单剂量缓释吗啡与传统吗啡用于剖宫产术后硬膜外镇痛的比较

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ObstetricAnesthesiology

SectionEditor:DavidJ.Birnbach

Single-Dose,Extended-ReleaseEpiduralMorphine(DepoDur™)ComparedtoConventionalEpiduralMorphineforPost-CesareanPain

BrendanCarvalho,MBBCh,FRCA

LauraM.Roland,MDLarryF.Chu,MD,MS

VincentA.Campitelli,III,MD

EdwardT.Riley,MD

BACKGROUND:Asingle-doseofneuraxialmorphinesulfateprovidesgoodpost-Cesareananalgesia;however,itsefficacyislimitedtothefirstpostoperativeday.InarecentphaseIIIstudy,extended-releaseepiduralmorphine(EREM)formulationprovidedmoreeffective,prolongedanalgesiaafterCesareandelivery,comparedtoconventionalepiduralmorphine.However,thestudyprotocoldidnotallowfortheuseofnonsteroidalantiinflammatorydrugs,usedvariouspostoperativeanalgesics,andmonitoringandtreatmentofrespiratorydepressionwerenotstandardized.Ouraimsinthisstudyweretocomparepostoperativeanalgesicconsumption,painscoresandsideeffectsofEREMwithconventionalmorphineforthemanagementofpost-Cesareanpaininasettingmorereflectiveofcurrentobstetricpractice.METHODS:SeventyhealthyparturientsundergoingelectiveCesareandeliverywereenrolledinthisrandomized,double-blindstudy.Usingacombinedspinalepiduraltechnique,patientsreceivedanintrathecalinjectionofbupivacaine12mgandfentanyl10mcg.Afterclosureofthefascia,asingle-doseofeitherconventionalmorphine4mgorEREM10mgwasadministeredepidurally.Postoperatively,allpatientsreceivedibuprofen600mgorallyevery6h.OraloxycodoneandIVmorphinewereavailableforbreakthroughpain.Allpatientsreceivedpulseoximetryandrespiratorymonitoringfor48hpost-Cesareandelivery.

RESULTS:Single-doseEREMsignificantlyimprovedpainscoresatrestandduringactivity.Themedian(interquartilerange)ofsupplementalopioidmedicationusagefor48hpost-Cesarean(inmilligram-morphineequivalents)decreasedfrom17(22)to10(17)mgwithEREMcomparedtoconventionalepiduralmorphine(Pϭ0.037).Bothdrugswerewelltoleratedwithnosignificantdifferenceinadverseeventprofiles.

CONCLUSION:EREMprovidessuperiorandprolongedpost-Cesareananalgesiacomparedtoconventionalepiduralmorphinewithnosignificantincreasesinadverseevents.

(AnesthAnalg2007;105:176–83)

euraxialopioidsprovidesuperiorpostoperativepainreliefcomparedtoIVanalgesia(1,2).Thepostop-erativeanalgesiaprovidedbyasingledoseofepiduralorintrathecalmorphineshiftsthepainexperiencedafterCesareandelivery(CD)fromthefirstdaytothesecond

FromtheDepartmentofAnesthesia,StanfordUniversitySchoolofMedicine,Stanford,California.

AcceptedforpublicationMarch15,2007.

SupportedbyEndo,PharmaceuticalsChaddsFord,PA(EndoPharmaceuticalshadnoinputinthestudydesign,studyconduct,dataanalysis,ormanuscriptpreparation);OfficeofResearchonWomen’sHealthandNationalInstituteofChildHealthandHumanDevelopmentoftheNationalInstitutesofHealth,grant5K12HD043452(toDr.Carvalho),andacareerdevelopmentawardfromtheNationalInstituteofGeneralMedicalSciencesoftheNationalInstitutesofHealth,grant5K23GM071400-02(toDr.Chu).

AddresscorrespondenceandreprintrequeststoBrendanCarvalho,MBBCh,FRCA,DepartmentofAnesthesia,H3580,Stan-fordUniversitySchoolofMedicine,Stanford,CA94305.Addresse-mailtobcarvalho@stanford.edu.

DOI:10.1213/01.ane.0000265533.13477.26

postoperativeday(2),withpeaklevelsaround36hpost-CD.(3)Peakpainlevelscoincidewithmaternalmobilizationandbreast-feedingactivityandmaydelayrecovery(2–4).Continuousepiduralcathetertechniquesprolonganalgesia,butreducepatientmobilityandin-creasenursingworkload(4).

Single-dose,extended-releaseepiduralmorphine(EREM)(DepoDur™,EndoPharmaceuticals,ChaddsFord,PA)isanoveldrugthatdeliversconventionalmorphinesulfateusingDepoFoam(SkyePharma,SanDiego,CA)technology.DepoFoamisadrugdeliverysystemcomposedofmultivesicularlipidparticlescontainingnonconcentricaqueouschambersthaten-capsulatetheactivedrug.Thisextended-releasemor-phinetechnologyisformulatedtoprovideanepiduraldepotofmorphineforupto48hafterasingleadministrationwithouttheneedforrepeatdosing(5,6).EREMthereforehasthepotentialtoextendanalgesiaintothesecondpostoperativeday,whenasingledoseofconventionalneuraxialmorphineisnolongereffectiveandpeakpost-CDpainlevelsareexperienced(2,3).Amulticenter,phaseIIIpost-CD

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studyfoundthatanalgesiawassignificantlypro-longedinpatientswhoreceivedsingle-doseepiduralEREMcomparedtoconventionalepiduralmorphine(7).However,thestudydesignhadanumberofweaknesses:

1.EREMwascomparedtoanactivecontrolof5mgepiduralmorphine,adosethatishigherthancommonlyusedpost-CD.

2.Thestudyprotocoldidnotallowfortheuseofnonsteroidalantiinflammatorydrugs(NSAIDs).NSAIDSareroutinelyusedincombinationwithneuraxialmorphinebecausemultimodaltherapyhasbeenshowntobesuperiortosingle-modetherapyforpost-CDpain(3,8).

3.Differentsitesinvolvedinthismulticenterstudyusedvariouspostoperativeanalgesics,whichwerelaterconvertedtoIVmorphineequivalents.4.ThestudyusedthreedifferentEREMdosesthatweakenedthestudypower.

5.Pulseoximetrywasnotusedandmonitoringandtreatmentofrespiratorydepressionwerenotstandardizedamongthedifferentsitespartici-patinginthestudy(7).ThestudyhypothesiswasthatEREMsignificantlyreducespost-CDanalgesicconsumptioncomparedtoconventionalepiduralmorphine.Theobjectivesofthisstudyweretocomparepostoperativeanalgesiccon-sumption,painscores,andsideeffectsofasingle-doseofepidurallyadministeredEREM10mgversuscon-ventionalmorphine4mgforthemanagementofpost-CDfor48hafterdelivery.Toensureaccurateefficacyandsafetyassessments,weaimedtostudyEREMinasettingmorereflectiveofcurrentobstetricanesthesiapractice,inparticular,usingNSAIDsandprovidingstandardizedpostoperativepainmanage-ment,respiratorymonitoring,andtreatmentprotocols.

protocol,duetoconcernforapotentialphysicochem-icalinteractionwithEREMandepidurallocalanes-theticsthatmayreducethesustained-releasederivedfromtheDepoFoam.PatientswererandomizedbeforetheirCD.Ifthestudydrugcouldnotbeadministeredduetoacontraindicationnotedabove,thepatientwasexcludedfromtheprimaryandsecondaryefficacyanalyses.

Parturientsreceivedspinalanesthesiaviaacom-binedspinal–epiduraltechniquewithhyperbaricbu-pivacaine12mgandfentanyl10␮gadministeredintrathecallyviathespinalcomponentofthetech-nique.Asingleepiduralinjectionofeither4mgmorphine(nϭ35)or10mgofEREM(nϭ35)wasgivenviatheepiduralcatheteratthetimeoffascialclosure.Groupallocationwasdoneusingcomputer-generatedrandomnumberallocation.Tomaintainblinding,theEREMandmorphinewerepreparedbythepharmacyinequallysizedsyringesandsecuredinanopaqueenvelop.Thestudydrugswereadminis-teredbyananesthesiologistnotinvolvedinthestudyanddatacollection.Theinvestigatorandallstudystaffremainedblindedtotheassignedtreatment.Theepi-duralcatheterwasremovedaftercompletionoftheCD.

PostoperativeAnalgesicManagement

Allpatientsreceivedibuprofen600mgorallyevery6hforthe48-hstudyperiodwiththefirstdoseadmin-isteredinthepostanestheticcareunit30minaftertheendofsurgery.Breakthroughpainwasmanagedac-cordingtoastrictstudyprotocolflow-sheet(Appendix).Theprimaryoralopioidanalgesicforbreakthroughpostoperativepainwasoraloxycodone5mgwithacet-aminophen325mg(Percocet®,EndoPharmaceuticals,ChaddsFord,PA).IVmorphinewasavailableforseverepainorpainnotrespondingtooralopioidanalgesics.AllotherNSAIDs,cycloxygenase-2inhibitorsandopioidswereprohibitedduringthepostoperativeperiod.

METHODS

StudyDesignandPatientPopulation

AfterIRBapprovalandwritteninformedconsent,70ASA1or2parturientshavinganelectiveCDunderspinalanesthesiawereenrolledinthissingle-center,randomized,double-blindstudy.Patientswereex-cludedfromstudyparticipationiftheymetanyofthefollowingcriteria:morbidobesity(bodymassindexϾ40kg/m2);emergencyCD;significantsurgicalcom-plicationsduringtheoperation;useofgeneralanesthesiafortheCD;historyofsleepapnea;anycontraindicationtoregionalanesthesia;hypersensitivityorpreviousreac-tiontoopioidmedications;historyofchronicopioiduse;orintolerancetoNSAIDs.Inaddition,thestudydrugwasnotadministerediftherewasaccidentalduralpunctureoriflocalanestheticwasadministeredthroughtheepiduralcatheterbeforethestudydrugadministration.Noepiduraltestdosewasadminis-teredtoanyofthestudypatients,asperstudy

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Assessments

AnalgesicEfﬁcacy

Theprimaryefficacyend-pointwasthetotalamountofsupplementalopioidanalgesicmedicationusedinthe48-hpostoperativeperiodaftertheadmin-istrationofthestudydrug.Foranalysis,alldosesoforaloxycodonewereconvertedtoIVmorphinemilli-gramequivalentsusingaconversionratioof20mgoraloxycodoneequivalentto10mgIVmorphine(9).Painintensitywasrecordedatrestandduringactivity(sittingupat90degree)usingaverbalratingscaleforpain(VRSP0–10with0ϭnopainto10ϭworstpainimaginable)atregularintervalspostopera-tively(2,6,12,24,30,36,and48h)bystudyinvesti-gators.TheendoftheCDwastakenastimezero.Patient’soverallratingsofpaincontrol(VRSP0–10)andsatisfactionwithanalgesia(0–100,0ϭtotallyunsatisfiedto100ϭtotallysatisfied)wereassessedat24and48hpost-CD.TheproportionofpatientsrequiringIVmorphineandtheproportionofpatients

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whoreceivednopostoperativeopioidmedicationwererecorded.Inaddition,timetofirstrequestforopioid-analgesicmedicationwasmeasured.

Functionalability(abilitytowalkwithoutassis-tance)wasassessedat24and48hpost-CDbystudyinvestigators.Thetimetofirstbreastfeed,thenumberoftimesthewomanmanagedtobreastfeedineach24hperiod,aswellaswhetherpainlimitedtheparturient’sabilitytobreastfeed(0ϭnotatall,1ϭminimally,2ϭsomewhat,3ϭverymuch,and4ϭunabletodosobecauseofpostoperativepain)weremeasured.Thenumberofsleephours,sleepquality(0–10with0ϭcompletelyunsatisfactorysleepqual-ity,10ϭcompletelysatisfactorysleepquality),andthenumberofawakeningspernightduetopainwererecordedforthefirstandsecondnightpost-CD.ThelengthofhospitalstayfromtheendofCDwasalsomeasured.

SideeffectsandSafetyProﬁle

Sideeffects(nausea,pruritus,andsedation)weremeasuredatregularintervalspostoperatively(2,6,12,24,30,36,and48h).Nauseaandprurituswereassessedusingavisualanalogscale(0–100mmwith0ϭnonausea/pruritusand100ϭworstnausea/pruritusimaginable).Sedationscoreswereassessedusinga5-pointordinalscale:0ϭalert,1ϭoccasionallydrowsy,2ϭfrequentlydrowsy,3ϭsleepybuteasytoarouse,4ϭsomnolentanddifficulttoarouse).Vomitingwasrecordedat24and48hpost-CDasyes/noandnumberofepisodesper24h.Anypatientrequestforeithernauseaorpruritusmedicationwasrecordedat24and48hpostoperatively.Nauseawastreatedwithondanse-tron4–8mgIVfollowedbymetoclopramide10–20mgIVasneeded.Prurituswastreatedwithuptofourdosesofnalbuphine2.5mg.

Respiratoryrateandoxygensaturationwereob-servedbynursingstaffat1-hintervalsbetween1and24hafterdoseandat2-hintervalsbetween24and48hafterdose.Thefollowingdefinitionsofadverseeventswereprovidedinthestudyprotocol:respira-torydepression(respiratoryrateϽ8breaths/min),hypoxicevent(pulseoximeteroxygensaturationonroomairϽ93%),hypotension(Ͼ25%reductioninsystolicbloodpressurefrombaseline),andbradycar-dia(heartrateϽ40bpm).Patientswereconsideredtohaveurinaryretentioniftheywereunabletovoidoriftheyhadbladderdistensionordiscomfort6hafterurinarycatheterremoval.Thetime(hourspost-CD)tourinarycatheterremovalandtheincidenceofurinaryretentionweredocumentedattheendofthestudyperiod.Thedecisiontoremovetheurinecatheterwaslefttotheobstetriciancaringforthepatient.

Hypoxiceventsandrespiratorydepressionweremanagedwithoxygen(nasaloxygenat4L/min).Nal-oxone(in100mcgincrements)wasreservedforrespira-torydepressionunresponsivetooxygenadministration.

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Thenumberofpatientsrequiringsupplementaloxygenand/ornaloxonewasalsorecorded.

StatisticalAnalyses

Thepreviousmulticenterpost-CDstudyfoundthattotal48hpostoperativerescuesupplementalopioidconsumption(inIVmorphinemilligram-equivalents)was25Ϯ21mgintheEREM10mggroupcomparedto47Ϯ34mgintheconventionalepidural5mgmorphinegroup(7).Basedonthesefindings,aprioripoweranalysispredictedthatwerequired35subjectsperstudyarmtodetectaclinicallymeaningful33%reductioninmilligram-morphineequivalentsofopi-oidanalgesicconsumption(Power0.8,PϽ0.05).Analysesweredoneonanintent-to-treatbasisusingallparturientswhometinclusionandexclusioncriteriaandwhoreceivedthestudydrugs.Descriptivestatisticswereusedtosummarizedemographic,out-come,andadverseeventsdata.OutcomemeasuresofinterestbetweenthetwogroupswerecomparedusingStudent’st-testfornormallydistributedvariablesandMann–Whitneytestforcorrespondingnonparametriccomparisons.NormaldistributionwasdeterminedusingQQplotsandtheKolmogorov–Smirnovtest.Associationsamongdiscretevariableswereinvesti-gatedusingPearson’s␹2andFisher’sexacttestwhereappropriate.Longitudinaldataanalyseswereper-formedusingrepeatedmeasuresANOVAtakingtimeasarepeatedmeasure.Sphericityofthecommoncovariancematrixofthetransformedwithin-subjectvariableswastestedusingMauchly’ssphericitytest.UnadjustedunivariatePvaluesarepresentedwhensphericityisvalidandmultivariateWilks’LambdaPvaluesarepresentedwhenthesphericityassumptionisviolated.Kaplan–Meiercurvesandsurvivalanaly-seswerecomputedandcomparedusinglog-ranktestswithSASPROCLIFEREG.AnalyseswereperformedwithMicrosoftExcelandSAS9.1statisticalpackage(Cary,NC)withPϽ0.05consideredstatisticallysignificant.

RESULTS

PatientCharacteristics

Ofthe70randomizedpatients,sevenwereex-cludedfromtheprimaryandsecondaryefficacyanal-ysis.Sixpatientsdidnotreceivethestudydrugduetothefollowingexclusioncriteria:inadequatespinalblockrequiringlocalanestheticadministrationthroughtheepiduralcatheter(twosubjectsinthemorphinegroupandthreesubjectsintheEREMgroup)andonesubjectintheEREMgroupafteraccidentalduralpuncturewiththeepiduralneedle.OnepatientintheEREMgroupwhoreceivedthestudydrugwasexcludedfromanaly-sisduetodeterminationinthepostanestheticcareunitthatthepatientmetexclusioncriteriaofapreviousreactiontoopioidmedications.Nopatientswerelosttofollow-upornoncompliance.Demographicandbaselinecharacteristicsweresimilarbetweentreatmentgroups(Table1).

ANESTHESIA&ANALGESIA

Extended-ReleaseComparedtoConventionalEpiduralMorphineforCesareanDelivery

Table1.BaselineDemographicandObstetricCharacteristicsbyTreatmentGroup

Morphine4mg

nϭ35

Age(years)Height(cm)Weight(kg)Nulliparous

Previouscesarean

34Ϯ5163Ϯ779Ϯ105(14%)26(74%)

EREM10mgnϭ35

34Ϯ5162Ϯ676Ϯ127(20%)29(83%)

analyzedbyKaplan–MeierProduct-Limitsurvivales-timates(Fig.3;log-rankϭ0.48).Firstrequestforsupplementalanalgesiaoccurredatamedian(IQR)of205(810)and215(692)minpoststudydrugadminis-trationintheEREMandmorphinegrouprespectively.FunctionalAbility,Breast-FeedingSuccess,

HospitalStay,andPostoperativeSleepPatternsImportantsecondaryend-pointsareoutlinedinTable4.Postoperativepaindidnotlimitanypatient’sabilitytobreastfeed,andtherewasnodifferenceintimetofirstsuccessfulbreast-feedingintheEREMandmorphinegroupsrespectively(log-ranktestϭ0.65).Therewerenodifferencesinthesleepqualityreportedduringthefirst(Pϭ0.74)andsecondday(Pϭ0.45)post-CD,andnopatientsreportedawakeningsduringthenightduetopain.

SideEffectsandSafety

Therewerenodifferenceinrespecttonausea(Pϭ0.33),pruritus(Pϭ0.79),orsedationscores(Pϭ0.82)overthe48hstudyperiodbetweengroupsusingrepeatedmeasuresANOVA.Wefoundnosignificantdifferencesbetweengroupsintermsoftheincidenceofvomiting(Table5).Therewerenodifferencesbetweenstudygroupsinthetotalnumberofvomitingepisodesperpatient(Pϭ0.50).Antiemeticandanti-puritisuseweresimilarinbothgroups(Table5).Nopatientsexperiencedanyhypotensionorbradycardiarelatedtothestudydrugs.Timetourinarycatheterremovalpost-CDwassimilar(25Ϯ5hand24Ϯ5h)intheEREMandmorphinegroupsrespectively(Pϭ0.281).Thenumberofpatientswithurinaryretentionbetweenthestudygroupswasnotsignificantlydiffer-ent(3patientsintheEREMgroupversus0inthemorphinegroup,Pϭ0.097).

RespiratoryDepressionandHypoxicEvents

Nopatientsineithergrouphadanysignificantrespiratorydepression(respiratoryrateϽ8/min)dur-ingtheentirestudyperiod.Threepatientshadhy-poxicevents(oxygensaturationsϽ93%),onepatientinthemorphinegroupandtwopatientsintheEREMgroup(Pϭ0.607).Thelowestrecordedoxygensatu-rationwas91%.Allhypoxiceventswereatisolatedtimepoints,occurringbetween11and18handresolvedspontaneouslyorwereresponsivetooxygenadministration.NopatientsinthemorphinegroupandtwopatientsintheEREMgroupreceivedpostop-erativesupplementaloxygeninresponsetooxygensaturationsϽ93%(Pϭ0.223).Nopatientineithergrouprequirednaloxonepostoperativelyforrespira-torydepression.

DataarepresentedasmeanϮstdevandnumber(percent).PϭNSunlessstated.Basedontwo-tailedStudent’sttestforcontinuousdataandPearson’s␹2forcategoricaldata.

Table2.TotalSupplementalOpioidAnalgesicConsumptionbyTreatmentGroupPresentedasIntravenousMorphineMilligramEquivalents

Morphine4mgnϭ33

Totalanalgesicuse0–48hours(mg)Analgesicuse0–24hours(mg)

Analgesicuse24–48hours(mg)

17(22)6(11)10(10)

EREM10mgnϭ30

10(17)5(8)4(12)

P-value

0.0370.3930.012

Dataarepresentedasmedian(interquartilerange).Pvalueisbasedontwo-sampleWilcoxon-Mann-Whitneytests.

Alldosesoforaloxycodonewereconvertedtointravenousmorphinemilligramequivalentsusingaconversionratioof20mgPOoxycodoneequivalentto10mgIVmorphineandaddedtoanyintravenousmorphineconsumptiontoderivethetotalsupplementalopioidanalgesicconsumption(9).

AnalgesicEfﬁcacy

AnalgesicConsumption

Therewasastatisticallysignificantreductioninthetotalandsecondday(24–48hafterdose)supplemen-talopioidanalgesicconsumptionbetweenthestudygroups(Table2).Themedian(IQR)ofacetaminophenconsumptionwas2113(3250)mgintheEREMgroupand3250(3900)mginthemorphinegroup(Pϭ0.07).Themajorityofpatients(83%intheEREMgroupand94%inthemorphinegroup)receivedsupplementalanalgesicsduringthe48hstudyperiod(Pϭ0.24betweentreatmentgroups).IVopioidsforsevereorunresponsivepainwererequiredin3%and13%ofpatientsintheEREMandmorphinegroupsrespec-tively(Pϭ0.36).

PainIntensity

Therewasasignificantdecreaseinpostoperativepain(VRSPatrestandduringactivity)intheEREMcomparedtothemorphinegroupoverthe48hstudyperiodafterCD.(Figs.1and2;Pϭ0.033and0.003,respectively).

OverallVRSPandsatisfactionwithanalgesiamea-suredat24and48hafterdoseareoutlinedinTable3.OverallVRSPinthe24–48hpost-CDstudyperiodwaslowerintheEREMcomparedwiththatinthemorphinegroup(Pϭ0.003;Table3).Therewerenodifferencesinthetimetofirstrequestforsupplemen-talpostoperativeanalgesiabetweenthegroupsas

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DISCUSSION

Thisstudydemonstratesthatsingle-doseEREM10mgprovidessuperiorandprolongedanalgesiapost-CDcomparedtoconventionalepiduralmorphine4mg.TheprolongedpharmacodynamicactionofEREM

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Figure1.Painintensityovertime(verbal

ratingscaleforpain(VRSP0–10)atrest)plottedasmeanswithstandarddeviations;Pϭ0.033forEREM(DepoDur)groupversusthemorphinegroup.

Figure2.Painintensityovertime(verbal

ratingscaleforpain(VRSP0–10)duringactivity(sittingup90degree))plottedasmeanswithstandarddeviations;Pϭ0.003forEREMgroupversusthemorphinegroup.

Table3.OverallPainandSatisfactionScores

Morphine4mgnϭ33

OverallVRSP(0–10)0–24h

OverallVRSP(0–10)24–48h

Analgesiasatisfaction0–24h

Analgesiasatisfaction24–48h

2.8(1.8)3.5(1.6)90(20)90(20)

EREM10mgnϭ30

2.3(1.8)2.2(1.7)95(10)95(10)

P-value

0.2310.0030.3200.082

Dataarepresentedasmedian(interquartilerange).Pvaluecomputedfromtwo-sampleWilcoxon-Mann-Whitneytests.

Patient’soverallverbalratingscaleforpain(VRSP0–10)andsatisfactionwithanalgesia(VAS0–100mm,0ϭtotallyunsatisﬁedto100ϭtotallysatisﬁed)wereassessedat24and48hpost-cesareandelivery.

wasdemonstratedbyadivergencebothinpainscoresandanalgesicconsumptiononthesecondpost-CDday.

Areductioninourprimaryoutcomemeasure,supplementalopioidanalgesicconsumption,hasbeenobservedinpreviousEREMstudiesinanumberofsettingsincludingpost-CD,aftertotalhipandkneearthroplastyaswellasafterlowerabdominalsurgery(7,10–12).Inthiscurrentstudy,EREMreducedthesupplementalpainmedicationoverthe48hstudyperiodbyapproximately40%(60%inthe24–48hpost-CDperiod).Thisreductioninanalgesiccon-sumptionissimilartothepreviousphaseIII,multi-center,post-CDEREMstudythatshowedadecreaseinoverallsupplementalopioidusepost-CDofap-proximately50%whencomparingthe10mgEREMandmorphine5mgstudygroups(7).However,inthis

ANESTHESIA&ANALGESIA

180Extended-ReleaseComparedtoConventionalEpiduralMorphineforCesareanDelivery

Figure3.Timetofirstsupplementalanalgesic

useinminutesfromthestudydrugs(mor-phineandEREM)administration(Kaplan–Meiersurvivalcurve;log-rankϭ0.48).

Table4.ImportantSecondaryEndpoints(functionalability,breastfeedingsuccess,sleepdurationandhospitalstay)

MorphineEREM4mg10mgnϭ33nϭ30

Functionalactivity

0–24h†

Functionalactivity24–48h†

Numberofbreastfeeding0–24h‡

Numberofbreastfeeding24–48h‡

Night-timesleep0–24h(hours)

Night-timesleep24–48h(hours)

Lengthofhospitalstay(hours)

17(52%)27(82%)7(3)8(4)4(2)4(1)97Ϯ24

12(41%)*30(100%)8(3)9(4)3(1)4(1)95Ϯ24

P-value

0.540.040.050.060.380.880.97

DataarepresentedasmeanϮstdev,median(interquartilerange)andnumber(percent).*Missingdatafromonepatient.PvaluecomputedfromPearson’s␹2test,two-sampleWilcoxon-Mann-Whitneytestandtwo-sampleStudent’sttest.

†Functionalabilityisnumber(percent)ofpatientsthatcanwalkwithoutassistance.

‡Thenumberofsuccessfulbreastfeedingsineach24hourperiodasreportedbythestudysubjects.Patientreportedtotalnight-timesleepwasmeasuredinhoursandthelengthofhospitalstaywasmeasuredinhoursfromendofsurgery.

Table5.AdverseEventsDuringthe48-hourStudyPeriod

MorphineEREM4mg10mgnϭ33nϭ30P-value

Vomiting0–24h

Vomiting24–48hAntiemetics0–24hAntiemetics24–48hPruritusmedication0–24h

Pruritusmedication24–48h

6(18%)2(6%)8(24%)1(3%)7(21%)3(9%)

8(26%)1(3%)5(17%)0(0%)12(40%)7(23%)

0.460.590.540.330.100.17

Dataarepresentednumber(percent).PvaluecomputedfromFisher’sexacttest.

previouspost-CDEREMstudy,manydifferentpost-operativeanalgesicswereusedandanalgesicmanage-mentprotocolsvariedamonginstitutions,makingprecisecalculationsofanalgesicconsumptiondifficultandpotentiallyunreliable.

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MultimodalanalgesiaandNSAIDshavebeenshowntogreatlyenhanceanalgesicefficacyafterneuraxialmorphineforCD.(3,8,13,14)NSAIDsareparticularlyeffectiveforrelievingvisceralpainofacrampingnaturepost-CD.(14)Inthecurrentstudy,patientsinbothgroupsconsumedsignificantlylessopioidanal-gesicspost-CDcomparedtothepreviouspost-CDEREMstudy.ThiswasprobablyduetotheadditionofNSAIDstothecurrentstudyprotocol.TheadditionoftheNSAIDsinourstudy,however,didnotabolishthedifferenceinanalgesiabetweentheEREMandcon-ventionalepiduralmorphinestudygroupsfoundinpreviousEREMstudiesthatdidnotallowNSAIDsadministration(7,10–12).AlthoughNSAIDsreducedanalgesicconsumptiontheydidnoteliminatetheuseofsupplementaloralopioidsandmostpatientsre-ceivedsupplementalopioidanalgesics.

Althoughallparturientsweregivenequalaccesstosupplementalopioids,patientswhoreceivedtheEREMhadbetterpaincontrol,bothatrestandduringactivity,especially24–48hpost-CD.Thisanalgesicadvantageisconsistentwiththepreviouspostopera-tiveEREMstudies(7,10–12);however,thepainscoresinthiscurrentstudywerelowercomparedwiththoseinthepreviouspost-CDEREMstudy(7).Improvedanalgesiainthecurrentpost-CDstudywasprobablyduetotheadditionofNSAIDs.Theprolongedanal-gesiceffectwasnotattheexpenseofasloweronset,andtherewerenodifferencesinthetimetofirstrequestforanalgesia.

Inassessingtheimpactofpainondailyfunctionpost-CD,weevaluatedanumberofsecondaryout-comesincludingmaternalfunctionalability,lengthofhospitalstay,andsleep.Similartothepreviouspost-CDEREMstudy,functionalactivitywasimprovedinthesecondpost-CDday(7).Althoughsuperiorpostopera-tivepaincontrolhasbeenassociatedwithashorterhospitalstay(15,16),wedidnotfindthatimprovedpaincontrolandfunctionalabilityresultedinashorterhospitalstay.However,wedidnotdeterminewhenpatientswereclinicallyreadyfordischargeandexter-nalfactors,includinginfantcare,insurancecoverage,

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homesituation,andavailabilityoftransportationmayhavehadagreaterimpactonthelengthofhospitalstaythansurgicalrecovery.Paincanaffecttheabilitytosleepandleadtofrequentnight-timeawakenings(16,17).Lackofsleepcanaffectdaytimefunctioningandmaternal–infantinteraction.Thepost-CDperiodisverydisruptivetosleeppatterns;however,wedidnotfindanydifferenceinmaternalsleeppatternsbetweenthestudygroups,despitesuperiorprolongedanalgesiaintheEREMgroup.Previousstudieshaveshownthatinfant-careandbreast-feedingsuccesscanbeimprovedbysuperiorpostoperativeanalgesia(18–20).Therewasatrendtowardsmoresuccessfulbreast-feedingsintheEREMgroup,butnopatientineitherstudygroupreportedthatpostoperativepainlimitedtheirabilitytobreastfeed.

EREMwaswelltolerated,andwefoundnosignifi-cantdifferencesintheincidenceofadverseeventsbetweenthestudygroups.Theadverseeventspro-filedweretypicalofepiduralopioidsandweresimilarwhencomparedtothepreviouspost-CDEREMstudy(7).AlthoughtheEREMgroupreceivedmoreepiduralmorphine,theconventionalmorphinegrouptookmoresupplementalopioids.Giventhatopioidsbyanyroute(oral,IV,epidural,orintrathecal)havesimilaradverseevents,itisnotsurprisingthatwefoundnodifferencesinthesideeffectprofiles.ItisinterestingtonotethattheconventionalmorphinegroupdidnottakeenoughsupplementalopioidstotreattheirpaintothesamedegreeastheEREMgroup,perhapsbecausepatientslimittheiranalgesicconsumptionsecondarytoadverseeventsorbecausethestudypost-CDanalgesicprotocolwastooconservativetoallowpatientsenoughopioidstomatchtherelativeanalgesicefficacyofEREMcomparedtoconventionalmorphine.

Therewerenosignificantrespiratorydepressionorhypoxiceventswiththedosagesusedinthisstudy.Unlikeinthepreviouspost-CDEREMstudy,wemonitoredmaternaloxygensaturationspost-CD.Thismayhaveallowedustobetteridentifythepatientsatriskforopioid-relatedrespiratorydepression.How-ever,inkeepingwithfindingsfromthepreviouspost-CDEREMstudy(7),weencounterednosignifi-cantproblemswithrespiratorydepression.Theover-allprevalenceofpostoperativerespiratorydepressionattributabletoneuraxialopioidadministrationisverylow(21),andneuraxialopioidshavealongsafetyrecordinthepost-CDsetting.Theyoung,healthy,obstetricpopulationisideallysuitedtoreceivesustained-releaseneuraxialopioids,becausepostoperativerespi-ratorydepressionislesslikelycomparedtootherpostsurgicalpopulations.However,althoughweob-servednosignificantrespiratorydepression,thisstudywasnotprimarilydesignedtoassessdifferencesinadverserespiratoryeventsbetweentreatmentgroups,andfuturestudiesinvolvinglargercohortsofpatientsareneededtoadequatelyaddressthisissue.

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Althoughwedidnotidentifyanysafetyconcernsamongourstudypatients,werecommendcarefulpostoperativerespiratorymonitoringandmanagementprotocolswhenusinganyneuraxialopioid,especiallyEREM.Therewerenocomplicationsfrominadvertentintrathecaladministration,butthereisthepotentialofaccidentallyadministeringalargedoseofEREMintrathecally,andadequateprotocolsandfacilitiesfortreatingsuchacomplicationshouldbeavailable.Wedidnotuseanyepidurallocalanesthetics,includingalidocainetestdosebeforeadministrationofEREM.Earlypharmacokineticstudiesindicatedthattheremaybeapotentialphysicochemicalinterac-tionwithEREMandepidurallocalanestheticsthatmayreducethesustained-releasederivedfromtheDepoFoam.However,arecentstudybyGamblingetal.(22)demonstratedsimilarEREMpharmacokineticsandpharmacodynamicswhenEREMwasadminis-tered15,30,and60minafterepiduralbupivacaine0.25%.Untilfurtherdataareobtained,wewouldrecommendfollowingthepackageinsertrecommen-dation,whichstatesthatlocalanestheticsotherthana3mLtestdoseoflidocainearenotpermittedandthatifthe3mLtestdoseisused,theepiduralcathetershouldbeflushed,afterwaiting15min,with1mLofsalinebeforeadministrationofEREM.

Apotentiallimitationofthestudyisthedoseselec-tionforanalgesicefficacycomparisonandadverseeventsprofiling.Weselecteda10mgEREMdosebasedondatafromthepreviouspost-CDEREMstudy.Inthatstudy,thereappearedtobeananalgesicceilingatapproximately10mg,withlittleaddedbenefitbeyondthisdose(7).Anactivecontrolof4mgepiduralmor-phinewaschosenbasedonastudybyPalmeretal.(23)thatdemonstratedananalgesicceilingatapproximately3.75mgofepiduralmorphinepost-CD.Theequianalge-sicdosesofEREMandconventionalmorphineinthepost-CDsettingarenotknown.Analgesicefficacyandadverseeventsareoftendose-related,andthehigherdosesofneuraxialopioidsmayincreaseadverseevents(24).However,giventhattheEREMandconventionalmorphinehadsimilaranalgesicefficacyandsideeffectprofilesinthefirst24h,webelieveweuseddosesthatwereapproximatelyequianalgesic.

AnotherpotentiallimitationistheuseofbothoralandIVopioidsforbreakthroughanalgesia.Thispro-tocoldesignallowedthestudytobeconductedunderconditionsreflectingcurrentpost-CDmanagement.WelimitedpatientstoonlyoneoralopioidandusedastandardizedconversiontoIVmilligram-morphineequivalents(9).Inaddition,veryfewpatientsrequiredIVmorphine,andthusthemajorityofthesupplemen-talanalgesicswereoxycodone.ThissuggeststhatdifferencesinopioidconsumptionfoundinthestudywereprobablyrelatedtoanalgesicefficacydifferencesbetweenEREMandconventionalepiduralmorphine.Inconclusion,thisnovelformulationofsingle-doseEREMdecreasedtheneedforsupplementalanalgesicsandimprovedpost-CDpaincomparedwiththatof

ANESTHESIA&ANALGESIA

Extended-ReleaseComparedtoConventionalEpiduralMorphineforCesareanDelivery

Appendix1.PostoperativePainManagementStudyProtocol

VerbalPainScore1–3

੬Percocet(5/325)1tabq4hrprn

®VerbalPainScoreϾ3–7

੬Percocet(5/325)2tabsq4hrprn