Oral oxycodone for pain after caesarean section : A randomized comparison with nurse-administered IV morphine in a pragmatic study

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http://www.diva-portal.org

This is the published version of a paper published in Scandinavian Journal of Pain.

Citation for the original published paper (version of record):

Niklasson, B., Arnelo, C., Georgsson Öhman, S., Segerdahl, M., Blanck, A. (2015)

Oral oxycodone for pain after caesarean section: A randomized comparison with

nurse-administered IV morphine in a pragmatic study.

Scandinavian Journal of Pain, 7: 17-24

http://dx.doi.org/10.1016/j.sjpain.2015.01.003

Access to the published version may require subscription.

N.B. When citing this work, cite the original published paper.

This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/

by-nc-sa/4.0/).

Permanent link to this version:

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ContentslistsavailableatScienceDirect

Scandinavian

Journal

of

Pain

j o u r n al ho me p ag e :w w w . S c a n d i n a v i a n J o u r n a l P a i n . c o m

Clinical

pain

research

Oral

oxycodone

for

pain

after

caesarean

section:

A

randomized

comparison

with

nurse-administered

IV

morphine

in

a

pragmatic

study

Boel

Niklasson

a,b,∗

_,

_Catarina

_Arnelo

a

_,

_Susanne

_Georgsson

_Öhman

b,c

_,

Märta

Segerdahl

d

_,

_Agneta

_Blanck

a

a_Department_of_Clinical_Science,_Intervention_and_Technology_(CLINTEC),_Division_of_Obstetrics_and_Gynecology,_Karolinska_Institute_at_the_Karolinska

UniversityHospital,Huddinge,14186Stockholm,Sweden

b_Sophiahemmet_University,_Box_5605,₁₁₄₈₆_Stockholm,_Sweden

c_Department_of_Women’s_and_Children’s_Health,_Karolinska_Institute,_Solna,₁₇₁₇₇_Stockholm,_Sweden d_Department_of_Physiology_and_{Pharmacology,}_Karolinska_Institute,₁₇₁₇₇_Stockholm,_Sweden

h

i

g

h

l

i

g

h

t

s

•OralOXY–betterpost-caesareansectionpaincontrolvs.nurse-administeredi.v.morphine/oralcodeine. •OralOXY–lessopioidconsumptionwithoxycodonevs.i.v.morphine/oralcodeine.

•OralOXY–lesstimeconsumingthangivingi.v.morphineduringtheﬁrst24h. •Bothtreatmentprotocolsaresafeforboththemotherandthenewborn.

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received26October2014

Receivedinrevisedform7January2015 Accepted9January2015

Availableonline14February2015 Keywords: Postoperativepain Multimodaltreatment Oxycodone Caesareansection Codeine Newborn

a

b

s

t

r

a

c

t

Backgroundandaims:Thepresentrandomizedopenlabelparallelgroupstudywasconductedto eval-uateifanoraloxycodone(OXY)regimencanbeatleastequallyeffectiveandassafeforpostoperative analgesiaaftercaesareansection(CS)asastandardofcareprogramusingnurse-administeredintravenous morphine(IVM),followedbyoralcodeine.

Methods:Eightywomen(40+40)werescheduledforelectiveCSunderspinalanaesthesia.Allpatients receivedpostoperativemultimodalanalgesictherapy,includingibuprofenandparacetamol.TheOXY groupgotstandardizedextendedreleaseandshortactingoraltreatment(andinafewcasesintravenous OXY)asneededandtheothergroupreceivedcurrentstandardofcare,IVMasneededfor24h,followedby codeine.Opioidtreatmentlastedmaximumﬁvedays.Outcomemeasureswerepainintensity (numer-icalratingscale,NRS),opioidrequirements,durationofadministeringopioidsandsafetyformother andnewborn.AllopioidsinthestudywereexpressedinOXYequivalents,usingaconversiontable.As thebioavailabilityofeachopioidhasacertainextentofinterindividualbioavailabilitythisconversion representsanapproximation.Thepossibleinﬂuenceofopioidsonthenewbornswasevaluatedbythe NeurologicalAdaptiveCapacityScoreatbirthandat24and48h.

Results:Duringthefirst24h,therewerenodifferencesbetweentreatmentsinopioidrequirements ormeanpainintensityatrestbutpainintensitywhenaskingforrescuemedicationwaslowerinthe OXYthanintheIVMgroup(mean±SD;5.41±6.42vs.6.42±1.61;p=0.027).Provokedpain(uterus palpation)duringthefirst6hwasalsolessintheOXYgroup(3.26±2.13vs.4.60±2.10;p=0.007). Duringthe25–48hperiodpostoperatively,patientsonOXYreportedsignificantlylowerpainintensity atrest(2.9±1.9vs.3.8±1.8;p=0.039)andconsumedlessopioids(OXYequivalents;mg)(31.5±9.6 vs.38.2±38.2;p=0.001)thanthoseonIVM/codeine.Thetotalamountofopioids0–5days postopera-tivelywassignificantlylowerintheOXYthanintheIVM/codeinegroup(108.7±37.6vs.138.2±45.1; p=0.002).DurationofadministeringopioidswassignificantlyshorterintheOXYgroup.Timetofirst spontaneousbowelmovementwasshorterintheOXYgroupcomparedwiththeIVM/codeinegroup.No

DOIofreferstoarticle:http://dx.doi.org/10.1016/j.sjpain.2015.01.007.

∗ Correspondingauthorat:CLINTEC,DivisionofObstetricsandGynecology,KarolinskaInstituteattheKarolinskaUniversityHospital,Huddinge,14186Stockholm,Sweden. Tel.:+46858580000.

E-mailaddress:boel.niklasson@ki.se(B.Niklasson). http://dx.doi.org/10.1016/j.sjpain.2015.01.003

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18 B.Niklassonetal./ScandinavianJournalofPain7(2015)17–24

seriousadverseeventswererecordedinthemothersbutthetotalnumberofcommonopioidadverse effectswashigheramongwomenonIVM/codeinethanamongthosereceivingOXY(15vs.3;p=0.007). Noadverseoutcomesinthenewbornsrelatedtotreatmentwereobservedineithergroup.

Conclusions:InamultimodalprotocolforpostoperativeanalgesiaafterCSbetterpaincontrolandlower opioidintakewasobservedinpatientsreceivingoralOXYascomparedtothoseonIVM/codeine.Nosafety risksformotherandchildwereidentiﬁedwitheitherprotocol.

Implications:OurﬁndingssupporttheviewthatuseoforalOXYisasimple,effectiveandtimesaving treatmentforpostoperativepainafterCS.

1. Introduction

Postoperativepaintreatmentinwomenundergoingcaesarean section(CS)needstobeeffectivetoenablefastandsmooth recov-erywithoutadverseoutcomesandtoimprovebreastfeedingand bondingbetweenmotherandchild.Itisalsoimportantthatpain treatmentshouldhaveminimalimpactonthenewborn[1].

Inspiteofthis,ineffectivepostoperativepaintreatment regi-mens are common[2,3]. Thereis a lack of guidelines for post caesareanpainmanagement,notonlyinSwedenbutalsoinmany othercountries,eventhoughneuraxialblockadeincombination withnon-opioids hasbeen suggested as goldenstandard [3,4]. Patientcontrolledanalgesia(PCA)withmorphine hasalsobeen usedforpostoperativepaincontrol[5].However,i.v. administra-tionofmorphinetowomenafterCSismostlyusedforashortperiod oftimeandthePCA-deviceitselfmightcausesomepractical incon-venienceforthemother.Alsoweakopioidsarestillcommonplace intheprolongedpostoperativeperiod,codeine+paracetamoloften beingthestandardofcareaftersurgeries[6].Multimodal postop-erativepaintreatmenthasbeenshowntobemoreeffectivethan monotherapy[7,8].Manyadvantagescanbeidentiﬁedwithoral medication,includingsimplicity,timesavingvs.i.v.medicationand makesthepatientmoreindependent[9].

Overall,orallow-techtreatmentregimensarepreferred,bothby patientsandwardstaff,buttheyneedtobeefﬁcientwithagood safetyproﬁleandallowforpatientstoambulatefreely.

Theprecursordrugcodeinemaybeproblematictorelyonfor efﬁcacy.Theanalgesiceffectofcodeineisattributedtothe indi-viduals’abilitytoconvertcodeinetomorphineviaCYP2D6.The CYP2D6genotypehasthreeimportantphenotypes:rapid(normal), slowandultrarapidmetabolizers.Thelatterwillhaveamarkedly higherexposuretomorphine[10,11].Thegeneticpredisposition foreitherphenotypehasconsiderablevariabilityduetoethnicity, whichmakesstandardizationoftreatmentregimenschallengingin amixedethnicpopulation.

Recentcasereportsaddressneonatalsafetyconcerns, includ-ing death, when the mother has been taking codeine for a prolongedperiod of time [12,13]. Using oral morphine instead ofcodeinewould reduceinter-individualvariation inexposure. Another option is to use oral oxycodone, which has a higher andmorepredictableoralbioavailability(67–80%)thanmorphine (19–47%)[14,15].SubstitutingcodeinewithoralOXYcan there-forebeexpectedtofurtherreducethevariationinbioavailability andanalgesiceffect[15,16].Seatonetal.studiedtowhatextent OXYpassesintobreastmilk,butonlyafewvariablesconcerning thechildwerereported[17].Thestandardmultimodaltreatment followingCSinourdepartmenthasincludedintravenous(i.v.) mor-phine(IVM), which after24hwassubstituted byoral codeine. Theethnic composition ofpatients inour departmentincludes groupswithhighprevalenceofslowmetabolizersaswellasgroups withhighprevalenceofultra-rapidmetabolizers,whichputshigh demandsonastandard ofcare thatissafeand efficientforall. Wehypothesizedthat astandardized multimodalpostoperative analgesicregimenforthefirstfivepostoperativedaysincluding

apotentopioid,OXY,wouldbeatleastaseffectivewithregardto painandtotalopioidrequirementasIVM/oralcodeinewhengiven asadjuncttoparacetamol+ibuprofen.Further,wehypothesized thatthisregimenwouldimprovepatientoverallsatisfaction with-outjeopardizingmaternalorneonatalsafetyintermsofrecognized opioidrelatedadverseeffects.

2. Materialsandmethods

Thepresentrandomizedopenparallelgroupstudyinwomen undergoingplannedCSwasapprovedbytheRegionalEthics Com-mitteeinStockholm,Sweden(2010/1062-31/1)SwedishMedical ProductsAgency(151:2010/42559)andEudra-CT(2010-018450). Healthy women, 18–50 years old, plannedfor CS from 38 full weeksofgestation,havingtheintentiontobreastfeed andwho hadsufﬁcientunderstandingoftheSwedishlanguage,were eligi-bleforinclusion.Exclusioncriteriaincluded:ongoingparticipation inanotherclinicaltrial,treatmentforchronicpain,drugabuse, mentalillness,patientstreatedwithantidepressants,known intol-eranceorallergytowardsanyofthestudydrugs,maternaldisease that could affect pregnancy and foetal complications e.g. large for gestational age or intrauterine growth retardation. Eighty healthy women who met the inclusion criteria were recruited from November 2010 to August 2012 at Karolinska University Hospital,Sweden.Afterobtainingverbalandwritteninformed con-sentpatientswererandomizedusingacomputer-basedprogram, in blocks of twenty. Each randomization number had a corre-sponding sealed-opaque envelope, containing study treatment information.Envelopesforeachpatientweredrawnsequentially fromasealedbox.Thedesignatedenvelopewasopenedtheday before CS by one of the investigators. The correct medication was prepared and ordained in the patient’s records. An open labeldesign was chosen forethical reasons,since we also col-lectedsamplesforanalysesofOXYexposurebutchosenottodo soformorphine/codeine. A timelinedescribesthestudydesign (Fig.1).

2.1. Studytreatment

2.1.1. Treatmentcommonforbothgroups

Onehourpreoperativelypatientsreceived2goralparacetamol (Alvedon®_,_AstraZeneca,_Sweden)_as_a_bolus_dose_according_to_local

routines.Spinal anaesthesia wasadministered using 1.8–2.6ml (body heightdepending) bupivacaine (Marcain Tung® ₅_mg/ml,

AstraZeneca, Sweden) plus 15␮g (0.3ml) fentanyl (Fentanyl®

50␮g/ml,MedaAB,Sweden)througha27GSprouttespinalneedle atL2–L3orL3–L4withthewomaninsittingposition. Immedi-atelyaftersurgery,beforeleavingtheoperatingroom,allpatients received oral ibuprofen 400mg (Brufen®_, _Abbott _{Laboratories,}

Sweden).Duringtherestofthehospitalstay,andlongerifneeded, allpatientscontinuouslyreceived200mgibuprofenevery6h.Oral parafﬁnemulsion(30ml)wasgiventwicedailytodiminish consti-pation.

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Oxycodone group

Intravenous morphine/codeine

group

24 hours

12 hours

36 hours

48 hours

CS

Intravenous morphine +ibuprofen/paracetamol Ibuprofen/paracetamol+codeine Ibuprofen/paracetamol

5 mg C. OxyNorm or i.v. OxyNorm if needed Ibuprofen/paracetamol

5 mg C. OxyNorm or i.v. OxyNorm if needed

Ibuprofen/paracetamol 5 mg C. OxyNorm if needed Ibuprofen/paracetamol 5 mg C. OxyNorm if needed T. OxyConn 20 mg T. Ibuprofen 400 mg T. Ibuprofen 400 mg NACS 1 NACS 1

1

= Paracetamol 2 g NACS 2 NACS 2 NACS 3 NACS 3

2

= Telephone interview 5 days pp. OXY group = T. OxyConn max 5 days + ibuprofen/paracetamol as long as needed IVM/Codeine group =

paracetamol/codeine/ibuprofen max 5 days + ibuprofen and paracetamol as long as needed

3

= Telephone interview 10 days pp. Some women in both groups sll on paracetamol and ibuprofen T. OxyConn 10 mg

T. OxyConn 10 mg T. OxyConn 10 mg T. OxyConn 10 mg

2

3

1

T (tablets) C (capsules) PP (postpartum)

NACS (neurologial adapve capasity score)

Fig.1. Timeline.

2.1.2. Postoperativetreatment–oxycodonegroup

Before leaving the operating room, women received 20mg longactingOXY(OxyContin®_,_Mundipharma,_Sweden)._Thereafter,

10mgOxyContin®_was_given_every₁₂_h_for_minimum₄₈_h._Rescue

medicationwasgivenasanoraldoseof5mgimmediaterelease OXY(OxyNorm®_,_Mundipharma,_Sweden)._In _the_case _of_severe

breakthroughpain,1–5mgofi.v.OXY(OxyNorm®_,_Mundipharma,

Sweden);10mg/ml,1mldilutedwith9mlsalinesolution (Natri-umklorid9mg/ml,Fresenius,Sweden)weregiven.Occasionally, shortactingOXY wasgivenbeforemobilization. Allpatientsin thisgroupreceived1goralparacetamolevery6huntildischarged, longerifneeded.

2.1.3. Postoperativetreatment–intravenousmorphine/codeine group

For24h,morphine(MorﬁnMEDA®₁₀_mg/ml,_MEDA,_Sweden),

diluted in saline (Natriumklorid 9mg/ml, Fresenius, Sweden) wasnurse-administered byslowi.v.injectionuntilanadequate response, NRS<4/10, was obtained (if more than 10mg the responsiblephysicianwascontacted).After24h, morphine and paracetamol were substituted by a combination treatment of paracetamol 500mg plus codeine30mg (Citodon®_, _BioPhausia,

Sweden),twotabletsevery6hforuptoatleast48h. 2.1.4. Postoperativedaysthreetoﬁve

Upondischarge,approximately 48hpostoperatively, women receivedoralanalgesicsforuptoﬁvedayspostoperatively.Women intheOXYgroupreceived10mgOxyContin®_,_six_tablets,_to_take

asneeded,twicedaily.WomenintheIVM/codeinegroupreceived

Citodon®_,_maximum_dose_eight_tablets_per_day._All_patients_were

recommendedtocontinuewithparacetamol/ibuprofenwhen opi-oidswerenolongerrequired.IntheIVM/codeinegroup,Citodon®

wasreplacedbyparacetamol. 2.2. Painassessments

PatientsreportedtheirpresentpainintensityonaNumerical RatingScale(NRS)(0–10,where0depicts“nopain”and10“worst painimaginable”).Painatrestwasassessedeveryhourfor6hand thereafteronceeveryworkingshift(morning,afternoonandnight) duringthehospitalstay.Provokedpain(duringuteruspalpation performedbytheresponsiblemidwife)wasevaluated6times dur-ing0–24hpostoperatively.Further,painwasassessedatrequest forrescuemedication(maximumpain).

2.3. Mobilization

Three steps of postoperative mobilization were recorded: the woman standing next to the bed, walking in the room for the ﬁrst time and being fully mobilized, i.e. back to circumstantially normal activities. Women received additional medicationbeforemobilizationifneeded.Earlymobilizationwas encouraged.

2.4. Opioidrequirements

Opioidconsumptionwasrecordedandaccumulatedfor0–24 and25–48haswellasforthewhole5-daypostoperativeperiod.

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Table1

Conversionratesforopioidsusedinthepresentclinicaltrial.

Drug Parenteral(mg) Oral(mg)

Codeine NA 200

Morphine 10 30

Oxycodone 10 20

AdaptedaccordingtoMcPherson[18].

AllopioidswereconvertedtooralOXYequivalentsaccordingto Table1[18].

2.5. Safetyvariables

Sideeffectsofopioidexposureinthemotherswererecorded basedonspontaneousreportingandopenquestions.Signsof sur-gicalsiteinfections(SSI)wererecordedandtreatedaccordingto clinicalroutines.Inthenewborns,birthweightandweight devel-opmentwererecorded.Atdelivery,Apgarscoresat1,5and10min wererecordedandumbilicalcordbloodwascollectedforacid–base analyses.Allnewbornswereevaluatedbyoneofthetwoauthors (BNorCA)familiarwiththeNeurologicalandAdaptiveCapacity Score(NACS)method[19].Thefirstevaluation,30minafter deliv-ery,wasusedasbaseline.NACSwasthenassessed24 and48h postpartum,todetectpossibleneurologicalsymptomsdueto opi-oidexposure.NACSisbasedon20criteriainfivegeneralareas: adaptivecapacity,activeandpassivetone,primaryreflexesand generalobservations(motoractivity,alertnessandcrying).Each itemisscoredas0,1or2,addinguptoamaximaltotalscoreof 40.Scores≥35indicatesahealthynewborn.Othervariables,e.g. increasedbilirubinoutsidethenormalrange,needforadditional feedingandadmissiontotheneonatalintensivecareunit(NICU) werealsorecorded.

Maternalserumand breastmilksamplesforanalysisofOXY anditsmetaboliteswerecollectedat24(±4)and48(±4)h post-operatively.Serumsamplesfromthenewbornsweretakenonlyat 48(±4)h,whensamplesforroutineneonatalscreeningwerealso secured.Thesedatawillbepublishedelsewhere.

2.6. Follow-up

Onthedayofdischarge,allwomencompletedaquestionnaire concerningtheirpainexperience.Questionsrelatedtosatisfaction withpainrelief,staffsacceptanceofanalgesicrequirement, under-standingofinstructionsregardingpaintreatmentand,ifapplicable, theirpostoperativepaincomparedtopreviousCS.

Onpostoperativedayﬁve,oneoftheinvestigators(BNorCA) contacted the women via telephone to determineopioid con-sumptionsincedischarge.Tendayspostoperativelyastructured follow-uptelephoneinterviewwasperformed.Womenwereasked iftheystillexperiencedpainandinthiscasethelocationandtype ofpain.Theywereaskedwhentheyendedintakeoriftheystill requiredanalgesics.Questionsalsoincludedpaininterferencewith dailylife,generalpostoperativerecovery,perceptionofundergoing aCSandofthegeneralcarereceived.

2.7. Collectionofdata

Demographics and medical data, except pharmaceutical records,werecollectedfromthecomputerbasedpatientrecord systemObstetrixTM _(Siemens,_Sweden)._Data_concerning

admin-istrationofdrugsweresecuredfromthecomputerbasedpatient chartsystemTakeCareTM_(CompuGroup_Medical,_Sweden)._The

pri-marydatacollectedwere:woman’sage,weightandbody mass index(BMI)atthetimeofsurgery,indicationforCS,parityandany

previousCS.Alldatawerecodiﬁedandmadeanonymousbefore dataentry.

2.8. Nursingaspects

Allmidwivesinthematernitywardrecordedthetimespent administering analgesics (from time of request, preparing and administeringthedrugandevaluatingtheeffect).Thenumberof occasionswhenpatientsrequiredsupplementarypainreliefand totaltimespentwererecorded.

2.9. Statisticalanalysis

Theprimaryoutcomevariablewaspainatrestduringthe48h postoperativeperiod. Main secondary variablewas total opioid requirementsduring days 0–5. Othersecondary variables were numberofrequestsforrescuemedication,painuponrequestfor rescuemedication,timetomobilization,patientsatisfactionand time to ﬁrst defecation.Exploratory variables includedtime to administer analgesics and midwife global impression. Neonate safety variables included NACS, weight development and any aberrant observations regarding thenewborns. Maternal safety variablesincludedSSIandspontaneousreportandopenquestions regardinganyadverseeffects.

ThestatisticssoftwareIBMPASWStatistics,version18.0,was usedtoanalysedifferencesbetweengroups.Two-tailedStudent’s t-testwasused whencomparingNRS, opioid consumption and safetyvariables.Fordemographicdata,interviewsand question-nairesthePearson’sChi-Squaretestwasused.Alevelofp≤0.05 wasconsideredsigniﬁcant.

3. Results

Eightypatientswererandomizedandthreepatientswere with-drawnbeforestudytreatmentduetofailedspinalblock,twointhe OXYgroupandoneintheIVM/codeinegroup(Fig.2).Therewereno signiﬁcantdifferencesbetweengroupsindemographicparameters (Table2).

3.1. Painintensity

Meanpain at restwassigniﬁcantly lowerin theOXYgroup at0–6h,25–48handwhenaskingforrescuemedication0–24h. Whenevaluatingthewhole0–24hperiodnosigniﬁcantdifference

Table2

Demographics.

Demographic OXYgroup

n=38

IVM/codeinegroup n=39

Age(years),median(range) 33.5(23–42) 34.0(21–44) Gravidamedian(range) 2.5(1–6) 3(1–6) Paritymedian(range) 1(0–4) 1(0–3)

Primiparas n=11 n=8

Multiparas n=27 n=31

Previouscaesareansection, median(range)

0.5(1–4) n=19

0.5(1–3) n=22 Previousabdominalsurgery

(includingCS),median (range) 1(1–4) n=19 1(1–4) n=25 Bodymassindex(BMI),

median(range) 29.5 (22.3–43.7) 29.0 (24.2–52.5) Educationa Compulsoryschool n=1 n=1

Seniorhighschool n=11 n=17

University n=23 n=20

Postgraduate n=2 n=1

Missing n=1 n=0

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Fig.2. Flowchart.

betweengroupswasobserved.Provokedpain(uteruspalpation) wassigniﬁcantlylessintheOXYgroupduringtheﬁrst6h(Table3). 3.2. Opioidrequirements

Therewerenosignificantdifferencesin opioid consumption duringthefirst24hpostoperatively.However,duringthe25–48h periodandfrom49huntil5dayspostoperativelytherewas sig-nificantlylessopioidconsumptionintheOXYgroupthaninthe IVM/codeine group (Table 4). The need for rescue medication during thefirst 24h wasless frequent in the OXYthan in the IVM/codeinegroup(Table3).Asastandardizedconversiontable wasusedforopioidcalculationsthesedatatosomeextent repre-sentanapproximation.

3.3. Postoperativerecovery

There was no difference in mobilization between groups. WomenintheOXYgrouphadasigniﬁcantlyshortertimeperiod untilﬁrstbowelmovement(Table5).

Table3

Pain(NRS)atrest,maximumpain,provokedpainandnumberofrescuemedications.

Variable OXYgroup n=38 IVM/codeinegroup n=39 pvalue Painatrest 0–6h 3.80±1.52 4.96±1.49 0.002 0–24h 3.43±1.74 3.93±1.30 n.s. 25–48h 2.89±1.88 3.80±1.83 0.039

Provokedpain(uteruspalpation)

0–6h 3.26±2.13 4.60±2.10 0.007

0–24h 5.98±2.13 6.62±2.02 n.s.

Maximumpainintensity(whenaskingforrescuemedication)

0–24h 5.41±2.17 6.42±1.61 0.027

Numberofrescuemedications

0–24h 4.3±3.6 8.4±11.7 0.047

Alldataareshownasmean±SD(Student’st-test,p≤0.05wasconsidered signiﬁ-cant).

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Table4

Amountofopioidsinoxycodoneequivalents(mg).

OXYgroupn=38 IVM/codeinegroupn=39 pvalue

0–24h 49.5±20.1 45.4±24.2 n.s.

25–48h 31.5±9.6 38.2±11.6 0.001

49h–5days 27.7±15.5 54.7±26.1 0.001 0–5days 108.7±37.6 138.2±45.1 0.002 Alldataareshownasmean±SD(Student’st-test,p≤0.05wasconsidered signiﬁ-cant).

Table5

Variablesrelatedtopostoperativemobilization. Variable OXYgroup

n=38

IVM/codeine group n=39

pvalue

Standnexttothe bed(h) 9.6±4.9(4–25) 11.9±6.2(5–26.5) n.s Walkingaround withhelp(h) 16.8±9.1(5–47) 20.1±8.4(5–44) n.s. Fullymobilized(h) 24.3±11.4(5–53) 30.6±17.7(5–67) n.s. Firstbowel movement (postopday) 2.9±1.4(1–7) 3.6±1.2(1–6) 0.038 Dischargefrom hospital(postop day) 2.4±0.6(2–3) 2.4±0.6(2–5) n.s.

Alldataareshownasmean±SD(range)(Student’st-test,p≤0.05wasconsidered signiﬁcant).

3.4. Telephoneinterviewattendays

WomenintheOXYgroupreportedpaintobelessofanobstacle thanwomenintheIVM/codeinegroup(79%vs.51%).On postopera-tiveday10,analgesicsrequirementswerelowandsimilarbetween groups(Table6).

3.5. Safetyvariables

Maternal:ThereweretwoSSIs reportedineachgroup.Three womenintheOXYgroupreportedadverseeffects(0–24h)vs.15 womenin theIVM/codeinegroup(p=0.007).In theOXYgroup threewomenfeltdizzinesswhenreceivingi.v.injectionsofOXY. IntheIVM/codeinegroupthefollowingsymptomswerereported: dizziness(n=9),nausea(n=4),beingtired(n=1)anditching(n=4). Neonates:ApgarscoresandumbilicalcordpHwerenormalin allbutthreenewborns.

Thesethreenewborns(twointheOXYandoneintheIVMgroup) hadacidosis(pH<7.20)and wereadmittedtotheNICUalready attheNACSbaselineassessment.Allthreedevelopedpulmonary adaptationsyndrome(PAS).OnenewbornfromtheIVMgroupwas admittedtotheneonatalwardwhen24hold,alsoduetoPAS.Forall mothers,treatmentcontinuedaccordingtoplan.Nonewbornswith signsofopioidexposurewereidentiﬁed.Nosigniﬁcantdifference inweightlosswasrecorded(Table7).

3.6. Patientglobalimpression(PGI)

IntheOXYgroup,16/19womenwithpreviousCSexperience, judgedthepresentoccasiontobelesspainful,whilethreejudged itassimilar.IntheIVM/codeinegroup,11/20womenwith previ-ousCSjudgedpainasless,eightjudgeditassimilarandoneas worsethistime.Tenwomen(fourintheOXYgroupandsixinthe IVM/codeinegroup)reportedunsatisfactorypainrelief.Despitethis allwomentoldthattheygainedsupportfortheirreportedneedfor painrelief.

Table6

Telephoneinterview10dayspostoperatively.

Variable OXYgroup (n=38) IVM/codeinegroup (n=39) pvalue Wellbeing Verygood/good 38(100%) 35(87%) n.s. Lessgood/bad 0 4(13%) Scarpain Yes 3(8%) 7(18%) n.s. No 23(60%) 19(49%)

Onlywhenmoving 12(32%) 13(33%)

Stillonpainmedication

Yes 13(34%) 14(36%) n.s.

No 18(48%) 15(38%)

Onlyoccasionally 7(18%) 10(26%)

Haspainbeenanobstacleinyoureverydaylife

Yes 8(21%) 19(49%) 0.011

No 30(79%) 20(51%)

Haspaineasedinexpectedtime

Yes/muchfaster 36(95%) 35(90%) n.s.

No 2(5%) 4(10%)

Rateyourperceptionofthehospitalstay

Very positive/positive 37(97%) 36(92%) n.s. Negative/very negative 0 1(3%) Neitherpositiveor negative 1(3%) 2(5%)

Rateyourperceptionundergoingacaesareansection

Verypositive 29(76%) 26(67%) n.s.

Positive 9(24%) 13(33%)

Numbersand(%)(Chi2_test,_p_≤_0.05_was_considered_{signiﬁcant).}

3.7. Nursingaspects

Total time (min) required for rescue treatment during the first24hwassignificantly(p=0.001)shorter in theOXYgroup (20.7±19.4)thanintheIVM/codeinegroup(66.4±38.7).Alsothe numberofrescuemedicationswassignificantlylower(p=0.047) in the OXY group (4.3±3.6) than in the IVM/codeine group (8.4±11.7).

4. Discussion

The present study results demonstrate that a postoperative treatmentregimenusinganoralformulationof apotentopioid (OXY) wasmore effective in reducing both pain and as opioid requirementduringthepostoperativeperiodafterCS,when com-paredwithourstandard ofcare,IVMand oralcodeine,bothas adjuncttoparacetamol+ibuprofen.Althoughpainatrestwaslower in the OXY group during theﬁrst 6hno signiﬁcant difference wasseen over thewhole0–24hperiod and neitherdidopioid consumption differ between groups. It is reasonable to expect that these observations are due to the fact that a higher dose ofopioidwasadministeredtotheOXYpatientsthantotheIVM patientsimmediatelyaftersurgery, but that allpatientsgot an adequatedosewhenaskingfor medication,which isconsistent withthefact thattotal opioid consumption wasalmost identi-cal.However,duringthefollowingdays,lowerpainintensityas wellasloweropioidrequirementwasdemonstratedintheOXY group.

Incisionalpainisshowntobemostintenseduringtheﬁrst24h aftersurgery,whiledeepvisceralpainisoflongerduration.Further LenzandcoworkerssuggestOXYasmorepotentinvisceralpain thanmorphine,whichmaycontributetothedifferencesobserved [20].

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Table7

Neonatalvariables.

Baselinevalues (before intervention)

Neonataloutcomewith mothersintheOXY group

(n=38)

Neonataloutcomewith mothersinthe IVM/codeinegroup (n=39)

Apgarscore(medianandrange)

1min 9(6–10) 9(7–10) 5min 10(8–10) 10(8–10) 10min 10(8–10) 10(8–10) Umbilicalcord bloodpH (mean±SD) 7.32±0.62a _7.32_±_0.06b Birthweight (mean±SD) 3561±387 3559±370 NACSc_(mean_±_SD) <60min,OXY n=38,IVM n=39 35.8±2.6 35.7±3.2 Neonatalcare admission(n) 2 2 NACSc_(mean_±_SD) 24h,OXY n=36,IVM n=38 37.2±1.7 37.2±1.8 48h,OXY n=35, IVM/codeine n=38 MissingOXY n=1 37.5±1.7 37.8±1.6 Numberof neonates decreasing>10% inweight(n) 5 10

Additionalfeeding(nand%)

No 28(74%) 23(59%)

Yes 10(26%) 16(41%)

a_Two_newborns_had_acidosis_(both_with_pH_7.11)_and_where_admitted_to_NICU. b_One_newborn_had_acidosis_(pH_7.18)_and_was_admitted_to_NICU._All_three

devel-opedPAS.

c _NACS_–_Neurological_Adaptive_Capacity_Sore.

Bothfrequency and intensityof breakthrough pain (0–24h) were lower in the OXY than in the IVM/codeine group. The pharmacokineticproﬁleofslowreleaseOXY(OxyContin)ensures thattherearenosuddendipsindrugexposureandtherebyreduces theriskofbreak-throughpain.Thelowertotalneedforopioids, lessfrequent needfor rescuemedication, shortertotal time for drugadministrationandlessopioidrelatedadverseeffectsinthe mothersoftheOXYgroupfurtherdemonstratetheadvantagesof thisprotocol.Thereisconﬂictingdataregardingthecomparison ofadverseeffectsbetweenOXYandmorphine[14,20]butseveral studiessuggesta bettertolerabilityof OXYatequipotentdoses [21–24].

InthepresentstudythemediandurationofOXYorcodeine intakewasthesameacrossgroups.OXYwasgivenuptofivedays aftersurgery,withdosesdaysfourandfiveofmaximum20mg, limitingtheriskforsignificantinfluenceontheneonate.Dueto theinterindividualdifferencesinbioactivationofcodeinethetotal opioidexposureoftheneonateinthegroupreceivingIVM/codeine canbeexpectedtovaryevenmorethanwhathasbeensuggested forOXY[17].

Therearesomelimitationswiththepresentstudy.First,itcan beconsideredaweaknessthatPCAmorphinewasnotusedas com-parator. However,theobjective of thestudy wasnot toassess theanalgesicefﬁcacyofoxycodone,buttocomparetwo alterna-tivelowtechtreatmentanalgesicregimensinordertooptimize theeffectiveness of postoperative care afterCS. PCAhas never

been introduced as routine treatment in our hospital as quick mobilizationis centralandwe madetheassessmentthat trans-portationofaPCAdevisewouldmakethemotherslessambulatory whentakingcareoftheirnewborns.Theintentionwiththestudy wastoevaluateifchangeofopioidcouldoptimizepain manage-ment. Second,thestudy design is notdouble-blind. Onemajor reasonforthisistheethicalaspectofobtainingsamplesofblood fromthenewbornaswellasbreastmilkduringtheveryfirstdays oflactation.Wewantedtodothisinasfewpatientsaspossible, limitingsamplingtotheOXYgroup,sincethereislessdata avail-ableforthisopioid.Itisimportanttoemphasizethatmothers’had noopportunitytoinfluencetreatmentallocationandno-one with-drewbecauseofthissampling.Third,painintensityassessments reported atregular intervals wereonly obtainedfor 48h post-operatively,whichiswhenmothersandbabiesweredischarged, accordingtoclinicalroutine.Thus,painintensitydataand anal-gesicrequirementdatafordays3–5arenotasrobust.Fourth,we didnotdo anyCYP2D6pharmacogenomicsanalyses, and there-foresomewomenintheIVM/codeinegroupmighthavebeenslow metabolizers,notrespondingtocodeine,affectingtheirresponseto treatment.Usingastandardizedconversiontableforopioid calcu-lationsalsocontributestosomeuncertaintyinthefinalevaluation. Noadverseeffectsoftreatmentonthenewbornswereobserved ineithergroup.BasedonNACSassessmentsnochildshowedany signofinfluenceofthemother’sintakeofopioidanalgesics.

TothebestofourknowledgethisisthefirsttimeOXYaspain reliefafterCShasbeencomparedtoanotherregimewithregard notonlytoefficiencyandsafetyofpostoperativeanalgesiaofthe mothersbutalsobyaquantifiedevaluationofpostnataladaptation inconnectiontobreastfeeding.TheNACShasbeenquestionedas areliabletool,withalowtest–retestreliabilityindetecting differ-encesbetweenneonataloutcomesafterdifferenttypesofobstetric anaesthesiaforCS[25].However,thereisagenerallackofbetter tools.Weconsideredthatsupervisedtraining ofonlytwo study ratersbyanexpertneonatologisthasoptimizedthistoolforthe presentuse.

Thestrengthofourstudyisthatitisprospectiveandthatthere was a highcompliance among thewomen participating in the study.ApreviousretrospectivecohortstudybyLametal.reported ahigherincidenceofcentralnervoussystemsymptomsinbreast fednewbornsbymotherstreatedwithOXYthanmotherstreated withparacetamolorcodeine[26].Aspointedoutinareplytothe studybyLam,thelongrecalltimewasapronouncedweaknessof thatstudy[27].StudiesprospectivelyexamininghowOXYaffects thebreastfedinfanthavebeenrequested[28].

Seatonetal.studiedmaternalserumandbreastmilklevelsafter OXYintakeandtransportthroughbreastmilktotheneonatewas investigated.OXYwasonlydetectedintheplasmaofoneneonate (outof41)butitwasconsideredpossiblethatthelevelsin breast-milkcouldexposethenursingneonatetomorethan10%ofthe therapeuticinfantdose[17,29].Theneedforopioidsishighest dur-ingthefirstpostoperativeday,anddecreasesovertime.Duringthe first24hthenormalrangeofbreastmilktransferisonly4–6ml/kg infantbodyweight[30].Anoptimizeddosingofanalgesics, includ-ingopioids,duringthefirst24hafterdelivery,whenbreastmilk productionisstillsparse,resultinginalowermaternal require-mentofopioidduringday2–5postCS,mayclearlyreducetherisk ofuntowardexposureofthenewborn,whilstthemotheris opti-mallypainrelieved.Thelongerperiodtoestablishedlactationafter CSthanaftervaginaldelivery,contributestolowchildexposures, withonlysmallamountsofopioidsbeingtransferredtothebaby.

Insummary,thepresentprospectivestudydemonstratesthat a standardized postoperative treatmentwithoral OXY afterCS providedabetterpaincontrol,withoveralllowerpainintensity andloweropioidintakethanaprotocolusingIVM/codeine,both ascomponentsofamultimodalanalgesicregime.Neitherdidthe

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24 B.Niklassonetal./ScandinavianJournalofPain7(2015)17–24 lowtechapproach,supportingearlyambulation,demonstrateany

safetyconcerns for mother and child. Further,an effective and reliableoralstandardizeddosingofpostoperativeanalgesicscan contributetotheself-sufﬁciencyofthemotherinself-careandcare ofthenewborn.

Conﬂictofintereststatement

Theauthorshavenoconﬂictsofinterest.

Acknowledgments

Wearegratefultoallthewomencontributingtothisstudyand tothestaffatthematernitywardK77attheKarolinskaUniversity HospitalHuddinge,Swedenforallvaluablehelp.Wearealso thank-fulfortheexpertinstructionsregardingtheNASCevaluationthat wereceivedfromProfessorMikaelNorman,attheNICU, Depart-mentofPediatrics,KarolinskaUniversityHospital.Thestudywas supportedbyagrantfromtheStockholmCountyCouncil(grantno. 2006023)andfundingfromSophiahemmetUniversity,Stockholm. MundipharmaprovidedﬁnancialsupportfortheOXYanalysesat theDepartmentof ClinicalPharmacology, KarolinskaUniversity Hospital,Huddinge.

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