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Behaviouralmeasuresreflectpain-mitigatingeffectsofmeloxicamincombinationwithTri-Solfen®inmulesedMerinolambsL.Inglis,S.Hancock ,M.Laurence andA.Thompson†SchoolofVeterinaryandLifeSciences,MurdochUniversity,Murdoch,WA6150,AustraliaFlystrikecoststheAustralianindustry$173to280Mperannumand70%to80%ofMerinolambsarecurrentlymulesedtoreducetheriskof ystrike.Toalleviatewelfareconcernstherehasbeenwidespreadadoptionofanalgesicstomitigatethepainassociatedwithmulesing.TheobjectiveofthisexperimentwastodeterminetheeffectivenessofTri-Solfen®andmeloxicam(Metacam®20)atreducingpain-relatedbehaviouralresponsestomulesinginMerinolambs.OnehundredandfortyMerinolambswereallocatedtooneofseventreatmentgroups:(1)non-mulesed(Control);(2)mulesedwithnopainrelief;(3)subcutaneous(s.c.)meloxicamadministered15minbeforemulesing;(4)Tri-Solfen®administeredattimeofmulesing;(5)Tri-Solfen®andsalineinjection(s.c.)15minbeforemulesing;(6)Tri-Solfen®andmeloxicam(s.c.)15minbeforemulesing;and(7)meloxicam(s.c.)attimetheofmulesing.Behaviouralresponsessuchasstanding,walkingandlyingweremeasuredevery15minfor6honthedayofmarkingandforupto2hfor4daysthereafter.Standing(hunchedv.normal)andwalking(stiffv.normal)behaviourswerethencategorisedintopain-andnormal-relatedbehaviourswhilelyingremainedinitsowncategory.Mulesedlambswithnopainreliefdisplayedsigni cantlymorepain-relatedbehavioursthanControllambsduringthe6hpost-mulesing(1.22v.0.22outofatotalscoreof3;RSD=1.15).Lambsthatreceivedacombinationofpainreliefdisplayedsigni cantlylesspain-relatedbehaviourthanmulesedlambswithnopainreliefonthedayofmulesing(0.85v.1.22outofatotalscoreof3;RSD=1.15).AdministrationofmeloxicamorTri-Solfen®ontheirownhadminimalifanysigni canteffectonpain-relatedbehavioursonthedayofmulesing.Theresultsofthisexperimentsupporttheuseofpain-relatedbehaviourstomeasuretheef cacyofanalgesicsandtheuseofmultimodalanalgesiaduringmulesingoflambs.Keywords:mulesing,analgesia,behaviour,sheep,welfareImplicationsThisresearchfurthersupportstheuseofanalgesiaduringmulesingoflambs.Differencesinpain-relatedbehaviours supportedtheuseofmeloxicamwhenusedincombinationwithTri-Solfen®(Bayer,Australia).Thismayencourageproducerstoalsoadministeranon-steroidalanalgesicwhenmulesinglambsandwherepreviouslytheymayonlyhave usedTri-Solfen®.IntroductionFlystrikeisknowntocausesubstantialphysiologicalandbehaviouralstresstoaffectedanimals(LeeandFisher,2007).Associatedlossofproduction,treatmentandanimaldeathis estimatedtocosttheAustraliansheepindustry$173to 280Mperannum(Sackett,2006;Laneetal.,2015).Theincidenceof ystrikecanbereducedbymulesing(Phillips,2009).Mulesingisasurgicalprocedurethatremovesfour stripsofperinealskinresultinginskintighteningand bre-lessscartissue.InAustralia,70%to80%ofMerinolambsaremulesed(reviewedbyPhillips,2009;Laneetal.,2015).Mulesingresultsinanimmediateincreaseinplasmacortisolconcentrationthatlastsforupto24to48h(Shuttetal.,1987;FellandShutt,1989;Chapmanetal.,1994;Paulletal.,2008).Behaviouralresponsestomulesingsuchashunchedstanding,stiffwalkingandreducedlyingcanpersist forupto3days(FellandShutt,1989;Paulletal.,2008).Theseposturalindicatorshavebeensuccessfulinde ningtheresponseinlambsfollowinghusbandrypainfulproce- dures(MellorandMurray,1989;MolonyandKent,1997; ThorntonandWaterman-Pearson,1999;Molonyetal.,2002;Grant,2004).Duringthelastdecadetherehasbeensig- ni cantadoptionofpost-operativeanalgesicstoreducethepaincausedbymulesing.Tri-Solfen®isapostoperativeanalgesicthatcontainslignocaine(ashort-actinglocalanaesthetic),bupivacaine(along-actinglocalanaesthetic),centrimideasan †E-mail:andrew.thompson@murdoch.edu.audoi:10.1017/S1751731119000491 animal 2586(Received20March2018;Accepted17January2019; First published online 2 April 2019)Animal(2019),13:11,pp2586 –2593©TheAnimalConsortium2019 antiseptictocleansethewoundandadrenalinetoreducebloodlosswhileenhancingtheanaestheticeffects.Paulletal.(2007)andLomaxetal.(2008)reportedthatTri-Solfen®reducedpain-relatedbehavioursinthe rst4to8haftermulesing.Lomaxetal.(2013)concludedthatTri-Solfen®reducedpain-relatedbehavioursforupto24h;however,thisstudyinvolvedverylownumbersofanimals. Otherthanthissinglestudy,thereislimitedevidenceto supportthepremisethatTri-Solfen®offerspainreliefbeyond4to8hpost-mulesinganditsdurationofaction maybemuchless.Non-steroidalanti-in ammatorydrugs(NSAIDs)provideanotheroptionformulesinganalgesia.Theyprovidelong actingpainreliefthroughinhibitionoftheCOX-1and COX-2pathwaysinprostanoidproductioninsofttissues. Thisresultsinrelieffrompainandin ammation(Mathews,2002;RicciottiandFitzGerald,2011).Non-steroidalanti- in ammatorydrugsmaythereforeprovidealongerperiodofpainrelieffollowingmulesingthanTri-Solfen®.Non-steroidalanti-in ammatorydrugshavebeenshowntobeeffectiveatmitigatingpaininarangeofspeciesfollowing docking,dehorningandcastration(Zölsetal.,2005;CoetzeeandSmith,2010;Keitaetal.,2010;Smalletal.,2014),however,therehasbeenlessworkontheireffec- tivenesstoreducepainassociatedwithmulesing.Paulletal.(2008)foundnodifferencesinpeakcortisolcon-centrationsorpain-relatedbehavioursbetweenlambsthatreceivedmeloxicamatthetimeofmulesingornopainrelief.Inthisstudydoseratesandtimeofadministration mayhavelimitedtheeffectivenessofmeloxicaminmiti- gatingpaininresponsetomulesing.Furthermore,no attemptwasmadetodetermineifmeloxicamcould enhanceorextendrelieffrompainprovidedbyTri-Solfen®followingmulesing.Theuseofmultimodalanalgesiawasconsideredpre-viouslybyPaulletal.(2007)whofoundthattreatmentwithatopicalanalgesicincombinationwiththeNSAIDs,carprofen or unixin,reducedpeakcortisolconcentrationsfollowingmulesingandreducedpain-relatedbehaviourscomparedto lambstreatedwithonlyatopicalanalgesic.Theypostulated thattheenhancedeffectivenessofcombininglocalanaes- theticandNSAIDsmightbeduetotheircomplementary durationsandmechanismsofaction.However,therewerenosigni cantdifferencesinplasmacortisolconcentrationsbetweenthesetreatments24haftermulesingandtherewasnoattempttomeasureimpactsonlambbehavioursbeyond 12hpost-mulesing.Thecurrentstudytestedthehypothesesthat(i)pain-relatedbehavioursinMerinolambscouldbeusedto assesstheef cacyofpainmitigationtreatmentsfollowingmulesing;(ii)acombinationofmeloxicamandTri-Solfen®wouldbethemosteffectivetreatmentinmitigatingpain inresponsetomulesinginMerinolambs,and(iii) administrationofmeloxicam15minbeforemulesing wouldbemoreeffectiveinmitigatingpaininresponseto mulesingthanadministrationofmeloxicamatthetimeof mulesing.MaterialandmethodsAnimalsTheresearchwasperformedatMurdochUniversity’sfarmatWhitbyFallsinWesternAustralia(32°17’35”S,116°00’55”E)betweenMayandJuly2017.Atotalof178pregnantMerino ewes(122singlebearingand57twinbearing)lambedbetween MayandJune2017.Sevendaysbeforemulesing,alllambsaged6to10weekswereweighed,eartagged,paint-brandedonbothsideswithauniquenumberandtheirdamwasrecorded.Two daysbeforemulesing,lambswereweighedagainwithan averageweightof12kg.OnehundredandfortyMerinolambs wereallocatedtooneofseventreatments(n=20lambspertreatment)basedonliveweight,sexandreartype(numberof lambsrearedperewe).Lambswerethenallocatedintofour plots(n=5lambs/treatmentperplot).Twinsiblingswereallo-catedtothesametreatmentandplot.Thefourplots(50×50m)wereadjacenttotheyardswherethelambsweretreated.Ewes weresupplementedwith1kgofoatenhay(9.0MJMetaboli- sableEnergyperkgDryMatter;6.0%CrudeProtein)and600g oflupins(13.1MJMetabolisableEnergyperkgDryMatter; 31.3%CrudeProtein)perdayperewefortheexperimental period,whichceased10dayspost-mulesing.Lambswere weighed10dayspost-mulesing.Theaverageweightofthelambsthatwerenotmulesedwere15.6kgandthosethatweremulesed,regardlessofpainreliefadministered,were13.5kg.ExperimentaldesignThetreatmentswereimplementedatmulesing(day0)which consistedoflambsthatwerenotmulesed(Control),lambs thatweremulesedandadministeredasalineinjectionas opposedtopainrelief(Placebo),lambsmulesedandadmi- nisteredmeloxicam(Metacam®20,BoehringerIngelheim,Sydney,Australia)15minbeforemulesing(MC-15),lambs mulesedandadministerdTri-Solfen®only(TS),lambsmulesedandadministeredacombinationofmeloxicam15minbefore mulesingandTri-Solfen®(MC-15+TS)andlambsmulesedandadministeredmeloxicaminthecradle(MC0).Atmarking,alllambswereplacedindorsalrecumbencyintoacradlethatrestrainstheanimalaroundthehocksofall fourlimbs.Alllambs,exceptfortheControl(un-mulesedand untreated)wereearmarked,vaccinatedwithScabiGard®(Zoetis,Sydney,Australia)viaascratchtotheskinontheinnerthighandGlanvac®(Zoetis,Sydney,Australia)viaasub-cutaneousinjection,bothpermanufacturer’sinstructions.Tailsweredockedusingagasheatedknifeandmulesed.FemaleswerealsovaccinatedwithGudair®(Zoetis,Sydney,Australia)viasubcutaneousinjectionhighontheneckskinandinaccordancewithmanufacturer’sinstructions.Maleswerecastratedusingrubberrings.MulesingwasperformedbyaprofessionalcontractoraccreditedbytheLivestockContractorsAssociationofAustralia.Mulesinginvolvedtheremovaloftwo stripsofskinfromthebreechareaoutsidethenon-wooled perinealareaandonestripofskinalongeachlateralsideofthe tail.LambsallocatedtotheControltreatmentwereplacedin thecradlefor60s(averagetimeofmarking)beforebeing releasedtotheirallocatedplots.2587Behaviouraleffectsofpainreliefformulesing Theliveweightofeachlambmeasuredtwodayspriortomulesingwasroundedtothenearest5kgandmeloxicamwasadministeredsubcutaneouslybasedonthemanu- facturersrecommendeddoseof1ml/20kgliveweight–1mg/kg(0.5to1mlperlamb).Thedoseofsalineadminis- teredtolambsinthePlacebotreatmentwasalsobasedon therecommendeddosesforMetacam®20.Tri-Solfen®wasadministeredimmediatelyaftermulesingat8mlforlambs between11and15kgand10mlforlambsbetween16and 20kg.AssessmentoflambbehaviourOnday0,fourobserverswereallocated veor10lambsperplottorecordthebehaviourscategorisedinTable1andwere blindedtothetreatments.Allobserverswereexperiencedin assessingsheepbehaviourhavingbeentrainedbeforethecommencementoftheexperimenttostandardisetheirobservationsforcomparability.Liveobservationsweremade 5minafterthelambwasreleasedfromthemarkingcradle andthenevery15minforthefollowing6h.Behaviours recordedwerestanding,walkingandlying;standingand walkingwerethenfurthercategorisedintonormaland abnormalbehavioursasdescribedbySmalletal.(2014)(Table1).Comparisonsoflambbehaviourweremadebetweenthreecompositetraits;totalpain(hunchedandabnormalstandingandstiffwalking),totalnormal(normal standingandwalking)andlying(ventral,lateralandventral/ laterallying).Thelambswereobservedforatotalof15sat eachtimepointandthemostdominantbehaviourexpressed wasrecordedforeach5-sinterval.Thedatawerethenscored as0(notobservedduring15s),1(dominantbehaviourin one5-sinterval),2(dominantbehaviourintwo5-sintervals)or3(dominantbehaviourinallthree5-sintervals)ateachmeasurementperiod.Oneobserverfromeachplotonday0 wasusedfortheobservationsondays1to4andeach observerassessedthesamelambseachday.Onday1, behaviourswererecordedevery15minfor2handondays2 to4behaviourswererecordedevery15minfor1.25h.On days1to4,observationsoflambbehaviouronthe rstplotcommencedat9amandoncecompletedtheobserversmovedthroughtheplotsinnumericalorder.StatisticalanalysesAllstatisticalanalyseswereperformedusingGENSTAT(18thedition;VSNInternational,2017,HemelHempstead,UK).Alldatawasanalysedusingthemethodofrestrictedmaximum likelihood.Comparisonsoflambbehaviourweremade betweenthethreecompositetraits;totalpain,totalnormal andlying.Datawereanalysedovertimeforeachhourandeachday,andforday0andday1combined,andthevaluesreportedarefromatotalscoreof3.Anumberofcorrelated structureswereexamined,withasplitplotintimestructure consideredappropriateforallanalyses.The xedeffectsweretreatment,timeofmeasurement,reartype,sexand interactionsthereof.Randomeffectsincludedplot,lamb (nestedwithinplot)andmeasurementperiod(nestedwithin lambwithinplot)alongwithobserverandewesource.Forliveweightchangeofthelambsbetweendays−7and10,treatment,sex,reartypeandinteractionsthereofwere ttedas xedeffectswhileplotandlamb(nestedwithinplot)alongwithewesourcewere ttedasrandomeffects.Forallanalysestherewerenosigni cantinteractionsandsothe nalmodelsonlyincludedmaineffectsofthe xedterms.Maineffectsandinteractionshavebeenconsideredsig-ni cantatthe5%level.DifferencebetweenmeanswereassessedusingLSD(P=0.05).Thereweregenerallynosig-ni cantdifferencesinbehaviouralmeasuresbetweenTri-Solfen®andTri-Solfen®andplaceboinjectionhenceonlydatafortheTri-Solfen®treatmentarereported.ResultsEffectofmulesingonlambbehaviourOnaverage,lambsthatweremulesedandnotadministeredpainreliefexhibitedsigni cantlymorepain-relatedbeha-vioursduringthe rst6hpost-mulesingthanlambsthatwerenotmulesed(1.22v.0.22;P<0.05;Table2).Theproportionofpain-relatedbehavioursformulesedlambswithoutpainreliefwasrelativelyconstantoverthe rst6h(P>0.05;Table3).Furthermore,overthe rst6hlambsthatweremulesedandnotadministeredpainreliefexhibited signi cantlyfewernormalbehavioursandlyingthanlambsthatwerenotmulesed(P<0.05;Table2). Table1CategoriesusedtoclassifybehaviourofMerinolambspost-mulesingCategoryBehaviourNormalNormalstandingLambstoodwithnoobviousposturalabnormality;straight-backed,withheadhigherthanorlevelwithbackNormalwalkingLambexhibitedausualgaitwhilewalking,withevenstepsandnoobvioushesitationPain-relatedAbnormalstandingLambstoodheadlowerthanhighestpointofbackHunchedstandingLambstoodwitharounded,hunchedappearance;backwasarched,withheadlowerthanhighestpointofbackStiffwalkingLambexhibitedstiffortentativemovementswhilewalkingLyingVentralLamblaidonitssternumandabdomenwithallfourlegsfoldedunderthebodyLateralLamblaidonitssidewithoneorbothforelegsandbothhindlegsstretchedoutlaterallyVentral/lateralLamblaidonitssternumandabdomenwithoneorbothhindlegsextendedlaterally2588Inglis,Hancock,LaurenceandThompson Therewerealsosigni cantdifferencesinpain-relatedbehaviours(0.50v.1.11;P<0.05;Table2)andnormalbehaviours(1.94v.1.31;P<0.05;Table2)onday1betweenlambsthatweremulesedwithoutpainreliefandthosethatwerenotmulesed;however,thesedifferences werenotevidentondays2to4.Therewerenosigni cantdifferencesinthefrequencyoflyingbetweenmulesedand non-mulesedlambsfromdays1to4.Therewerenosexor reartypeeffectsbetweenlambsineachtreatmentthrough- outtheexperiment.Therewasasigni cantdifferencebetweentreatmentsinliveweightchangeofthelambsbetweendays−7and10.Onaverage,lambsthatwerenotmulesedgained3.9kgcom- paredto1.9kgforlambsmulesedwithoutpainrelief (P<0.001).EffectofpainreliefonlambbehaviourOnaverage,lambsthatwereadministeredacombinationof Tri-Solfen®andmeloxicam15minbeforemulesingexhibitedsigni cantlyfewerpain-relatedbehavioursthroughoutday0thanthosemulesedwithnopainrelief(0.85v.1.22;P<0.05;Table2).Furthermore,lambsthatwereadminis-teredthecombinationofpainreliefdisplayedsigni cantlyfewerpain-relatedbehavioursthanlambsadministeredTri- Solfen®onlyonday0(0.85v.1.16;P<0.001;Table2).Themagnitudeofpain-relatedbehavioursexhibitedbylambs fromallotherpainrelieftreatmentsdidnotdifferpost-mulesing.Overallmeloxicamadministered15minbeforemulesingdidnotsigni cantlyaffectpain-relatedbehaviouronday0.However,at4and5hpost-mulesing,thelambsexhibitedsigni cantlyfewerpain-relatedbehavioursincomparisontolambsmulesedwithnopainrelief(P<0.05).Thiswascon-sistentwiththeresponseat4and5hforlambstreatedwith thecombinationofmeloxicamandTri-Solfen®(Table3).Therewerenosigni cantdifferencesinpain-relatedbehaviourbetweenmulesedlambsthatreceivedpainrelief andthosethatdidnotondays2,3or4.Inaddition,there wasnosigni cantdifferencebetweenlambsthatweremulesedandadministeredpainreliefandthosethatwere notwhenpain-relatedbehaviouralscoreswereaveraged acrossdays0and1(1.17v.1.11;P=0.12).Therewerenosexorreartypeeffectsonpain-relatedbehaviourbetweenlambsthatwereprovidedpainreliefandthosethatwerenot.Furthermore,liveweighthadnosigni cantimpactonpain-relatedbehaviourbetweenlambsthatreceivedpainrelief andthosethatdidnot(P=0.264).Normalbehavioursexhibitedbylambsonday0,onaverage,werenotsigni cantlydifferentbetweentreat-mentsregardlessofwhetherpainreliefwasadministeredornot.Thenumberofobservationsofnormalbehaviourincreasedsigni cantlyinthe6hfollowingmulesing(P<0.05;Table3).Femalelambsalsodisplayedmorenor-malbehaviourthanmales(1.38v.1.16;P=0.01).Fromdays1to4,therewerenosigni cantdifferencesinnormalbehaviourbetweenpainrelieftreatments,sexorreartypeofthelambs. Table2Effectsofpainreliefonaveragedailybehaviour5dayspost-mulesinginMerinolambsBehavioursPain1Normal2Lying3DayControlPlaceboMC-15TSMC-15+TSMC0P-ValueLSD*ControlPlaceboMC-15TSMC-15+TSMC0P-ValueLSD*ControlPlaceboMC-15TSMC-15+TSMC0P-ValueLSD*00.22B1.22A1.03A1.16A0.85AB0.94A<0.0010.3041.62B1.131.321.08A1.10A1.300.0180.3220.83B0.46A0.47A0.55A0.88A0.51A<0.0010.26710.50B1.11A1.31A1.33A1.40A1.18A<0.0010.4281.94B1.31A1.11A1.19A1.13A1.36A<0.0010.4580.540.570.530.480.420.420.2650.29720.130.300.420.360.64A0.470.0990.3361.661.721.331.431.211.200.2550.5161.130.931.281.181.091.320.7410.47930.010.120.110.160.150.100.5130.1611.481.381.191.101.401.500.2920.4441.531.511.701.741.461.400.6310.45440.010.090.020.13A0.030.060.2780.1091.97B1.23A1.37AA1.28A1.72B1.47A0.0420.4851.041.68A1.62A1.60AA1.271.47<0.0010.490Valuesarerespresentedasobservationsscoredoutofthree.Control=lambswerenotmulesed;Placebo=lambsweremulesedandadministerednopainrelief;MC-15=lambsweremulesedandadministeredMetacam®2015minbeforemulesing;TS=lambsweremulesedandadministeredTri-Solfen®;MC-15+TS=lambsweremulesedandadministeredacombinationofMetacam®2015minbeforemulesingandTri-Solfen®;MC0=lambsweremulesedandadministeredMetacam®20inthecradle.AMeanswithinarowaresigni cantlydifferenttotheControltreatment(P<0.05).BMeanswithinarowaresigni cantlydifferenttothePlacebotreatment(P<0.05).1Totalpain=hunchedandabnormalstandingandstiffwalking.2Totalnormal=normalstandingandwalking.3Totallying=ventral,lateralandventral/laterallying.*LSD(P=0.05).2589Behaviouraleffectsofpainreliefformulesing Table3Effectsofpainreliefonaveragehourlybehaviour6hpost-mulesinginMerinolambsAveragehourlybehavioursonday0Pain1Normal2Lying3HourControlPlaceboMC-15TSMC-15+TSMC0P-valueLSD*ControlPlaceboMC-15TSMC-15+TSMC0P-valueLSD*ControlPlaceboMC-15TSMC-15+TSMC0P-valueLSD*10.39B1.21A1.09A1.08A0.840.99A0.0150.4781.60B0.92A0.80A0.84A1.091.01A0.0210.5130.330.480.83A0.720.710.750.3320.47020.19B0.88A0.82A0.99A0.88A0.86A0.0090.4701.381.331.160.71AB0.931.060.2340.5541.030.600.700.950.990.770.5930.54730.30B1.21A1.36A1.32A0.86A0.99A<0.0010.5111.37B0.751.06A0.811.071.100.3230.5381.170.760.43A0.60A0.940.640.1710.54740.16B1.47A0.93AB1.18A0.72AB1.08A<0.0010.5091.581.081.571.290.89A1.570.1820.6190.89B0.28A0.430.39A1.27B0.24A<0.0010.46950.11B1.37A0.83AB1.55A0.71AB0.94A<0.0010.4811.841.351.661.321.381.490.5340.5760.87B0.26A0.440.440.83B0.41A0.0690.45560.05B0.95A1.01A1.07A0.87A0.60A<0.0010.4922.001.541.771.511.42A1.890.3040.5490.780.420.07A0.330.570.25A0.0740.458Valuesarerespresentedasobservationsscoredoutofthree.Control=lambswerenotmulesed;Placebo=lambsweremulesedandadministerednopainrelief;MC-15=lambsweremulesedandadministeredMetacam®2015minbeforemulesing;TS=lambsweremulesedandadministeredTri-Solfen®;MC-15+TS=lambsweremulesedandadministeredacombinationofMetacam®2015minbeforemulesingandTri-Solfen®;MC0=lambsweremulesedandadministeredMetacam®20inthecradle.AMeanswithinarowaresigni cantlydifferenttotheControltreatment(P<0.05).BMeanswithinarowaresigni cantlydifferenttothePlacebotreatment(P<0.05).1Totalpain=hunchedandabnormalstandingandstiffwalking.2Totalnormal=normalstandingandwalking.3Totallying=ventral,lateralandventral/laterallying.*LSD(P=0.05).Inglis,Hancock,LaurenceandThompsonInglis,Hancock,LaurenceandThompson2590 LambsthatwereadministeredthecombinationofTri-Solfen®andmeloxicam15minbeforemulesingspentmoretimelyingthanlambsadministerednopainreliefonday0(P<0.05;Table2).Thisagainre ectedtreatmentdifferences4hpost-mulesing(Table3).Therewerenosig-ni cantdifferencesinlyingbehaviourbetweensexesorreartypesfromdays0to4.Therewasalsonosigni cantdiffer-enceinliveweightchangefromdays−7to10betweenlambsadministeredpainreliefandthosethatwerenot (P>0.05).DiscussionMulesingsigni cantlyincreasedthepain-relatedbehavioursasevidencedbyhunchedstandingandstiffwalkingincomparisontolambsthatwerenotmulesed.The20%dif- ferenceinpain-relatedbehavioursacrossdays0and1was similarinmagnitudetothatreportedbyPaulletal.(2007and2008).Lambsthatwerenotmuleseddisplayedsig-ni cantlyfewerpain-relatedbehavioursinthe30hfollowingmarkingcomparedtolambsthatweremulesed.Thisresult,andtheresultsreferredtofrompreviousresearch,provides evidenceinsupportoftheinitialhypothesisthatbehavioural observationscanbeusedtoassesstheeffectofpainreliefin mulesedlambs.ThecombinationofmeloxicamandTri-Solfen®sig-ni cantlyreducedpain-relatedbehavioursinthe6hpost-mulesingcomparedtolambsmulesedandadministeredno painrelief,supportingoursecondhypothesis.Independently, Tri-Solfen®,meloxicamadministered15minbeforemulesingandmeloxicamadministeredinthecradledidnotaffectthe averageincidenceofpain-relatedbehaviourduringtheday aftermulesingcomparedtolambsmulesedandgivenno painrelief.Astherewerenodifferencesinpain-related behavioursbetweentheadministrationtimesofmeloxicamourthirdhypothesiswasrejected.Overall,our ndingssug-gestthatundertheconditionsofthisstudyacombinationofatopicalanalgesiaandmeloxicamwasmosteffectiveat decreasingpain-relatedbehavioursassociatedwithmulesing inMerinolambs.Theeffectivenessofcombiningmeloxicam andTri-Solfen®todecreasepain-relatedbehavioursiscon-sistentwithPaulletal.(2007).Theyfoundthecombinationofcarprofenandatopicalanaestheticreducedtheacuteriseincortisolfor24handpeakplasmacortisolconcentrationswerenotsigni cantlydifferenttonon-mulesedanimals.Twelvehoursofbehaviouralobservationsalsoindicatedthat animalsadministeredthecombinationofanalgesicsspent lesstimestandingandinahunchedpostureandwerenot differentfromnon-mulesedanimals.Painalleviationislikely duetotwomechanisms;theanaestheticpropertiesofthe topicalanalgesiaworkingdirectlyonnerve brestoblockpainsignals(Sheil,2015),andtheNSAIDinhibitingin am-mationandassociatedpainbyreducingpressureonnerve endings(Daviesetal.,1984).Thecontributionofthesemechanismstotheexpressionofthepainrelatedbehavioursobservedinresponsetomulesinginthecurrentstudyare unknown.LambsthatwereonlytreatedwithTri-Solfen®hadsig-ni cantlymorepain-relatedbehavioursonday0incompar-isontolambstreatedwiththecombinationofmeloxicamand Tri-Solfen®,andtherewasnodifferenceinpainrelatedbehaviourswhencomparedtolambsmulesedandadminis- terednopainrelief.TheabsenceofaneffectofTri-Solfen®aloneonlambbehaviourinresponsetomulesing,iscontrary topreviousstudies(Paulletal.,2007;Lomaxetal.,2008and2013).Paulletal.(2007)foundTri-Solfen®tohavemoderateanalgesiceffects4hpost-mulesingasevidencedbyless hunchedstandingcomparedtolambsmulesedwithoutpain relief.However,Lomaxetal.(2013)foundwoundsensitivityandpain-relatedbehaviourswerereducedfor24h.The shortertermofpainreliefobservedbyPaulletal.(2007)wassuggestedtobecausedbythecollectionofbloodsamplesto measurecortisolconcentrations,whichlikelyexacerbatedpain responses.Thepresentstudysuggeststhiswasnotthecaseastheexperimentaldesignmimickedanon-farmscenariowithnophysicaldisturbancesandtheeffectivenessofTri-Solfen®wasnotre ectedinbehaviour.Thepreviousstudiesdiscussedhadrelativelylowanimalnumbersincomparisontothisstudy, andtheanimalsusedwereeitherhousedindoorsoron pasture-coveredpenslessthanone-tenththesizeofwhatwas usedinthisexperiment.Thismayaccountforthedifferences observedbetweenexperimentsintheeffectivenessofTri-Solfen®inreducingpain-relatedbehaviours.Theaverageincidenceofpainrelatedbehavioursonday0wassimilarforlambsadministeredthecombinationofmeloxicamandTri-Solfen®andindividualadministrationofmeloxicam15minbeforemulesing.Furthermore,adminis- trationofmeloxicam15minbeforemulesingsigni cantlydecreasedpain-relatedbehavioursat4and5hpost- mulesingwhencomparedtolambsthatreceivednopainrelief.Therefore,thepresentstudysuggeststhemainanalgesiaresponsiblefortheeffectivenessofthecombina- tiontreatmentwasmeloxicam.ThisisconsistentwithSmalletal.(2014)whoreportedthatbuccalmeloxicamdecreasedthecombinedabnormalbehaviours(hunchedstanding, standingwithstretchedpostureandwalkingstif y)for8hfollowingknifecastrationandtaildockingcomparedto lambsofferednopainrelief.Therelativeeffectivenessofmeloxicaminreducingpain-relatedbehavioursmayberelatedtodoseandtimeof administration.Paulletal.(2008)foundmeloxicamadmi-nisteredattimeofmulesingat0.5mg/kghadnoeffecton behaviour.Colditzetal.(2011)administeredmeloxicamat1mg/kg,whichrelievedsheepfromlamenessat6to8h overa24-hperiod.Mulesingcausessofttissuedamagethat resultsinrapidin ammation.GivenNSAIDspreferentiallyaccumulateinin amedtissue,administrationofaNSAIDatthetimeofmulesingwillallowforquickabsorption(Paulletal.,2008;Schweitzeretal.,2009).However,theanalgesiceffectwilldependlargelyonthedoseadministered.Phar- macokineticsofNSAIDscannotbetransferredfromone2591Behaviouraleffectsofpainreliefformulesing speciestoanother(Welshetal.,1993),andtotheauthors’knowledgeonlytwostudieshaveinvestigatedthepharma-cokineticsofmeloxicaminsheepandshowedthatplasmaconcentrationsofmeloxicamweredetectablefor24to72h(Shuklaetal.,2007;Stocketal.,2013).Doseratesandexpecteddurationofactionformeloxicam(andother NSAIDs)inprevioussheepresearchhasbeenextrapolated fromdatafromotherspecies(Paulletal.,2008).Thisincludesosteoarthritisincatsanddogsandcastrationof cattleandpigs(Leesetal.,1998;Mathews,2002;Zölsetal.,2005).Coetzeeetal.(2009)documentedahalf-lifeof27.5hincalves,supportingthenotionthatmeloxicamisagood choiceforlong-lastinganalgesiainruminants.Withthe amountofsofttissuedamagecausedbymulesingand minimalanalgesiaobservedinthiscurrentexperiment, increaseddoseratesofmeloxicamadministeredinthecradle couldbeinvestigatedincombinationwithTri-Solfen®.Toenhanceadoptionofinjectablemeloxicambycommercial sheepproducerseaseofapplicationiscrucial,suchastheabilitytoadministerpainreliefinthemarkingcradle.WeconcludethatusingacombinationofmeloxicamandTri-Solfen®canreducepain-relatedbehavioursinthe rst6hpost-mulesing.However,thisstudydidnotobserveanalgesiceffectsthroughbehaviouralmeasures24hpost- mulesingregardlessofthetypeofpainreliefadministered. Thispaperaddssupporttothepremisethatmulesingsheep ispainful,thispainismeasurableusingpain-relatedbeha-viourandthatacombinationofanalgesicsismosteffectiveinmitigatingthepain.AcknowledgementsTheauthorsthankBoehringerIngleheim(Sydney,Australia)forfunding.L.I.wastherecipientofanAustralianWoolEducation TrustandUniversitiesFederationforAnimalWelfare(UK) scholarshipandtheirsupportissincerelythanked. S.Hancock,0000-0002-4115-4642 M.Laurence,0000-0003-1215-2848DeclarationofInterestNone.EthicsStatementAllproceduresdescribedwereperformedinaccordancewith theAustralianCodeofPracticefortheUseofAnimalsfor Scienti cPurposes2013andwereapprovedbytheMurdochUniversityAnimalEthicsCommittee(R2903/17).SoftwareanddatarepositoryresourcesTherearenosoftwareand/ordatarepositoryresources.ReferencesChapmanR,FellLandShuttD1994.Acomparisonofstressinsurgicallyandnon-surgicallymulesedsheep.AustralianVeterinaryJournal71, 243–247.CoetzeeJF,MosherRandAllenPS2009.Phatmacokenticsofintraveousand oralMeloxicaminruminantcalves.VeterinaryTherapeutics10,1–8.CoetzeeHandSmithR2010.Recommendationsforcastrationanddehorningof cattle.InProceedingsofthe43rdAnnualConferenceoftheAmericanAssocia- tionofBovinePractitioners,Albuquerque,NM,USA,19–21August2010,pp.40–45.ColditzI,PaullD,HervaultG,AubriotDandLeeC2011.Developmentofa lamenessmodelinsheepforassessingef cacyofanalgesics.AustralianVeter-inaryJournal89,297–304.DaviesP,BaileyPJ,GoldenbergMMandFord-HutchinsonAW1984.Theroleofarachidonicacidoxygenationproductsinpainandin ammation.AnnualReviewofImmunology2,335–357.FellLandShuttD1989.Behaviouralandhormonalresponsestoacutesurgicalstressinsheep.AppliedAnimalBehaviourScience22,283–294.GrantC2004.Behaviouralresponsesoflambstocommonpainfulhusbandry procedures.AppliedAnimalBehaviourScience87,255–273.KeitaA,PagotE,PrunierAandGuidariniC2010.Pre-emptivemeloxicamfor opst-operativeanalgesiainpigletsundergoingsurgicalcastration.Veterinary AnaesthesiaandAnalgesia37,367–374.LaneJ,JubbT,ShephardR,Webb-WareJandFordyceG2015.Prioritylistof endemicdiseasesfortheredmeatindustries.Meat&LivestockAustralia, Sydney,NSW,Australia.LeeCandFisherAD2007.Welfareconsequencesofmulesingofsheep.AustralianVeterinaryJournal85,89–93.LeesP,McKellarQ,FootRandGettinbyG1998.Pharmacodynamicsand pharmacokineticsoftolfenamicacidinruminatingcalves:evaluationinmodels ofacutein ammation.TheVeterinaryJournal155,275–288.LomaxS,SheilMandWindsorP2008.Impactoftopicalanaesthesiaonpain alleviationandwoundhealinginlambsaftermulesing.AustralianVeterinary Journal86,159–168.LomaxS,SheilMandWindsorP2013.Durationofactionofatopicalanaes-theticformulationforpainmanagementofmulesinginsheep.AustralianVeterinaryJournal91,160–167.MathewsKA2002.Non steroidalanti in ammatoryanalgesics:areviewofcurrentpractice.JournalofVeterinaryEmergencyandCriticalCare12, 89–97.MellorDandMurrayL1989.Effectsoftaildockingandcastrationonbehaviour andplasmacortisolconcentrationsinyounglambs.ResearchofVeterinary Science46,387–391.MolonyVandKentJ1997.Assessmentofacutepaininfarmanimalsusing beahviouralandphysiologicalmeasurements.JournalofAnimalScience75, 266–272.MolonyV,KentJandMcKendrickI2002.Validationofamethodforassess- mentofanacutepaininlambs.AppliedAnimalBehaviourScience76, 215–238.PaullD,LeeC,AtkinsonSandFisherA2008.Effectsofmeloxicamortolfenamic acidadministrationonthepainandstressresponsesofMerinolambstomulesing.AustralianVeterinaryJournal86,303–311.PaullD,LeeC,ColditzI,AtkinsonSandFisherA2007.Theeffectofatopical anaestheticformulation,systemic unixinandcarprofen,singlyorincombina-tion,oncortisolandbehaviouralresponsesofMerinolambstomulesing.Aus-tralianVeterinaryJournal85,98–106.PhillipsCJ2009.Areviewofmulesingandothermethodstocontrol ystrike(cutaneousmyiasis)insheep.AnimalWelfare18,113–121.RicciottiEandFitzGeraldGA2011.Prostaglandinsandin ammation.Arterio-sclerosis,Thrombosis,andVascularBiology31,986–1000.SackettD,HolmesP,AbbottK,JephcottSandBarberM2006.Assessingthe economiccostofendemicdiseaseonthepro tabilityofAustralianbeefcattleandsheepproducers.MeatandLivestockAustralia,Sydney,NSW, Australia.SchweitzerA,Hasler-NguyenNandZijlstraJ2009.Preferentialuptakeofthenonsteroidanti-in ammatorydrugdiclofenacintoin amedtissuesafterasingleoraldoseinrats.BMCPharmacology9,5.2592Inglis,Hancock,LaurenceandThompson SheilML2015.Analgesiaforsurgicalhusbandryproceduresinsheepandotherlivestock.AnimalEthicsPtyLtd,AssociateSydneyUniversityFacultyofVeter- inaryScience,Sydney,NSW,Australia.ShuklaM,SinghG,SindhuraB,TelangA,RaoGandMalikJ2007.Comparativeplasmapharmacokineticsofmeloxicaminsheepandgoatsfollowingintrave- nousadministration.ComparativeBiochemistryandPhysiologyPartC:Tox-icology&Pharmacology145,528–532.ShuttD,FellL,ConnellR,BellA,WallaceCandSmithA1987.Stress-induced changesinplasmaconcentrationsofimmunoreactiveß-endorphinandcortisolinresponsetoroutinesurgicalproceduresinlambs.AustralianJournalofBio- logicalSciences40,97–104.SmallA,BelsonS,HolmMandColditzI2014.Ef cacyofabuccalmeloxicamformulationforpainreliefinMerinolambsundergoingknifecastrationand taildockinginarandomised eldtrial.AustralianVeterinaryJournal92,381–388.StockML,CoetzeeJF,KuKanichBandSmithBI2013.Pharmacokineticsof intravenouslyandorallyadministeredmeloxicaminsheep.AmericanJournalof VeterinaryResearch74,779–783.ThorntonPandWaterman-PearsonA1999.Quanti cationofthepainanddistressresponsestocastrationinyounglambs.ResearchofVeterinaryScience 66,107–118.VSNInternational2017.GenstatReferenceManual.VSNInternational,Hemel Hempstead,UK.WelshE,McKellarQandNolanA1993.Thepharmacokineticsof unixinmeglumineinthesheep.JournalofVeterinaryPharmacologyandTherapeutics16,181–188.ZölsS,RitzmannMandHeinritziK2005.Effectofanalgesicsonthecastrationof malepiglets.BerlinerUndMunchenerTierarztlicheWochenschrift119,193–196.2593Behaviouraleffectsofpainreliefformulesing

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Behaviouralmeasuresreflectpain-mitigatingeffectsofmeloxicamincombinationwithTri-Solfen®inmulesedMerinolambsL.Inglis,S.Hancock ,M.Laurence

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ing,analgesia,behaviour,sheep,welfareImplicationsThisresearchfurthersupportstheuseofanalgesiaduringmulesingoflambs.Differencesinpain-relatedbehaviours supportedtheuseofmeloxicamwhenusedincombinationwithTri-Solfen®(Bayer,Australia).Thismayencourageproducerstoalsoadministeranon-steroidalanalgesicwhenmulesinglambsandwherepreviouslytheymayonlyhave usedTri-Solfen®.IntroductionFlystrikeisknowntocausesubstantialphysiologicalandbehaviouralstresstoaffectedanimals(LeeandFisher,2007).Associatedlossofproduction,treatmentandanimaldeathis estimatedtocosttheAustraliansheepindustry$173to 280Mperannum(Sackett,2006;Laneetal.,2015).Theincidenceof ystrikecanbereducedbymulesing(Phillips,2009).Mulesingisasurgicalprocedurethatremovesfour stripsofperinealskinresultinginskintighteningand bre-lessscartissue.InAustralia,70%to80%ofMerinolambsaremulesed(reviewedbyPhillips,2009;Laneetal.,2015).Mulesingresultsinanimmediateincreaseinplasmacortisolconcentrationthatlastsforupto24to48h(Shuttetal.,1987;FellandShutt,1989;Chapmanetal.,1994;Paulletal.,2008).Behaviouralresponsestomulesingsuchashunchedstanding,stiffwalkingandreducedlyingcanpersist forupto3days(FellandShutt,1989;Paulletal.,2008).Theseposturalindicatorshavebeensuccessfulinde ningtheresponseinlambsfollowinghusbandrypainfulproce- dures(MellorandMurray,1989;MolonyandKent,1997; ThorntonandWaterman-Pearson,1999;Molonyetal.,2002;Grant,2004).Duringthelastdecadetherehasbeensig- ni cantadoptionofpost-operativeanalgesicstoreducethepaincausedbymulesing.Tri-Solfen®isapostoperativeanalgesicthatcontainslignocaine(ashort-actinglocalanaesthetic),bupivacaine(along-actinglocalanaesthetic),centrimideasan †E-mail:andrew.thompson@murdoch.edu.audoi:10.1017/S1751731119000491 animal 2586(Received20March2018;Accepted17January2019; First published online 2 April

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mail:andrew.thompson@murdoch.edu.audoi:10.1017/S1751731119000491 animal 2586(Received20March2018;Accepted17January2019; First published online 2 April 2019)Animal(2019),13:11,pp2586 –2593©TheAnimalConsortium2019

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antiseptictocleansethewoundandadrenalinetoreducebloodlosswhileenhancingtheanaestheticeffects.Paulletal.(2007)andLomaxetal.(2008)reportedthatTri-Solfen®reducedpain-relatedbehavioursinthe rst4to8haftermulesing.Lomaxetal.(2013)concludedthatTri-Solfen®reducedpain-relatedbehavioursforupto24h;however,thisstudyinvolvedverylownumbersofanimals. Otherthanthissinglestudy,thereislimitedevidenceto supportthepremisethatTri-Solfen®offerspainreliefbeyond4to8hpost-mulesinganditsdurationofaction maybemuchless.Non-steroidalanti-in ammatorydrugs(NSAIDs)provideanotheroptionformulesinganalgesia.Theyprovidelong actingpainreliefthroughinhibitionoftheCOX-1and COX-2pathwaysinprostanoidproductioninsofttissues. Thisresultsinrelieffrompainandin ammation(Mathews,2002;RicciottiandFitzGerald,2011).Non-steroidalanti- in ammatorydrugsmaythereforeprovidealongerperiodofpainrelieffollowingmulesingthanTri-Solfen®.Non-steroidalanti-in ammatorydrugshavebeenshowntobeeffectiveatmitigatingpaininarangeofspeciesfollowing docking,dehorningandcastration(Zölsetal.,2005;CoetzeeandSmith,2010;Keitaetal.,2010;Smalletal.,2014),however,therehasbeenlessworkontheireffec- tivenesstoreducepainassociatedwithmulesing.Paulletal.(2008)foundnodifferencesinpeakcortisolcon-centrationsorpain-relatedbehavioursbetweenlambsthatreceivedmeloxicamatthetimeofmulesingornopainrelief.Inthisstudydoseratesandtimeofadministration mayhavelimitedtheeffectivenessofmeloxicaminmiti- gatingpaininresponsetomulesing.Furthermore,no attemptwasmadetodetermineifmeloxicamcould enhanceorextendrelieffrompainprovidedbyTri-Solfen®followingmulesing.Theuseofmultimodalanalgesiawasconsideredpre-viouslybyPaulletal.(2007)whofoundthattreatmentwithatopicalanalgesicincombinationwiththeNSAIDs,carprofen

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ng.Theuseofmultimodalanalgesiawasconsideredpre-viouslybyPaulletal.(2007)whofoundthattreatmentwithatopicalanalgesicincombinationwiththeNSAIDs,carprofen or unixin,reducedpeakcortisolconcentrationsfollowingmulesingandreducedpain-relatedbehaviourscomparedto lambstreatedwithonlyatopicalanalgesic.Theypostulated thattheenhancedeffectivenessofcombininglocalanaes- theticandNSAIDsmightbeduetotheircomplementary durationsandmechanismsofaction.However,therewerenosigni cantdifferencesinplasmacortisolconcentrationsbetweenthesetreatments24haftermulesingandtherewasnoattempttomeasureimpactsonlambbehavioursbeyond 12hpost-mulesing.Thecurrentstudytestedthehypothesesthat(i)pain-relatedbehavioursinMerinolambscouldbeusedto assesstheef cacyofpainmitigationtreatmentsfollowingmulesing;(ii)acombinationofmeloxicamandTri-Solfen®wouldbethemosteffectivetreatmentinmitigatingpain inresponsetomulesinginMerinolambs,and(iii) administrationofmeloxicam15minbeforemulesing wouldbemoreeffectiveinmitigatingpaininresponseto mulesingthanadministrationofmeloxicamatthetimeof mulesing.MaterialandmethodsAnimalsTheresearchwasperformedatMurdochUniversity’sfarmatWhitbyFallsinWesternAustralia(32°17’35”S,116°00’55”E)betweenMayandJuly2017.Atotalof178pregnantMerino ewes(122singlebearingand57twinbearing)lambedbetween MayandJune2017.Sevendaysbeforemulesing,alllambsaged6to10weekswereweighed,eartagged,paint-brandedonbothsideswithauniquenumberandtheirdamwasrecorded.Two daysbeforemulesing,lambswereweighedagainwithan averageweightof12kg.OnehundredandfortyMerinolambs wereallocatedtooneofseventreatments(n=20lambspertreatment)basedonliveweight,sexandreartype(numberof lambsrearedperewe).Lambswerethenallocatedintofour

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wereallocatedtooneofseventreatments(n=20lambspertreatment)basedonliveweight,sexandreartype(numberof lambsrearedperewe).Lambswerethenallocatedintofour plots(n=5lambs/treatmentperplot).Twinsiblingswereallo-catedtothesametreatmentandplot.Thefourplots(50×50m)wereadjacenttotheyardswherethelambsweretreated.Ewes weresupplementedwith1kgofoatenhay(9.0MJMetaboli- sableEnergyperkgDryMatter;6.0%CrudeProtein)and600g oflupins(13.1MJMetabolisableEnergyperkgDryMatter; 31.3%CrudeProtein)perdayperewefortheexperimental period,whichceased10dayspost-mulesing.Lambswere weighed10dayspost-mulesing.Theaverageweightofthelambsthatwerenotmulesedwere15.6kgandthosethatweremulesed,regardlessofpainreliefadministered,were13.5kg.ExperimentaldesignThetreatmentswereimplementedatmulesing(day0)which consistedoflambsthatwerenotmulesed(Control),lambs thatweremulesedandadministeredasalineinjectionas opposedtopainrelief(Placebo),lambsmulesedandadmi- nisteredmeloxicam(Metacam®20,BoehringerIngelheim,Sydney,Australia)15minbeforemulesing(MC-15),lambs mulesedandadministerdTri-Solfen®only(TS),lambsmulesedandadministeredacombinationofmeloxicam15minbefore mulesingandTri-Solfen®(MC-15+TS)andlambsmulesedandadministeredmeloxicaminthecradle(MC0).Atmarking,alllambswereplacedindorsalrecumbencyintoacradlethatrestrainstheanimalaroundthehocksofall fourlimbs.Alllambs,exceptfortheControl(un-mulesedand

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tmarking,alllambswereplacedindorsalrecumbencyintoacradlethatrestrainstheanimalaroundthehocksofall fourlimbs.Alllambs,exceptfortheControl(un-mulesedand untreated)wereearmarked,vaccinatedwithScabiGard®(Zoetis,Sydney,Australia)viaascratchtotheskinontheinnerthighandGlanvac®(Zoetis,Sydney,Australia)viaasub-cutaneousinjection,bothpermanufacturer’sinstructions.Tailsweredockedusingagasheatedknifeandmulesed.FemaleswerealsovaccinatedwithGudair®(Zoetis,Sydney,Australia)viasubcutaneousinjectionhighontheneckskinandinaccordancewithmanufacturer’sinstructions.Maleswerecastratedusingrubberrings.MulesingwasperformedbyaprofessionalcontractoraccreditedbytheLivestockContractorsAssociationofAustralia.Mulesinginvolvedtheremovaloftwo stripsofskinfromthebreechareaoutsidethenon-wooled perinealareaandonestripofskinalongeachlateralsideofthe tail.LambsallocatedtotheControltreatmentwereplacedin thecradlefor60s(averagetimeofmarking)beforebeing releasedtotheirallocatedplots.2587Behaviouraleffectsofpainreliefformulesing

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Theliveweightofeachlambmeasuredtwodayspriortomulesingwasroundedtothenearest5kgandmeloxicamwasadministeredsubcutaneouslybasedonthemanu- facturersrecommendeddoseof1ml/20kgliveweight–1mg/kg(0.5to1mlperlamb).Thedoseofsalineadminis- teredtolambsinthePlacebotreatmentwasalsobasedon therecommendeddosesforMetacam®20.Tri-Solfen®wasadministeredimmediatelyaftermulesingat8mlforlambs between11and15kgand10mlforlambsbetween16and 20kg.AssessmentoflambbehaviourOnday0,fourobserverswereallocated veor10lambsperplottorecordthebehaviourscategorisedinTable1andwere blindedtothetreatments.Allobserverswereexperiencedin assessingsheepbehaviourhavingbeentrainedbeforethecommencementoftheexperimenttostandardisetheirobservationsforcomparability.Liveobservationsweremade 5minafterthelambwasreleasedfromthemarkingcradle andthenevery15minforthefollowing6h.Behaviours recordedwerestanding,walkingandlying;standingand walkingwerethenfurthercategorisedintonormaland abnormalbehavioursasdescribedbySmalletal.(2014)(Table1).Comparisonsoflambbehaviourweremadebetweenthreecompositetraits;totalpain(hunchedandabnormalstandingandstiffwalking),totalnormal(normal standingandwalking)andlying(ventral,lateralandventral/ laterallying).Thelambswereobservedforatotalof15sat eachtimepointandthemostdominantbehaviourexpressed wasrecordedforeach5-sinterval.Thedatawerethenscored as0(notobservedduring15s),1(dominantbehaviourin one5-sinterval),2(dominantbehaviourintwo5-sintervals)or3(dominantbehaviourinallthree5-sintervals)ateachmeasurementperiod.Oneobserverfromeachplotonday0 wasusedfortheobservationsondays1to4andeach observerassessedthesamelambseachday.Onday1, behaviourswererecordedevery15minfor2handondays2 to4behaviourswererecordedevery15minfor1.25h.On

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1to4andeach observerassessedthesamelambseachday.Onday1, behaviourswererecordedevery15minfor2handondays2 to4behaviourswererecordedevery15minfor1.25h.On days1to4,observationsoflambbehaviouronthe rstplotcommencedat9amandoncecompletedtheobserversmovedthroughtheplotsinnumericalorder.StatisticalanalysesAllstatisticalanalyseswereperformedusingGENSTAT(18thedition;VSNInternational,2017,HemelHempstead,UK).Alldatawasanalysedusingthemethodofrestrictedmaximum likelihood.Comparisonsoflambbehaviourweremade betweenthethreecompositetraits;totalpain,totalnormal andlying.Datawereanalysedovertimeforeachhourandeachday,andforday0andday1combined,andthevaluesreportedarefromatotalscoreof3.Anumberofcorrelated structureswereexamined,withasplitplotintimestructure consideredappropriateforallanalyses.The xedeffectsweretreatment,timeofmeasurement,reartype,sexand interactionsthereof.Randomeffectsincludedplot,lamb (nestedwithinplot)andmeasurementperiod(nestedwithin

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weretreatment,timeofmeasurement,reartype,sexand interactionsthereof.Randomeffectsincludedplot,lamb (nestedwithinplot)andmeasurementperiod(nestedwithin lambwithinplot)alongwithobserverandewesource.Forliveweightchangeofthelambsbetweendays−7and10,treatment,sex,reartypeandinteractionsthereofwere ttedas xedeffectswhileplotandlamb(nestedwithinplot)alongwithewesourcewere ttedasrandomeffects.Forallanalysestherewerenosigni cantinteractionsandsothe nalmodelsonlyincludedmaineffectsofthe xedterms.Maineffectsandinteractionshavebeenconsideredsig-ni cantatthe5%level.DifferencebetweenmeanswereassessedusingLSD(P=0.05).Thereweregenerallynosig-ni cantdifferencesinbehaviouralmeasuresbetweenTri-Solfen®andTri-Solfen®andplaceboinjectionhenceonlydatafortheTri-Solfen®treatmentarereported.ResultsEffectofmulesingonlambbehaviourOnaverage,lambsthatweremulesedandnotadministeredpainreliefexhibitedsigni cantlymorepain-relatedbeha-vioursduringthe rst6hpost-mulesingthanlambsthatwerenotmulesed(1.22v.0.22;P<0.05;Table2).Theproportionofpain-relatedbehavioursformulesedlambswithoutpainreliefwasrelativelyconstantoverthe rst6h(P>0.05;Table3).Furthermore,overthe rst6hlambsthatweremulesedandnotadministeredpainreliefexhibited signi cantlyfewernormalbehavioursandlyingthanlambsthatwerenotmulesed(P<0.05;Table2).

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he rst6hlambsthatweremulesedandnotadministeredpainreliefexhibited signi cantlyfewernormalbehavioursandlyingthanlambsthatwerenotmulesed(P<0.05;Table2). Table1CategoriesusedtoclassifybehaviourofMerinolambspost-mulesingCategoryBehaviourNormalNormalstandingLambstoodwithnoobviousposturalabnormality;straight-backed,withheadhigherthanorlevelwithbackNormalwalkingLambexhibitedausualgaitwhilewalking,withevenstepsandnoobvioushesitationPain-relatedAbnormalstandingLambstoodheadlowerthanhighestpointofbackHunchedstandingLambstoodwitharounded,hunchedappearance;backwasarched,withheadlowerthanhighestpointofbackStiffwalkingLambexhibitedstiffortentativemovementswhilewalkingLyingVentralLamblaidonitssternumandabdomenwithallfourlegsfoldedunderthebodyLateralLamblaidonitssidewithoneorbothforelegsandbothhindlegsstretchedoutlaterallyVentral/lateralLamblaidonitssternumandabdomenwithoneorbothhindlegsextendedlaterally2588Inglis,Hancock,LaurenceandThompson

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Therewerealsosigni cantdifferencesinpain-relatedbehaviours(0.50v.1.11;P<0.05;Table2)andnormalbehaviours(1.94v.1.31;P<0.05;Table2)onday1betweenlambsthatweremulesedwithoutpainreliefandthosethatwerenotmulesed;however,thesedifferences werenotevidentondays2to4.Therewerenosigni cantdifferencesinthefrequencyoflyingbetweenmulesedand non-mulesedlambsfromdays1to4.Therewerenosexor reartypeeffectsbetweenlambsineachtreatmentthrough- outtheexperiment.Therewasasigni cantdifferencebetweentreatmentsinliveweightchangeofthelambsbetweendays−7and10.Onaverage,lambsthatwerenotmulesedgained3.9kgcom- paredto1.9kgforlambsmulesedwithoutpainrelief (P<0.001).EffectofpainreliefonlambbehaviourOnaverage,lambsthatwereadministeredacombinationof Tri-Solfen®andmeloxicam15minbeforemulesingexhibitedsigni cantlyfewerpain-relatedbehavioursthroughoutday0thanthosemulesedwithnopainrelief(0.85v.1.22;P<0.05;Table2).Furthermore,lambsthatwereadminis-teredthecombinationofpainreliefdisplayedsigni cantlyfewerpain-relatedbehavioursthanlambsadministeredTri- Solfen®onlyonday0(0.85v.1.16;P<0.001;Table2).Themagnitudeofpain-relatedbehavioursexhibitedbylambs fromallotherpainrelieftreatmentsdidnotdifferpost-mulesing.Overallmeloxicamadministered15minbeforemulesingdidnotsigni cantlyaffectpain-relatedbehaviouronday0.However,at4and5hpost-mulesing,thelambsexhibitedsigni cantlyfewerpain-relatedbehavioursincomparisontolambsmulesedwithnopainrelief(P<0.05).Thiswascon-sistentwiththeresponseat4and5hforlambstreatedwith thecombinationofmeloxicamandTri-Solfen®(Table3).Therewerenosigni cantdifferencesinpain-relatedbehaviourbetweenmulesedlambsthatreceivedpainrelief andthosethatdidnotondays2,3or4.Inaddition,there wasnosigni cantdifferencebetweenlambsthatweremulesedandadministeredpainreliefandthosethatwere

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inrelief andthosethatdidnotondays2,3or4.Inaddition,there wasnosigni cantdifferencebetweenlambsthatweremulesedandadministeredpainreliefandthosethatwere notwhenpain-relatedbehaviouralscoreswereaveraged acrossdays0and1(1.17v.1.11;P=0.12).Therewerenosexorreartypeeffectsonpain-relatedbehaviourbetweenlambsthatwereprovidedpainreliefandthosethatwerenot.Furthermore,liveweighthadnosigni cantimpactonpain-relatedbehaviourbetweenlambsthatreceivedpainrelief andthosethatdidnot(P=0.264).Normalbehavioursexhibitedbylambsonday0,onaverage,werenotsigni cantlydifferentbetweentreat-mentsregardlessofwhetherpainreliefwasadministeredornot.Thenumberofobservationsofnormalbehaviourincreasedsigni cantlyinthe6hfollowingmulesing(P<0.05;Table3).Femalelambsalsodisplayedmorenor-malbehaviourthanmales(1.38v.1.16;P=0.01).Fromdays1to4,therewerenosigni cantdifferencesinnormalbehaviourbetweenpainrelieftreatments,sexorreartypeofthelambs.

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haviourthanmales(1.38v.1.16;P=0.01).Fromdays1to4,therewerenosigni cantdifferencesinnormalbehaviourbetweenpainrelieftreatments,sexorreartypeofthelambs. Table2Effectsofpainreliefonaveragedailybehaviour5dayspost-mulesinginMerinolambsBehavioursPain1Normal2Lying3DayControlPlaceboMC-15TSMC-15+TSMC0P-ValueLSD*ControlPlaceboMC-15TSMC-15+TSMC0P-ValueLSD*ControlPlaceboMC-15TSMC-15+TSMC0P-ValueLSD*00.22B1.22A1.03A1.16A0.85AB0.94A<0.0010.3041.62B1.131.321.08A1.10A1.300.0180.3220.83B0.46A0.47A0.55A0.88A0.51A<0.0010.26710.50B1.11A1.31A1.33A1.40A1.18A<0.0010.4281.94B1.31A1.11A1.19A1.13A1.36A<0.0010.4580.540.570.530.480.420.420.2650.29720.130.300.420.360.64A0.470.0990.3361.661.721.331.431.211.200.2550.5161.130.931.281.181.091.320.7410.47930.010.120.110.160.150.100.5130.1611.481.381.191.101.401.500.2920.4441.531.511.701.741.461.400.6310.45440.010.090.020.13A0.030.060.2780.1091.97B1.23A1.37AA1.28A1.72B1.47A0.0420.4851.041.68A1.62A1.60AA1.271.47<0.0010.490Valuesarerespresentedasobservationsscoredoutofthree.Control=lambswerenotmulesed;Placebo=lambsweremulesedandadministerednopainrelief;MC-15=lambsweremulesedandadministeredMetacam®2015minbeforemulesing;TS=lambsweremulesedandadministeredTri-Solfen®;MC-15+TS=lambsweremulesedandadministeredacombinationofMetacam®2015minbeforemulesingandTri-Solfen®;MC0=lambsweremulesedandadministeredMetacam®20inthecradle.AMeanswithinarowaresigni cantlydifferenttotheControltreatment(P<0.05).BMeanswithinarowaresigni cantlydifferenttothePlacebotreatment(P<0.05).1Totalpain=hunchedandabnormalstandingandstiffwalking.2Totalnormal=normalstandingandwalking.3Totallying=ventral,lateralandventral/laterallying.*LSD(P=0.05).2589Behaviouraleffectsofpainreliefformulesing

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Table3Effectsofpainreliefonaveragehourlybehaviour6hpost-mulesinginMerinolambsAveragehourlybehavioursonday0Pain1Normal2Lying3HourControlPlaceboMC-15TSMC-15+TSMC0P-valueLSD*ControlPlaceboMC-15TSMC-15+TSMC0P-valueLSD*ControlPlaceboMC-15TSMC-15+TSMC0P-valueLSD*10.39B1.21A1.09A1.08A0.840.99A0.0150.4781.60B0.92A0.80A0.84A1.091.01A0.0210.5130.330.480.83A0.720.710.750.3320.47020.19B0.88A0.82A0.99A0.88A0.86A0.0090.4701.381.331.160.71AB0.931.060.2340.5541.030.600.700.950.990.770.5930.54730.30B1.21A1.36A1.32A0.86A0.99A<0.0010.5111.37B0.751.06A0.811.071.100.3230.5381.170.760.43A0.60A0.940.640.1710.54740.16B1.47A0.93AB1.18A0.72AB1.08A<0.0010.5091.581.081.571.290.89A1.570.1820.6190.89B0.28A0.430.39A1.27B0.24A<0.0010.46950.11B1.37A0.83AB1.55A0.71AB0.94A<0.0010.4811.841.351.661.321.381.490.5340.5760.87B0.26A0.440.440.83B0.41A0.0690.45560.05B0.95A1.01A1.07A0.87A0.60A<0.0010.4922.001.541.771.511.42A1.890.3040.5490.780.420.07A0.330.570.25A0.0740.458Valuesarerespresentedasobservationsscoredoutofthree.Control=lambswerenotmulesed;Placebo=lambsweremulesedandadministerednopainrelief;MC-15=lambsweremulesedandadministeredMetacam®2015minbeforemulesing;TS=lambsweremulesedandadministeredTri-Solfen®;MC-15+TS=lambsweremulesedandadministeredacombinationofMetacam®2015minbeforemulesingandTri-Solfen®;MC0=lambsweremulesedandadministeredMetacam®20inthecradle.AMeanswithinarowaresigni cantlydifferenttotheControltreatment(P<0.05).BMeanswithinarowaresigni cantlydifferenttothePlacebotreatment(P<0.05).1Totalpain=hunchedandabnormalstandingandstiffwalking.2Totalnormal=normalstandingandwalking.3Totallying=ventral,lateralandventral/laterallying.*LSD(P=0.05).Inglis,Hancock,LaurenceandThompsonInglis,Hancock,LaurenceandThompson2590

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LambsthatwereadministeredthecombinationofTri-Solfen®andmeloxicam15minbeforemulesingspentmoretimelyingthanlambsadministerednopainreliefonday0(P<0.05;Table2).Thisagainre ectedtreatmentdifferences4hpost-mulesing(Table3).Therewerenosig-ni cantdifferencesinlyingbehaviourbetweensexesorreartypesfromdays0to4.Therewasalsonosigni cantdiffer-enceinliveweightchangefromdays−7to10betweenlambsadministeredpainreliefandthosethatwerenot (P>0.05).DiscussionMulesingsigni cantlyincreasedthepain-relatedbehavioursasevidencedbyhunchedstandingandstiffwalkingincomparisontolambsthatwerenotmulesed.The20%dif- ferenceinpain-relatedbehavioursacrossdays0and1was similarinmagnitudetothatreportedbyPaulletal.(2007and2008).Lambsthatwerenotmuleseddisplayedsig-ni cantlyfewerpain-relatedbehavioursinthe30hfollowingmarkingcomparedtolambsthatweremulesed.Thisresult,andtheresultsreferredtofrompreviousresearch,provides evidenceinsupportoftheinitialhypothesisthatbehavioural observationscanbeusedtoassesstheeffectofpainreliefin mulesedlambs.ThecombinationofmeloxicamandTri-Solfen®sig-ni cantlyreducedpain-relatedbehavioursinthe6hpost-mulesingcomparedtolambsmulesedandadministeredno painrelief,supportingoursecondhypothesis.Independently, Tri-Solfen®,meloxicamadministered15minbeforemulesingandmeloxicamadministeredinthecradledidnotaffectthe averageincidenceofpain-relatedbehaviourduringtheday aftermulesingcomparedtolambsmulesedandgivenno painrelief.Astherewerenodifferencesinpain-related behavioursbetweentheadministrationtimesofmeloxicamourthirdhypothesiswasrejected.Overall,our ndingssug-gestthatundertheconditionsofthisstudyacombinationofatopicalanalgesiaandmeloxicamwasmosteffectiveat decreasingpain-relatedbehavioursassociatedwithmulesing inMerinolambs.Theeffectivenessofcombiningmeloxicam

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picalanalgesiaandmeloxicamwasmosteffectiveat decreasingpain-relatedbehavioursassociatedwithmulesing inMerinolambs.Theeffectivenessofcombiningmeloxicam andTri-Solfen®todecreasepain-relatedbehavioursiscon-sistentwithPaulletal.(2007).Theyfoundthecombinationofcarprofenandatopicalanaestheticreducedtheacuteriseincortisolfor24handpeakplasmacortisolconcentrationswerenotsigni cantlydifferenttonon-mulesedanimals.Twelvehoursofbehaviouralobservationsalsoindicatedthat animalsadministeredthecombinationofanalgesicsspent lesstimestandingandinahunchedpostureandwerenot differentfromnon-mulesedanimals.Painalleviationislikely duetotwomechanisms;theanaestheticpropertiesofthe topicalanalgesiaworkingdirectlyonnerve brestoblockpainsignals(Sheil,2015),andtheNSAIDinhibitingin am-mationandassociatedpainbyreducingpressureonnerve endings(Daviesetal.,1984).Thecontributionofthesemechanismstotheexpressionofthepainrelatedbehavioursobservedinresponsetomulesinginthecurrentstudyare unknown.LambsthatwereonlytreatedwithTri-Solfen®hadsig-ni cantlymorepain-relatedbehavioursonday0incompar-isontolambstreatedwiththecombinationofmeloxicamand Tri-Solfen®,andtherewasnodifferenceinpainrelatedbehaviourswhencomparedtolambsmulesedandadminis- terednopainrelief.TheabsenceofaneffectofTri-Solfen®aloneonlambbehaviourinresponsetomulesing,iscontrary topreviousstudies(Paulletal.,2007;Lomaxetal.,2008and2013).Paulletal.(2007)foundTri-Solfen®tohavemoderateanalgesiceffects4hpost-mulesingasevidencedbyless hunchedstandingcomparedtolambsmulesedwithoutpain relief.However,Lomaxetal.(2013)foundwoundsensitivityandpain-relatedbehaviourswerereducedfor24h.The shortertermofpainreliefobservedbyPaulletal.(2007)wassuggestedtobecausedbythecollectionofbloodsamplesto measurecortisolconcentrations,whichlikelyexacerbatedpain

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rmofpainreliefobservedbyPaulletal.(2007)wassuggestedtobecausedbythecollectionofbloodsamplesto measurecortisolconcentrations,whichlikelyexacerbatedpain responses.Thepresentstudysuggeststhiswasnotthecaseastheexperimentaldesignmimickedanon-farmscenariowithnophysicaldisturbancesandtheeffectivenessofTri-Solfen®wasnotre ectedinbehaviour.Thepreviousstudiesdiscussedhadrelativelylowanimalnumbersincomparisontothisstudy, andtheanimalsusedwereeitherhousedindoorsoron pasture-coveredpenslessthanone-tenththesizeofwhatwas usedinthisexperiment.Thismayaccountforthedifferences observedbetweenexperimentsintheeffectivenessofTri-Solfen®inreducingpain-relatedbehaviours.Theaverageincidenceofpainrelatedbehavioursonday0wassimilarforlambsadministeredthecombinationofmeloxicamandTri-Solfen®andindividualadministrationofmeloxicam15minbeforemulesing.Furthermore,adminis- trationofmeloxicam15minbeforemulesingsigni cantlydecreasedpain-relatedbehavioursat4and5hpost- mulesingwhencomparedtolambsthatreceivednopainrelief.Therefore,thepresentstudysuggeststhemainanalgesiaresponsiblefortheeffectivenessofthecombina- tiontreatmentwasmeloxicam.ThisisconsistentwithSmalletal.(2014)whoreportedthatbuccalmeloxicamdecreasedthecombinedabnormalbehaviours(hunchedstanding, standingwithstretchedpostureandwalkingstif y)for8hfollowingknifecastrationandtaildockingcomparedto lambsofferednopainrelief.Therelativeeffectivenessofmeloxicaminreducingpain-relatedbehavioursmayberelatedtodoseandtimeof administration.Paulletal.(2008)foundmeloxicamadmi-nisteredattimeofmulesingat0.5mg/kghadnoeffecton behaviour.Colditzetal.(2011)administeredmeloxicamat1mg/kg,whichrelievedsheepfromlamenessat6to8h overa24-hperiod.Mulesingcausessofttissuedamagethat

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ton behaviour.Colditzetal.(2011)administeredmeloxicamat1mg/kg,whichrelievedsheepfromlamenessat6to8h overa24-hperiod.Mulesingcausessofttissuedamagethat resultsinrapidin ammation.GivenNSAIDspreferentiallyaccumulateinin amedtissue,administrationofaNSAIDatthetimeofmulesingwillallowforquickabsorption(Paulletal.,2008;Schweitzeretal.,2009).However,theanalgesiceffectwilldependlargelyonthedoseadministered.Phar- macokineticsofNSAIDscannotbetransferredfromone2591Behaviouraleffectsofpainreliefformulesing

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speciestoanother(Welshetal.,1993),andtotheauthors’knowledgeonlytwostudieshaveinvestigatedthepharma-cokineticsofmeloxicaminsheepandshowedthatplasmaconcentrationsofmeloxicamweredetectablefor24to72h(Shuklaetal.,2007;Stocketal.,2013).Doseratesandexpecteddurationofactionformeloxicam(andother NSAIDs)inprevioussheepresearchhasbeenextrapolated fromdatafromotherspecies(Paulletal.,2008).Thisincludesosteoarthritisincatsanddogsandcastrationof cattleandpigs(Leesetal.,1998;Mathews,2002;Zölsetal.,2005).Coetzeeetal.(2009)documentedahalf-lifeof27.5hincalves,supportingthenotionthatmeloxicamisagood choiceforlong-lastinganalgesiainruminants.Withthe amountofsofttissuedamagecausedbymulesingand minimalanalgesiaobservedinthiscurrentexperiment, increaseddoseratesofmeloxicamadministeredinthecradle couldbeinvestigatedincombinationwithTri-Solfen®.Toenhanceadoptionofinjectablemeloxicambycommercial sheepproducerseaseofapplicationiscrucial,suchastheabilitytoadministerpainreliefinthemarkingcradle.WeconcludethatusingacombinationofmeloxicamandTri-Solfen®canreducepain-relatedbehavioursinthe rst6hpost-mulesing.However,thisstudydidnotobserveanalgesiceffectsthroughbehaviouralmeasures24hpost- mulesingregardlessofthetypeofpainreliefadministered. Thispaperaddssupporttothepremisethatmulesingsheep ispainful,thispainismeasurableusingpain-relatedbeha-viourandthatacombinationofanalgesicsismosteffectiveinmitigatingthepain.AcknowledgementsTheauthorsthankBoehringerIngleheim(Sydney,Australia)forfunding.L.I.wastherecipientofanAustralianWoolEducation TrustandUniversitiesFederationforAnimalWelfare(UK) scholarshipandtheirsupportissincerelythanked. S.Hancock,0000-0002-4115-4642 M.Laurence,0000-0003-1215-2848DeclarationofInterestNone.EthicsStatementAllproceduresdescribedwereperformedinaccordancewith

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Hancock,0000-0002-4115-4642 M.Laurence,0000-0003-1215-2848DeclarationofInterestNone.EthicsStatementAllproceduresdescribedwereperformedinaccordancewith theAustralianCodeofPracticefortheUseofAnimalsfor Scienti cPurposes2013andwereapprovedbytheMurdochUniversityAnimalEthicsCommittee(R2903/17).SoftwareanddatarepositoryresourcesTherearenosoftwareand/ordatarepositoryresources.ReferencesChapmanR,FellLandShuttD1994.Acomparisonofstressinsurgicallyandnon-surgicallymulesedsheep.AustralianVeterinaryJournal71, 243–247.CoetzeeJF,MosherRandAllenPS2009.Phatmacokenticsofintraveousand oralMeloxicaminruminantcalves.VeterinaryTherapeutics10,1–8.CoetzeeHandSmithR2010.Recommendationsforcastrationanddehorningof cattle.InProceedingsofthe43rdAnnualConferenceoftheAmericanAssocia- tionofBovinePractitioners,Albuquerque,NM,USA,19–21August2010,pp.40–45.ColditzI,PaullD,HervaultG,AubriotDandLeeC2011.Developmentofa lamenessmodelinsheepforassessingef cacyofanalgesics.AustralianVeter-inaryJournal89,297–304.DaviesP,BaileyPJ,GoldenbergMMandFord-HutchinsonAW1984.Theroleofarachidonicacidoxygenationproductsinpainandin ammation.AnnualReviewofImmunology2,335–357.FellLandShuttD1989.Behaviouralandhormonalresponsestoacutesurgicalstressinsheep.AppliedAnimalBehaviourScience22,283–294.GrantC2004.Behaviouralresponsesoflambstocommonpainfulhusbandry procedures.AppliedAnimalBehaviourScience87,255–273.KeitaA,PagotE,PrunierAandGuidariniC2010.Pre-emptivemeloxicamfor opst-operativeanalgesiainpigletsundergoingsurgicalcastration.Veterinary AnaesthesiaandAnalgesia37,367–374.LaneJ,JubbT,ShephardR,Webb-WareJandFordyceG2015.Prioritylistof endemicdiseasesfortheredmeatindustries.Meat&LivestockAustralia,

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aandAnalgesia37,367–374.LaneJ,JubbT,ShephardR,Webb-WareJandFordyceG2015.Prioritylistof endemicdiseasesfortheredmeatindustries.Meat&LivestockAustralia, Sydney,NSW,Australia.LeeCandFisherAD2007.Welfareconsequencesofmulesingofsheep.AustralianVeterinaryJournal85,89–93.LeesP,McKellarQ,FootRandGettinbyG1998.Pharmacodynamicsand pharmacokineticsoftolfenamicacidinruminatingcalves:evaluationinmodels ofacutein ammation.TheVeterinaryJournal155,275–288.LomaxS,SheilMandWindsorP2008.Impactoftopicalanaesthesiaonpain alleviationandwoundhealinginlambsaftermulesing.AustralianVeterinary Journal86,159–168.LomaxS,SheilMandWindsorP2013.Durationofactionofatopicalanaes-theticformulationforpainmanagementofmulesinginsheep.AustralianVeterinaryJournal91,160–167.MathewsKA2002.Non steroidalanti in ammatoryanalgesics:areviewofcurrentpractice.JournalofVeterinaryEmergencyandCriticalCare12, 89–97.MellorDandMurrayL1989.Effectsoftaildockingandcastrationonbehaviour andplasmacortisolconcentrationsinyounglambs.ResearchofVeterinary Science46,387–391.MolonyVandKentJ1997.Assessmentofacutepaininfarmanimalsusing beahviouralandphysiologicalmeasurements.JournalofAnimalScience75, 266–272.MolonyV,KentJandMcKendrickI2002.Validationofamethodforassess- mentofanacutepaininlambs.AppliedAnimalBehaviourScience76, 215–238.PaullD,LeeC,AtkinsonSandFisherA2008.Effectsofmeloxicamortolfenamic acidadministrationonthepainandstressresponsesofMerinolambstomulesing.AustralianVeterinaryJournal86,303–311.PaullD,LeeC,ColditzI,AtkinsonSandFisherA2007.Theeffectofatopical

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hepainandstressresponsesofMerinolambstomulesing.AustralianVeterinaryJournal86,303–311.PaullD,LeeC,ColditzI,AtkinsonSandFisherA2007.Theeffectofatopical anaestheticformulation,systemic unixinandcarprofen,singlyorincombina-tion,oncortisolandbehaviouralresponsesofMerinolambstomulesing.Aus-tralianVeterinaryJournal85,98–106.PhillipsCJ2009.Areviewofmulesingandothermethodstocontrol ystrike(cutaneousmyiasis)insheep.AnimalWelfare18,113–121.RicciottiEandFitzGeraldGA2011.Prostaglandinsandin ammation.Arterio-sclerosis,Thrombosis,andVascularBiology31,986–1000.SackettD,HolmesP,AbbottK,JephcottSandBarberM2006.Assessingthe economiccostofendemicdiseaseonthepro tabilityofAustralianbeefcattleandsheepproducers.MeatandLivestockAustralia,Sydney,NSW, Australia.SchweitzerA,Hasler-NguyenNandZijlstraJ2009.Preferentialuptakeofthenonsteroidanti-in ammatorydrugdiclofenacintoin amedtissuesafterasingleoraldoseinrats.BMCPharmacology9,5.2592Inglis,Hancock,LaurenceandThompson

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SheilML2015.Analgesiaforsurgicalhusbandryproceduresinsheepandotherlivestock.AnimalEthicsPtyLtd,AssociateSydneyUniversityFacultyofVeter- inaryScience,Sydney,NSW,Australia.ShuklaM,SinghG,SindhuraB,TelangA,RaoGandMalikJ2007.Comparativeplasmapharmacokineticsofmeloxicaminsheepandgoatsfollowingintrave- nousadministration.ComparativeBiochemistryandPhysiologyPartC:Tox-icology&Pharmacology145,528–532.ShuttD,FellL,ConnellR,BellA,WallaceCandSmithA1987.Stress-induced changesinplasmaconcentrationsofimmunoreactiveß-endorphinandcortisolinresponsetoroutinesurgicalproceduresinlambs.AustralianJournalofBio- logicalSciences40,97–104.SmallA,BelsonS,HolmMandColditzI2014.Ef cacyofabuccalmeloxicamformulationforpainreliefinMerinolambsundergoingknifecastrationand taildockinginarandomised eldtrial.AustralianVeterinaryJournal92,381–388.StockML,CoetzeeJF,KuKanichBandSmithBI2013.Pharmacokineticsof intravenouslyandorallyadministeredmeloxicaminsheep.AmericanJournalof VeterinaryResearch74,779–783.ThorntonPandWaterman-PearsonA1999.Quanti cationofthepainanddistressresponsestocastrationinyounglambs.ResearchofVeterinaryScience 66,107–118.VSNInternational2017.GenstatReferenceManual.VSNInternational,Hemel Hempstead,UK.WelshE,McKellarQandNolanA1993.Thepharmacokineticsof unixinmeglumineinthesheep.JournalofVeterinaryPharmacologyandTherapeutics16,181–188.ZölsS,RitzmannMandHeinritziK2005.Effectofanalgesicsonthecastrationof malepiglets.BerlinerUndMunchenerTierarztlicheWochenschrift119,193–196.2593Behaviouraleffectsofpainreliefformulesing

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