofeightpatientsfromthefeverfewgroupreportedgoodtoexcellenteffectiveness,whilethiswasreportedbyonlyonepatientintheplacebogroup.etal.randomized72patientstoreceiveeitheronecapsuleoffeverfeworplacebofor4monthsaftera1-monthplaceborun-inperiod.Patientsweresubsequentlycrossedoverintotheothergroupforthesecond4-monthperiod.Feverfewtreatmentwasassociatedwitha24%inattackfrequencyandasignificantinmigraine-associatednauseaandvomitingcomparedwithplacebo.Inpatientswithcommonmigraine,feverfewreducedthenumberofattacksby21%whileitwasreducedby32%patientswithclassicalmigraine.etal.assessedtheeffectoffeverfewonserotoninuptakeandplateletactivityin20migrainepatients.Eachpatientreceived100mgoffeverfeworplacebodailyfor2months.Noeffectonserotoninuptakeandplateletactivitywasfound.Withoutprovidingdetailsofclinicaldata,theauthorsconcluded:`100mgoffeverfewadaywasfoundtobeineffectiveintheprophylaxisofWeerdtetal.administeredeitheronecapsuleofanalcoholicfeverfewextractorplaceboto50patientsinacrossoverRCT.A1-monthplaceborun-inphasewasfollowedbytwotreatmentperiodsof2monthseach.Thefrequencyofheadacheattacksandthenumberofworkdayslostwerereportedinadailycalendar.Theresultsshowednostatisticallysignificantbeneficialeffectoffeverfewcomparedwithplacebo.AcrossovertrialconductedbyPalevitchetal.57migrainepatients.Duringthepreliminaryphaseofthisstudyeachpatientwastreatedwith100mgfeverfewdailyfor2months.Thereafter,onegroupreceivedplaceboforanadditional30dayswhiletheothergroupcontinuedtakingfeverfew.Inthethirdphase,thetreatmentgroupwascrossedovertotheplaceboarmandviceversa.Pain
intensityandseverityoftheaccompanyingsymptomssuchasnausea,vomitingandsensitivitytonoiseandlightwerereported.TheresultsofthepreliminaryphaseshowedasignificantdecreaseinpainintensityafterthetreatmentwithfeverfewcomparedwithbaselineInthecrossoverphase,asignificantreductionofpainintensitywasreportedinthetreatmentgroupcomparedwiththeplacebogroupTherewasalsoasignificantreductionintheseverityofnauseaandvomitinginfavouroffeverfew.etal.conductedadouble-blind,placebo-controlled,multicentreRCTwhich,sofar,hasonlybeenpublishedasanabstract(forthisreasonnoJadadscorewasattributedtothisstudy).Threedosageregimens(2.08mgvs.6.25mgvs.18.75mg,each3timesperdayadminis-teredfor12weeks)ofanovelCOfeverfewextractwerecomparedwithplacebo.Onehundredandfortysevenpatientswithmigraine(accordingtoInternationalHead-acheSocietycriteria)wereenrolled.Theprimaryendpointhadbeenpre-definedasthetotalnumberofmigraineattacksduringthelast28daysoftreatmentcomparedwiththe4-weekbaselineperiod.Theresultsshowedsignificanteffectscomparedwithplaceboandadose±responserelationship.Theoptimaleffectivenesswasnotedwith325mgextractperday.Theauthorsconcludedthatthisextractwas`particularlyeffectiveinmigraineprophylaxisinpatientswithatleast4attacksduring28dayspriortoonsetofprophylaxis'.Adverseeffects,asreportedintheabovetrials,aresummarizedinTable2.Feverfewwasgenerallywelltoleratedandadverseeffectswereusuallymildandreversible.Twostudiesreportedahigherandonetrialasimilarincidenceofadverseeffectsintheplacebogroupcomparedwiththefeverfewgroup.Intotal,threewith-drawalswerenecessitatedbyadverseeffectsinthefeverfewgroupscomparedwithfiveintheplacebogroups.Efficacyandsafetyoffeverfew K W W S V G R L R U J 6 3 X E O L V K H G R Q O L Q H E \ & D P E U L G J H 8 Q L Y H U V L W \ 3 U H V V A`post-feverfewsyndrome'hasbeendescribedafterallocatingpatientswhopreviouslyweretakingfeverfewtoplacebotreatment.Feverfewdidnotappeartoaffectbloodpressure,heartrate,bodyweight,ortheresultsofhaematologicalandbiochemicalsafetyparameters.Sourcesotherthantheabove-mentionedRCTsneedtobeconsultedtogeneratereliableinformationonthesafetyoffeverfew.Informationfromseveralrecentreference10±15hasbeenextractedandissummarizedinTable3.Thesecumulativedatasuggestthatfeverfewisnotentirelyfreeofrisksbutthatadverseeffectsareusuallytransientandmild.Inviewofthepopularityoffeverfew,thepaucityoftheexistingRCTsonthesubjectisdisappointing.Mostofthestudiesthatexistarenotfullysatisfactoryintermsofmethodologicalquality.Collectively,however,thedatadoimplythatfeverfewiseffectiveinpreventingmigraineWhilethestudywiththehighestJadadscoreshowednobeneficialeffects,fourofthesixtrials5±7,9feverfew.Amongstthefourtrialswithanacceptablesamplesize,threestudiesreportedfeverfewtobesuperiortoplacebowhileonedidnot.Thefrequencyofmigrainewaspositivelyaffectedbyfeverfewinthree.Feverfewreducedtheseverityofmigraineinonewhiletwostudiesreportednosucheffect.Theincidenceofnauseaandvomitingwasposit
ivelyaffectedinoffourtrials,whileseveritywasreducedinoneItisoftenassumedthatparthenoliderepresentstheactiveprincipaloffeverfew.ThishypothesisissupportedinvitroexperimentsdemonstratingthatfeverfewhasinhibitoryeffectsonplateletaggregationaswellasreleaseofserotoninfrombloodplateletsandleucocytesFeverfewalsoinhibitsprostaglandinbiosynthesisinterferingwithphospholipaseA.However,adefinitive Table2AdverseeffectsoffeverfewasreportedinRCTsFirstauthor[reference]Typeofadverseeffect(feverfew/placebo)Commentsetal.[5]Nervousness,tensionheadache,insomnia,stiffnessinjoints,tiredness,nausea,heavierorlighterperiods,palpitations,colickyabdominalpain(0/2)Allpatientstakingplaceboreportedoneeventwithadverseeffects,whereasfourpatientstakingfeverfewreportednoneetal.[6]Mouthulceration,indigestion,heartburn,dizziness,skinrash,diarrhoea,abdominalbloating,soremouth,weightgain,flatulence,nausea,constipation(2/3)Mouthulcerationwasmorecommonwithplaceboetal.[8]n.r.n.r.Onlyreportedinabstractformetal.[3]Diarrhoea(1/0)Noneetal.[7]n.r.n.r.Noneetal.[9]MinorGIsymptomsn.r.Onlyreportedinabstractformn.r.,notreported. Table3Risksoffeverfew±informationfrommajorrecentreferencetextsAdverseeffectsCautionsandcontraindicationsDruginteractionsAbdominalpainChildrenunder12yearsEnhancedeffectsofplateletinhibitorsBittertaste*Notlongerthanfor4monthsEffectreducedwhentakenwithNSAIDsContactdermatitisKnownhypersensitivityDiarrhoeaPregnancy/lactationDry,soretongue*FeverfewisnoteffectiveintreatingacutemigraineattacksGIsymptomsInflammationoflipsortongue*Jointpain²Lossoftaste*Mouthulceration*Nausea/vomitingNervousness²Swollenlips**Notwhentakenincapsules.²Duringfeverfewwithdrawal.EErnstandMHPittler K W W S V G R L R U J 6 3 X E O L V K H G R Q O L Q H E \ & D P E U L G J H 8 Q L Y H U V L W \ 3 U H V V linkbetweentheaetiologyofmigraineandparthenolideoranyotherfeverfewconstituenthasnotbeenestablishedbeyondreasonabledoubt.Onetrialusinganextractoffeverfewwithastandardizedconcentrationofparthenolidedidnotshowanybeneficialeffect.Thislackofeffective-nessmaybeduetotheabsenceofessentialtherapeuticcomponentsofthegranulatedfeverfewleaves.Adivorcefromtheserotonininhibitiontheorymightleadtomoreattentionbeinggiventotheothercomponentsofthefeverfewleaf.Thisissupportedbyastudythatstatesasecondaryroleofserotoninintheaetiologyofmigraine.TheresultsoftheDutchstudysuggestedthattheessentialoilconstituentoffeverfew,chrysanthemylacetate,maybeimportant.Thiscomponentinhibitsprostaglandinsynthe-invitroandseemstopossessanalgesicpropertiesOtherinvestigatorsalsoagreethatparthenolideisnottheonlypharmacologicalactiveconstituentinfeverfewlinkbetweentherelativelyhighconcentrationofmelatoninindifferentfeverfewvarietiesandadecreaseinmelatoninexcretionduringmigraineattackshasbeensuggested.Analternativeexplanationfornegativetrialresultsisofferedbythefactthatsomecommercialpreparationsareunder-dosed,possiblyduetotheinstabilityoftheactiveconstituentsinthes
eextractsHowsafeisfeverfew?Chronicprophylacticuseoffeverfewdidnotaffectthefrequencyofchromosomalaberrationinlymphocytesorurinemutagenicity.Anec-dotalreportsrelatetocontactdermatitis(e.g.Refs.28and29).IntheRCTsreviewedhere,adverseeffectsweregenerallymildandreversible.Mouthulcerationandgastrointestinalsymptomswerethemostfrequentadverseeffect,alsoexperiencedbylong-termfeverfewusersObviouslysuchproblemscanbeavoidedthroughade-quategalenicdesignoftheHMP.A`postfeverfewsyndrome'includingareboundofmigrainesymptoms,anxiety,insomnia,andmuscleandjointstiffnesswasreportedbylong-termconsumersafterdiscontinuationofHowusefularesystematicreviews?SRsminimizeselectionandrandombiases,yettheyarenottotallybias-free.Thetendencyfornegativetrialstoremainunpub-lishediswellknown.Conversely,injournalsofcomplementaryoralternativemedicinepositivestudiesmaybeover-represented.SuchpublicationbiasesmaydistorttheoverallresultofSRs.OtherproblemsofSRsofHMPspertaintotheheterogeneityofextractsandtheoftenlowmethodologicalqualityoftheoriginaltrials.Never-theless,atmydepartmentwefirmlybelievethatSRsofHMPsdoofferavaluablestepforwardandhavethereforeconductednumerousSRssimilartotheonepresentedhere.ThisworkhasbeenrecentlysummarizedelsewhereInconclusion,theresultsofRCTsfavourfeverfewoverplaceboasapreventivetreatmentformigraine.However,severalcaveatspreventfirmconclusionsastotheefficacyoffeverfew.Majorsafetyproblemsdonotseemtoexist.References1EisenbergDM,DavidRB,EttnerSL,etal.TrendsinalternativemedicineuseintheUnitedStates,1990±1997.:1569±75.2HeptinstallS,WhiteA,WilliamsonL,MitchelJRA.Extractsoffeverfewinhibitgranulesecretioninbloodplateletsandpolymorphonuclearleucocytes.:1071±4.3DeWeerdtCJ,BootsmaHPR,HendriksH.Herbalmedicinesinmigraineprevention:randomizeddouble-blindplacebo-con-trolledcrossovertrialofafeverfewpreparation.:225±30.4JadadAR,MooreRA,CarrolD,JenkinsonC,ReynoldsDJM,GavaghanDJ,etal.Assessingthequalityofreportsofrandomizedclinicaltrials:isblindingnecessary?ControlledClin.Trials:1±12.5JohnsonES,KadamNP,HylandsDM,HylandsPJ.Efficacyoffeverfewasprophylactictreatmentofmigraine.:569±73.6MurphyJJ,HeptinstallS,MitchellJRA.Randomizeddouble-blindplacebo-controlledtrialoffeverfewinmigrainepreven-:189±92.7PalevitchD,EaronG,CarassoR.Feverfew()asaprophylactictreatmentformigraine:Adouble-blindplacebo-controlledstudy.Phytother.Res.:508±11.8KuritzkyA,ElhachamY,YerushalmiZ,HeringR.Feverfewinthetreatmentofmigraine:itseffectonserotoninuptakeandplateletactivity.Neurology(Suppl.2):293P.9PfaffenrathV,FischerM,FriedeM,HeinneickeV,ZepelinHH.Clinicaldose±responsestudyfortheinvestigationofefficacyandtolerabilityofTanacetumpartheniuminmigraineProceedingsofDeutscherSchmerzkongress10FetowCW,AvilaJR.ComplementaryandAlternativeMedi-.Springhouse:Philadelphia,1999.11BoonH,SmithM.TheBotanicalPharmacy.Kingston,Canada:QuarryPress,1999.12ErnstE.Possibleinteractionsbetweensyntheticandherbalmedicinalproducts.Part1:asystematicreviewoftheindirectPerfusion:4±15.13LiningerSW.A±ZGuidetoDrug±Herb±
VitaminInteractionsRocklin,CA:PrimaPublishing,1999.14NewallCA,AndersonLA,PhillipsonJD.HerbalMedicinesLondon:ThePharmaceuticalPress,1996.15BrinkerR.HerbContraindicationsandDrugInteractionsSandy,OR:EclecticMedicalPublications,1998.16Tfelt-HansenP,NielsenSL.Patientnumbersneededinprophylacticmigrainetrials.Neuroepidemiology214±19.17HeptinstallS,GroenewegenWA,SpangenbergP,LoescheW.Extractsoffeverfewmayinhibitplateletbehaviourvianeutralizationofsulphydrylgroups.J.Pharm.Pharmacol.:459±65.18PughWJ,SamboK.ProstaglandinsynthetaseinhibitorsinJ.Pharm.Pharmacol.:743±5.19MakhejaAN,BaileyJM.Aplateletphospholipaseinhibitorfromthemedicinalherbfeverfew(TanacetumpartheniumProstaglandinsLeukotrienesMed.:653±60.20AwangDVC.Prescribingtherapeuticfeverfew((L.)SchultzBip.,synChrysanthemumparthe-(L.)Bernh.).IntegrativeMed.:11±13.21GoadsbyPJ.Howdothecurrentlyusedprophylacticagentsworkinmigraine?:85±92.22BrownAMG,EdwardsCM,DaveyMR,PowerB,LoweKC.Pharmacologicalactivityoffeverfew(Tanacetumparthenium(L.)Schultz-Bip.):Assessmentbyinhibitionofhumanpoly-morphonuclearleucocytechemiluminescencein-vitro.Pharm.Pharmacol.:558±61.23HendriksH,BosR,WoerdenbagHJ.TheessentialoilofEfficacyandsafetyoffeverfew K W W S V G R L R U J 6 3 X E O L V K H G R Q O L Q H E \ & D P E U L G J H 8 Q L Y H U V L W \ 3 U H V V Tanacetumparthenium(L.)Schultz-Bip.FlavourFragranceJ.:367±71.24MurchSJ,SimmonsCB,SaxenaPK.Melatonininfeverfewandothermedicinalplants.:1598±9.25BrunJ,ClaustratB,SaddierP,ChazorG.Nocturnalmelatoninexcretionisdecreasedinpatientswithmigrainewithoutauraattacksassociatedwithmenses.136±9.26WilligmannJ,FreudensteinJ.ProductionofastablefeverfewTanacetumparthenium)extractasanactivesubstanceforapharmaceuticalproduct.ScharperBruÈmmer1999(internal27AndersonD,JenkinsonPC,DewdneyRS,BlowersSD,JohnsonES,KadamNP.Chromosomalaberrationsandsisterchromatidexchangesinlymphocytesandurinemutagenicityofmigrainepatients:acomparisonofchronicfeverfewusersandmatchednon-users.Hum.Toxicol.:145±52.28BurryJN.CompositaedermatitisinSouthAustralia:ContactdermatitisfromChrysanthemumpartheniumContactDer-:445.29HausenBM,OsmundsenPE.ContactallergytoparthenolideinTanacetumparthenium(L.)Schulz-Bip.(Feverfew,Astera-ceae)andcross-reactionstorelatedsesquiterpenelactonecontainingcompositaespecies.ActaDerm.Venereol.308±14.30JohnsonES.Patientswhochewchrysanthemumleaves.1983;15May:32±531EasterbrookPJ,BerlinJA,GopalanR,MatthewsDR.Publica-tionbiasinclinicalresearch.:867±72.32ErnstE,PittlerMH.Alternativetherapybias[letter].Nature:480.33PittlerMH,AbbotNC,HarknessEF,ErnstE.Locationbiasincontrolledclinicaltrialsofcomplementarymedicine.J.Clin.:485±9.34ErnstE,ed.HerbalMedicine.AConciseOverviewforProfessionals.Oxford:Butterworth-Heinemann,2000.EErnstandMHPittler K W W S V G R L R U J 6 3 X E O L V K H G R Q O L Q H E \ & D P E U L G J H 8 Q L Y H U V L W \ 3 U H V V