Effect of Medetomidine, Dexmedetomidine, and Their ... - MDPI

Medetomidine, an alpha-2 agonist routinely used to provide sedation and pain relief in dogs, is a mixture of dexmedetomidine and levomedetomidine in equal ... NextArticleinJournal HistoricalChangesandDescriptionoftheCurrentHungarianHuculHorsePopulation PreviousArticleinJournal ReviewofLivestockWelfareIndicatorsRelevantfortheAustralianLiveExportIndustry 25thAnniversary Journals Information ForAuthors ForReviewers ForEditors ForLibrarians ForPublishers ForSocieties ArticleProcessingCharges OpenAccessPolicy InstitutionalOpenAccessProgram EditorialProcess Awards ResearchandPublicationEthics AuthorServices Initiatives Sciforum MDPIBooks Preprints Scilit SciProfiles Encyclopedia JAMS ProceedingsSeries About SignIn/SignUp Notice Youcanmakesubmissionstootherjournals here. clear Notice Youareaccessingamachine-readablepage.Inordertobehuman-readable,pleaseinstallanRSSreader. 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Levionnois,O.Louis FullArticleText /ajax/scifeed/subscribe share announcement question_answer thumb_up ... textsms ... NeedHelp? Support Findsupportforaspecificprobleminthesupportsectionofourwebsite. GetSupport Feedback Pleaseletusknowwhatyouthinkofourproductsandservices. GiveFeedback Information VisitourdedicatedinformationsectiontolearnmoreaboutMDPI. GetInformation clear OpenAccessArticle EffectofMedetomidine,Dexmedetomidine,andTheirReversalwithAtipamezoleontheNociceptiveWithdrawalReflexinBeagles by JoëlleSiegenthaler1,TeklaPleyers1,MathieuRaillard1,2,ClaudiaSpadavecchia1andOlivierLouisLevionnois1,* 1 SectionofAnaesthesiologyandPainTherapy,DepartmentofClinicalVeterinarySciences,VetsuisseFaculty,UniversityofBerne,3012Bern,Switzerland 2 UniversityVeterinaryTeachingHospital,SchoolofVeterinaryScience,FacultyofScience,TheUniversityofSydney,Sydney2006,Australia * Authortowhomcorrespondenceshouldbeaddressed. Animals2020,10(7),1240;https://doi.org/10.3390/ani10071240 Received:17June2020/Revised:17July2020/Accepted:17July2020/Published:21July2020 (ThisarticlebelongstotheSectionCompanionAnimals) DownloadPDF BrowseFigures Review Reports CitationExport BibTeX EndNote RIS CiteThisPaper SimpleSummary Medetomidine,analpha-2agonistroutinelyusedtoprovidesedationandpainreliefindogs,isamixtureofdexmedetomidineandlevomedetomidineinequalproportions.Dexmedetomidine,consideredtobetheonlyactivecomponentinthemixture,isalsomarketedalone.Sedationcausedbybothformulationscanbereversedusingatipamezole,whichshortensrecovery.Dexmedetomidineprovidesanalgesiceffectssimilartomedetomidine,butitremainsunclearatwhichdoseandwhethertheanalgesiceffectsofmedetomidineordexmedetomidinedisappearonceatipamezoleisinjected.Thepresenttrialaimedatelucidatingtheseuncertaintiesusingthenociceptivewithdrawalreflexmodel.Thismodelallowsforquantificationofanalgesiabymeasuringspecificactivityfrommusclesinvolvedinlimbwithdrawalinresponsetomildelectricalstimulation.Ineightbeagles,themodelwasappliedtocomparetheextentofpainreliefprovidedbymedetomidineanddexmedetomidineandtoinvestigatewhethercompletereversaloccursaftertheadministrationofatipamezole.Nodifferenceinanalgesicefficacywasidentifiedbetweenthetwoformulations.Bothsedationandpainreliefterminatedrapidlywhenatipamezolewasadministered.Thesefindingsindicatethatmedetomidineanddexmedetomidineprovidecomparablelevelsofpainreliefandthatadditionalanalgesicsmaybenecessarywhenatipamezoleisadministeredtodogsexperiencingpain. Abstract Theobjectiveswere:(1)tocomparetheantinociceptiveactivityofdexmedetomidineandmedetomidine,and(2)toinvestigateitsmodulationbyatipamezole.Thisprospective,randomized,blindedexperimentaltrialwascarriedoutoneightbeagles.Duringthefirstsession,dogsreceivedeithermedetomidine(MED)(0.02mgkg−1intravenously(IV)]ordexmedetomidine(DEX)[0.01mgkg−1IV),followedbyeitheratipamezole(ATI)(0.1mgkg−1)oranequivalentvolumeofsaline(SAL)administeredintramuscularly45minlater.Theoppositetreatmentswereadministeredinasecondsession10–14dayslater.Thenociceptivewithdrawalreflex(NWR)thresholdwasdeterminedusingacontinuoustrackingapproach.Sedationwasscored(0to21)every10min.Bothdrugs(MEDandDEX)increasedtheNWRthresholdssignificantlyupto5.0(3.7–5.9)and4.4(3.9–4.8)timesthebaseline(p=0.547),atseven(3–11)andsix(4–9)minutes(p=0.938),respectively.SedationscoreswerenotdifferentbetweenMEDandDEXduringthefirst45min(15(12–17),p=0.67).Atipamezoleantagonizedsedationwithin25(15–25)minutes(p=0.008)andantinociceptionwithinfive(3–6)minutes(p=0.008).Followingatipamezole,additionalanalgesicsmaybeneededtomaintainpainrelief. Keywords: antinociception;atipamezole;dexmedetomidine;dog;nociceptivewithdrawalreflex;sedation antinociception;atipamezole;dexmedetomidine;dog;nociceptivewithdrawalreflex;sedation 1.IntroductionMedetomidineanddexmedetomidinearealpha-2adrenoreceptoragonistsroutinelyusedtoproducesedationandanalgesiaindogs[1,2,3,4].Medetomidineisaracemicmixtureoftwoopticalisomers,levomedetomidineanddexmedetomidine[5].Asdexmedetomidineisconsideredtheonlyactiveisomer,itiscommonlyadministeredathalfoftheadministereddoseofmedetomidinetoobtainsimilarlevelsofsedation[6,7]andantinociception[4,6].However,contrastingevidenceindicatesthatdexmedetomidineinducesweakersedation[8]andstrongerantinociception[3]thanmedetomidine,thusraisingsomequestionsaboutthecommonassumptionofequipotency.Sofar,theantinociceptiveeffectsofmedetomidineanddexmedetomidinehavebeenmainlyevaluatedusingbehavioralmodelsbasedonthermal,electricalormechanicalstimulation.Thesemodelstypicallyrelyonthedirectobservationofnocifensivereactionsasend-points[3,4,6,9,10,11,12,13,14,15].Whenusedtoevaluateantinociceptioninducedbyalpha-2adrenoreceptoragonists,theconcomitantsedationandmusclerelaxationelicitedbythesedrugscanintroducesignificantbias[2].Inaddition,theprocessofnociceptivethresholddeterminationcangenerallybeperformedonlyatrelativelywidetimeintervals(every10–30min)[3,4,9,10,11,13,15].Amoreaccuratecomparisonoftheantinociceptivepropertiesofthesedrugsandtheirtemporalcharacteristicsmightbeobtainedwiththenociceptivewithdrawalreflex(NWR)model[16].Basedonnon-invasivetranscutaneouselectricalstimulationofperipheralnervesandsurfaceelectromyographic(EMG)recordings,itallowsareliabledeterminationofthenociceptivethresholdthroughtheneurophysiologicalcharacterizationoftheevokedresponse.TheNWRmodel,validatedinseveralanimalspecies[16,17,18],hasbeenappliedtoquantifytheantinociceptiveeffectsofanalgesicandanestheticdrugs[19,20,21],includingalpha-2agonists[22,23,24].Therecentintroductionofanautomatedthresholdtrackingmethodology,allowinganalmostcontinuousNWRthresholddetermination,furtherimprovedthemodel[25],makingitidealforhighlightingsubtletemporaldifferencesbetweendrugs,asitwouldberequiredtoreliablycomparesimilardrugssuchasmedetomidineanddexmedetomidine.Atipamezole,analpha-2adrenoreceptorantagonist,iscommonlyadministeredtoreversemedetomidine-ordexmedetomidine-inducedsedationandtoshortenrecovery.Previousworksuggeststhatatipamezolemightcontemporaneouslyreverseantinociception[4,26],whichcanbeconsideredaratherundesiredpropertyinclinicalsettings.Todate,specificinvestigationsonpotentialdifferentialeffectsofatipamezoleonsedationversusantinociceptionarescarceanddonotprovideconclusiveevidence.Again,theNWRmodelcouldprovideinterestingquantitativedatatofillthisclinicallyrelevantknowledgegap.Theaimsofthisstudywere:(1)tocomparetheeffectsofintravenous(IV)dexmedetomidineandmedetomidineonsedationandantinociceptionindogs,and(2)toinvestigatetheirdifferentialmodulationbyintramuscular(IM)atipamezole.Weintendedtotestthehypothesesthat(1)dexmedetomidineathalfthedoseofmedetomidinewouldevokehigherNWRthresholdsthanmedetomidineusingthecontinuousNWRthresholdtrackingmethod,and(2)followingatipamezoleadministration,theNWRthresholdswouldreturntobaselinelaterthansedationscores.2.MaterialsandMethodsThisexperimentwasapprovedbytheCantonalCommitteeforAnimalExperimentation(approvalnumber30356).Duringthestudy,theinvestigatorswereunawareofthetreatmentsadministered(blindeddesign).2.1.SampleSize,DesignThefirstobjectiveofthestudywastodetectadifferenceinpeakNWRthresholdsafteradministrationofmedetomidineordexmedetomidine.InpreviousstudiesitwasshownthatthemedianNWRthresholdofnon-medicateddogsisapproximately2.5(2–3)mA[19].Medetomidinewasexpectedtoincreaseitby5(4–6)times(personalexperience).A20%differencebetweentheNWRthresholdsinducedbydexmedetomidinecomparedtomedetomidinewasarbitrarilyconsideredarelevantendpoint.Withacrossoverdesign,eightdogsatleastwereconsiderednecessary(Wilcoxonsigned-ranktest,paired,two-tailed,effectsize=1.4,α=0.05,1-β=0.9,GPower3.1,Germany).Thesecondobjectiveofthestudywastodetectadifferenceindurationofeffectbetweenantinociceptionandsedationafteradministrationofatipamezole.Reversalofsedationisexpectedtooccurwithin10(8–12)minutes[4].A10mindelayforreversalofantinociceptionwasconsideredarelevantendpoint.Withacrossoverdesign,threedogsatleastwereconsiderednecessary(Wilcoxonsigned-ranktest,paired,two-tailed,effectsize=5,α=0.05,1-β=0.9,GPower3.1,Germany).Aparallelstudyevaluatingselectedrespiratoryeffectsofmedetomidineanddexmedetomidineusingelectricalimpedancetomography(EIT)wasalsocarriedoutatthesametime(datareportedelsewhere[27]).AbsenceofinterferencebetweenEITandNWRrecordingswasconfirmedbymanufacturersofbothdevicesandduringtheexperiment.2.2.AnimalsAtotalofeightintactexperimentalbeagles(twofemalesandsixmales)wereenrolledinthisstudy.Dogswerehousedwithotherkennel-matesingroupsofthree,hadaccesstoanenrichedindoorandoutdoorcourse.Theywerenotinvolvedinanyotherexperiments,anddidnotreceiveanydrugotherthananthelminthicinthetwomonthsprecedingthetrial.Theywereconsideredhealthybasedonphysicalexaminationandselectedhematologyandbloodchemistryanalysis.Totalbodyweight(BW)wasmeasuredforeachdogbeforeeachsession.Allthedogshadabodyconditionscoreof5or6onascaleof9(bodyconditionsystem,NestléPurina,Vevey,Switzerland).Mandibularlymphnodesweremoderatelyincreasedinsizeinfiveanimals;thiswasattributedtomilddentaldiseasewithoutanysignofpain.2.3.Randomization,BlindingandTreatmentDogsweresedatedtwice(crossoverdesign)with10to14dayswash-outbetweenthetwosessions.Eachsessionincludedtwoconsecutivephases:(1)sedationattimezero(T0),and(2)reversal,45minlater(T45).Thesedation(Phase1,T0–T45)consistedofeithermedetomidine(“MED”;Domitor,1mgmL−1;OrionPharma,Switzerland;0.02mgkg−1BWIV)ordexmedetomidine(“DEX”;Dexdomitor,0.5mgmL−1;OrionPharma,Switzerland;0.01mgkg−1BWIV).Thereversal(Phase2,T45–T210)consistedofeitheratipamezole(“ATI”;Antisedan,5mgmL−1;OrionPharma,Switzerland;0.1mgkg−1BWIM)orsaline(“SAL”;NaCl0.9%,BBraunMelsungenAG,Melsungen,Germany;volumeequivalenttoATI,IM).Beforetheexperiment,dogswererandomlyassigned(http://www.randomization.com)tooneoffourblocks(MED/ATI,MED/SAL,DEX/ATI,DEX/SAL,n=2perblock)forthefirstsession.Theoppositetreatmentswereadministeredduringthesecondsession.Forexample,adogreceivingMED/ATIatthefirstsessionwouldreceiveDEX/SALatthesecond.Treatmentswerepreparedeachdaybyapersonnotinvolvedinthedatacollectionbutfamiliarwiththestudydesign;similarvolumesofcolorlesssolutionswereadministeredsoinvestigatorswereunawareofthetreatmentsadministered.Experimentstookplaceovera4-weekperiodinNovemberandDecember,2018.Eachday,onlyonedogwassedated.Aquiet,dedicatedroomwithinthesamefacilitywheredogswerehousedwasused.Thedogswereacclimatizedtotheroomandtotheinvestigatorsthedaybeforetheexperiment.Astandardmealwasprovidedinthenightbefore;waterremainedavailableovernight.Experimentsstartedaround09:00a.m.foralldogs.2.4.AnimalPreparationThedaybeforetheexperiment,hairwasclippedoverstimulationandrecordingsitesonthelefthindlimb,atthesiteofinsertionofIVcannulasandaroundthethoraxfortheEITbelt.Onthedayoftheexperiment,dogswereweighed,theidentificationnumber(electronicchip)wascheckedandaphysicalexaminationwasperformed.Iftheanimalpresentedwithabnormalitiesatphysicalexaminationordevelopedunexpectedcomplicationsduringthestudy,itwouldbeexcludedandreplaced.Aeutecticmixtureoflocalanesthetics(Emlacream5%;AspenPharmaGmbH,Switzerland)wasappliedoverbothrightandleftcephalicveinsandcoveredwithanocclusivedressingapproximatelyonehourbeforeplacementofintravenouscatheters(22gauge,25mm,Optiva2IVCatheter;SmithsMedicalInternationalLtd.,LowerPemberton,UK).Electrodepositioningwasstandardizedtoavoiddifferencesamongbodyregionandbiologicalfunction[28,29,30].Thestimulationandrecordingsiteswereshavedanddegreasedandgentleabrasionwasperformedwithabrasivetape(RedDotTracePrep;3M,Switzerland).Twoself-adhesivestimulationelectrodes(BluesensorN;Ambu,Germany)wereplaced0.5cmapartovertheleftlateralplantardigitalnervewiththeanodeinthedistalposition.Twoself-adhesiverecordingelectrodes(BluesensorN;Ambu,Germany)wereplaced0.5cmapartoverthelefttibialiscranialismuscle,3cmdistaltothekneejoint.Aself-adhesivegroundelectrode(BluesensorVL;Ambu,Germany)wasplacedoverthelatero-distalfemoralepicondyle.Theelectrodeswerefixedwithbandagestoavoiddisplacement.Electrodeimpedancewasmeasuredcontinuously,andtheelectrodeswerereplacedifabove3kΩ.Thedogswerepositionedandgentlymaintainedinrightlateralrecumbencyonasoftpillow.Attheendoftheexperiment(latestT210),theelectrodeswereremovedandalayerofmultipurposeantisepticcream(BepanthenOnguent;BayerAG,Switzerland)wasappliedtoavoidskinirritationattheelectrodesites.Aheparin-basedcream(Hirudoidcream;MedinovaAG,Switzerland)wasappliedatthesitesofvenouscatheterizationtopreventphlebitis.Thedogsweremonitoredforafurther4htopreventcomplications,discomfortorre-sedation,beforebeingre-introducedtotheirnormalenvironment.2.5.NWRThresholdDeterminationAfterinstrumentation,electricalstimulationandEMGrecordingwereinitiatedusingadedicatedunit(Dolosyspaintracker;DolosysGmbH,Germany).Eachstimulationconsistedofatrainoffiverectangularpulses(1millisecond,200Hz).TheEMGwasrecordedat1kHzover500milliseconds,starting100millisecondsbeforestimulation.The100-millisecondtimewindowprecedingstimulationwasusedtoevaluatetheEMGbackgroundnoise(“noiserange”).Thetimewindowbetween30and100millisecondsafterstimulationwasusedtoevaluatetheNWR(“NWRrange”).TheresponsewasconsideredpositivewhentheintervalpeakZscorewasabove10,meaningthatthepeakEMGamplitudewithintheNWRrangehadtoexceedthemeanEMGamplitudewithinthenoiserangebyatleast10timesitsstandarddeviation.Thefirststimulationstartedat1mA.TheNWRthresholdwasthenevaluatedfollowinganup-and-downbracketingdesignwithmaximalcut-offintensitysetat50mA.Itwaspossibletostopstimulationatanytimeincaseofevidentdiscomfortorpain(vocalizationorescapemovement).Stimulationswererepeatedevery10s(with30%intervalrandomization)changingintensitybystepsof0.3mA.Whentheintensityincreasedordecreasedthreeconsecutivetimes,thestepbecame0.5mAuntiltheintensitychangeddirectionagain.AmeasurementwasautomaticallydiscardedwhentheEMGamplitudeexceeded10µVwithinthenoiserange.Inthiscase,stimulationwasrepeatedatthesameintensity.TheNWRthresholdwasautomaticallyestimatedaftereachstimulationthroughalogisticregressionofthelast12validstimuli[25].AstablebaselineNWRthresholdmeasurementforatleast5minwasobtainedbeforethefirsttreatment(phase1).MedetomidineordexmedetomidinewereinjectedoveraminuteintherightcephalicIVcatheter.TheendoftheinjectionwasdefinedasT0.Thethresholdwasthencontinuouslydetermineduntilitreturnedtobaseline,oruntilthedogsbecameintoleranttotheexperimentalsettings(impatienttomove,notstayingquietorlying),oruntil210minafterT0(T210).IfthemeasurementswerediscontinuedbeforeT210,thethresholdwasarbitrarilygiventhevalueofitsbaselineintheremainingtimeperiodtoavoidmissingdataforgroupcomparison.2.6.SedationThedepthofsedationwasscoredatbaselineandevery10minuntiltheendoftheexperimentsusingapreviouslydescribeddescriptivescale[31].Sevenitemswereevaluated.Thescoresattributedtoeachindividualitemweresummedtoobtainatotalsedationscorerangingfrom0(nosedation)to21(deepestpossiblesedation).Accordingtothescoringsystem,sedationwasdefinedasmildwithascoreof4to6,moderatewithascoreof6to12andprofoundwithascoreof13to21.Thesametwoinvestigators,bothunawareoftheadministeredtreatment,alwaysscoredthedepthofsedationtogether(agreementforeachitemscore).2.7.PhysiologicalVariablesHeartrate(HR,beatsminute−1),respiratoryrate(fR,breathsminute−1)andtemperature(T,°C)weremeasured(thoraxauscultationandrectalthermometer)andrecordedevery10min.Thoracicimpedancewascontinuouslyrecordedbyelectricalimpedancetomography(SwisstomBB2,SwisstomAG,Switzerland)[27].Bloodsamples(2mL)wereobtainedfromtheleftIVcatheterintoEDTAcollectiontubesat2,4,8,16,30,60,90,120and180minafterT0forfuturepharmacokineticanalysis(notperformedyet).2.8.DataAnalysisToeasecomparisonbetweenanimalsandtreatments,themeanbaselineNWRthresholdwascalculatedoverthe5minimmediatelyprecedingdrugadministration.ThemeanrelativeNWRthreshold(absolutethresholddividedbyitsbaseline)[32]wasthencalculatedforeveryminuteafterT0.Dataarepresentedasmedian(interquartilerange).InaccordancewiththerecommendationsoftheAmericanStatisticalAssociation[33,34],differencesinmedianarepresentedtogetherwiththep-valuefortherespectivestatisticaltest(Sigmaplotv14.0;SystatsoftwareInc.,SanJose,CA,USA).Sincep-valuesbelow0.001couldnotbedetermined,theyarereportedasp<0.001.Forphase1(T0–T45),differencesbetweentreatments(paireddata,MEDversusDEX)forbaselineNWRthresholds,timetorelativeNWRthresholdpeakandpeakintensityweretestedusingaWilcoxonsigned-ranktest.DifferencesbetweentreatmentsforNWRthresholdsandsedationscoresweretestedusingatwo-wayANOVAforrepeatedmeasures,accountingforeffectoftimeandtreatmentwithineachsubject.PosthocpairwiseanalysiswasperformedwithaHolm–Sidaktest.Forphase2(T45–T210),differencesbetweentreatments(paireddata,ATIversusSAL)forrelativeNWRthresholdsatT44,timetorelativeNWRthreshold≤1.5,timetosedationscore≤3andcomparisonofthetwolattervariablesweretestedusingaWilcoxonsigned-ranktest.DifferencesbetweentreatmentsforNWRthresholdsandsedationscoresweretestedusingatwo-wayANOVAforrepeatedmeasures,accountingforeffectoftimeandtreatmentwithineachsubject.PosthocpairwiseanalysiswasperformedwithaDunnett’stest.Additionally,differencesbetweenMED/SAL(n=4)andDEX/SAL(n=4)subgroupsandbetweenMED/ATI(n=4)andDEX/ATI(n=4)subgroupsfortimetorelativeNWRthreshold≤1.5andtimetosedationscore≤3wereevaluated.Two-wayANOVAforrepeatedmeasuresandWilcoxonsigned-ranktestswereused.CorrelationbetweenNWRthresholdsandsedationscoreswastestedusingPearsonproductmomentandlinearregression.3.ResultsThedogswereseven(5–8)yearsoldandweighed12.9(11.7–15.8)kg.Onefemalepresentedsignsofproestrusduringthesecondsessionofthetrialbutwasnotexcluded.Onemaledogvomitedshortlyafteradministrationofthealpha-2adrenergicagonistonbothsessions(oncewithmedetomidine,oncewithdexmedetomidine),withoutfurthercomplication.Alldogstoleratedwelltheexperimentalsettinginlateralrecumbency.ElectricalstimulationscouldbecontinuedinalldogsuntilreturntoarelativeNWRthresholdofone(0.9–1.1)withinthedurationoftheexperiment,exceptinonedogononeoccasion(groupMED/SAL)whenmeasurementswerestoppedatT210whiletherelativeNWRthresholdwasstill>1.5andsedationscorewas>5.3.1.Phase1(T0–T44,MEDVersusDEX)3.1.1.SedationSedationscores>13(profoundsedation)wereobservedinalldogswithinaminuteaftertheendoftheIVinjectionofbothMEDandDEX.Peaksedationscoresof17(16–17)werereached10minafterT0inalldogs.Sedationscoresvariedsignificantlyovertime(p<0.001),butwerenotdifferentbetweentreatments(MEDversusDEX,p=0.67,Figure1a).3.1.2.NociceptiveWithdrawalReflexesBaselineNWRthresholdsweresimilarbetweengroups:1.1(0.9–1.3)mAforMEDand1.2(1.1–1.5)mAforDEX(p=0.313).RelativeNWRthresholdsvariedovertime(p<0.001)butnotbetweentreatments(MEDversusDEX,p=0.317).PeakrelativeNWRthresholdswerereachedatseven(3–11)minutesforMEDandsix(4–9)minutesforDEX(p=0.938).Peaksof4.4(3.9–4.8)timesthebaselineand5.0(3.7–5.9)timesthebaselinewerereachedforMEDandDEX,respectively(p=0.547,Figure2a).Thiscorrespondedtoadifferenceof14%,whichwasbelowthepredefinedrelevantendpointof20%.3.1.3.PhysiologicalVariablesAftertreatmentadministration,theHRdecreasedfrom106(100–118)beatsminute−1atT0to45(34–60)beatsminute−1atT44forMED(p<0.001),andfrom100(96–104)beatsminute−1atT0to44(34–57)beatsminute−1atT44forDEX(p<0.001).Therewasnorelevantdifferencebetweentreatments(p=0.114).Respiratoryratesandtemperaturesremainedinthephysiologicalrange.3.2.Phase2(T45–T210,ATIVersusSAL)3.2.1.SedationSedationscoreswerelowerinthedogstreatedwithATIthanSAL(p<0.001).Timetosedationscore≤3was25(15–25)minutesforATIand90(68–118)minutesforSAL(p=0.008,Figure1b).3.2.2.NociceptiveWithdrawalReflexesTherelativeNWRthresholdsrecordedduringthefirstphase(T0–T44)werenotdifferentforgroupsATIandSAL(p=0.293).TherelativeNWRthresholdswerealsosimilaratT44:2.5(1.9–3.3)forATIand2.3(1.9–3.1)forSAL(p=0.461,Figure2a).BetweenT45andT210,therelativeNWRthresholdsdifferedbetweengroups(p<0.001).TimetoarelativeNWRthreshold≤1.5wasfive(3–6)minutesforATIand41(28–97)minutesforSAL(p=0.008).IndogsreceivingATI,arelativeNWRthreshold≤1.5wasreached18(11–22)minutesbeforesedationscoresreturnedtovalues≤3(p=0.008,Figure2b).3.2.3.PhysiologicalVariablesAfteratipamezoleadministration,HRincreasedto88(80–107)beatsminute−1within5min.Respiratoryratesandtemperaturesdidnotchange.3.3.AdditionalObservationsontheEffectOffsetInthetimeintervalT45–T210,sedationscoreswerehigherforMED/SALthanforDEX/SAL(p=0.02,Figure3).Furthermore,timetosedationscores≤3were155(133–200)minutesforMED/SALand115(88–135)minutesforandDEX/SAL(p=0.057).RelativeNWRthresholdsdidnotdifferbetweenMED/SALandDEX/SALsubgroups(p=0.241,Figure4);similarly,timetorelativeNWRthreshold≤1.5didnotdifferbetweenthegroups,at116(75–158)minutesforMED/SALand80(73–118)minutesforDEX/SAL(p=0.686).Thisdifferenceof30%wasabovetherelevantendpointof20%,butatleast12animalspergroupwouldhavebeenrequiredtoconfirmthisresult(Mann–Whitneytest,unpaired,two-tailed,effectsize=1.3,α=0.05,1-β=0.9,GPower3.1,Germany).IntheSALgroups,thetimetosedationscores≤3was135(113–163)minutes,whereasthetimetorelativeNWRthreshold≤1.5was86(73–142)minutes(p=0.008),suggestingthatsedationlastslongerthanantinociception.Asignificantpositivecorrelationbetweenthesetwovariableswasfound(p=0.005,p=0.87)andintercept-freelinearregressionhadaslopeof0.81(r2=0.74,Figure5).NorelevantdifferencewasobservedbetweenMED/ATIandDEX/ATIsubgroups.4.Discussion4.1.InterpretationTheadministrationofasingleIVdoseofmedetomidine(0.02mgkg−1)ordexmedetomidine(0.01mgkg−1)rapidlyinducedcomparablesedationandantinociceptionindogs.DexmedetomidinedidnotinducesignificantlyhigherNWRthresholdsthanmedetomidine.BotheffectsrapidlyterminatedafterIMadministrationofatipamezoleandtheNWRthresholdsdecreasedearlierthansedationscores.Indogs,thesedativeeffectsofdexmedetomidineadministeredalone[35]oraspartoftheracemicmixture[9,36]havealreadybeenreported.Inourstudy,profoundsedation(sedationscores≥13outof21)andpeaksedationscoreswererapidlyachievedaftertreatmentadministration.Therewasnodifferenceinonsetandqualityofsedationbetweentreatments.ThisisincontrastwithRaszplewiczetal.[8],whoreportedthatmoredogsachievedprofoundsedationaftermedetomidine(0.01mgkg−1)thanafterdexmedetomidine(0.005mgkg−1)administeredIMincombinationwithbutorphanol.Ontheotherside,inourstudy,thedurationofdrugs’actionwasdifferent:sedationlastedlongeraftermedetomidinecomparedtodexmedetomidine.SimilarresultswerereportedincatsreceivinghighIMdosesofalpha-2agonists[37].Otherstudiescouldnotdemonstrateanydifferenceinsedationqualitynorindurationofactionbetweenmedetomidineanddexmedetomidine[3,4,15],butthesedationscoresappliedwerepoorlysensitive(numericalsubjectivescalefromzerotothree)comparedtothescoringsystemusedhere[38].Differencesindurationofactionprobablydependonthedosesadministered,therouteofadministrationandtheco-administrationofotherdrugs.Differencesineffectbetweendexmedetomidineadministeredaloneandmedetomidineasaracemicmixturearemostprobablyduetotheadditionoflevomedetomidine.Whenadministeredalonetodogs,levomedetomidinedidnotcauseanybehavioraleffect[15]ordecreasehalothaneminimumalveolarconcentration(MAC)[39].Onlyathighdosages,itmoderatelyimpairedthequalityofthesedationinducedbydexmedetomidine[15].Therefore,thelongerdurationofsedationobservedinourstudyaftermedetomidineisunlikelytobetheresultofasedativeeffectfromlevomedetomidine.However,apharmacokineticinteractionbetweenthetwoenantiomerscouldoccur,forinstance,aslowereliminationofdexmedetomidineinpresenceoflevomedetomidine.Whilethishasnotbeeninvestigatedyet,differencesbetweendex-andlevomedetomidineconcentrationswereobservedafteradministrationoftheracemicmixture[13],suggestinganenantioselectivepharmacokinetic.Antinociceptivepropertiesdidnotsignificantlydifferbetweentreatmentsinthepresentstudy.Previousresultscomparinganalgesiainducedbyeithermedetomidineordexmedetomidinewereinconclusive.Longerlastinganalgesiawasreportedwithdexmedetomidine(0.02mgkg−1IV)comparedtomedetomidine(0.04mgkg−1IV)inresponsetotoepinch(assessedbyasubjectivescoreofthenocifensiveresponse)[3].DexmedetomidinewasnotdifferentfrommedetomidineatdecreasinghalothaneMACindogs[39].Likewise,nodifferenceinnocifensivereactiontotoepinchwasobservedbetweendexmedomidine(0.04mgkg−1IM)andmedetomidine(0.08mgkg−1IM)inbothdogs[4]andcats[40].Theseresultswouldalsobenefitfrombeinginterpretedinperspectivewithpharmacokineticstudies.Ifsedationishypothesizedtobeshorterwhendexmedetomidineisadministeredaloneduetolowerplasmaconcentrations,asmentionedabove,similarlevelsofantinociceptioncouldpotentiallysupportastrongerintrinsicanalgesicefficacyfordexmedetomidinecomparedtomedetomidine.Anxietymaybedifficulttoobserveintrainedbeagles.Itcouldhavepotentiallyoccurredduringbaselinemeasurementswhenthedogswereunmedicated,whichcouldaffectourresults.AnxietyhasbeenreportedtoincreasecentralhyperexcitabilityandtopotentiallylowertheNWRthreshold[41,42],thoughthisiscontroversial[43,44].Effortsweremadetoacclimatizethedogstotheexperimentalroom,staffandmethodology.Nosignofanxietywasnoticedduringtheexperiment.BaselinevaluesforNWRthresholdwerecomparabletopreviousstudies[20]andtofinalvaluestowardstheendofthemeasurements.Itisunlikelythatanxietyaffectedtheresultspresentedhere.Oneobjectiveofthepresentstudywastoapplyamethodologythatcouldpotentiallyhighlightdifferencesindurationandefficacybetweentreatments.Usingtheautomatedcontinuoustrackingdevice,evensubtlevariationintheNWRthresholdscanbequantifiedovertime.Moreover,theEMG-basedNWRmodelislesslikelytobeinfluencedbysedationandmusclerelaxationthanvisualscoringofagrossmovementinresponsetostimulation.Finally,theevaluationcanberepeatedathighfrequency(every10s)withoutriskinghabituation,sensitizationorskindamage.Ourresultsconfirmthatthereisnodifferenceinantinociceptiveefficacybetweenmedetomidineanddexmedetomidineindogsatthedosesused.Anotherobjectiveofthisstudywastocomparethetimecoursesofsedationandanalgesia,inparticularafteratipamezole.ArelevantobservationwasthattheNWRthresholdsreturnedtobaselinebeforesedation,indicatingthatanalgesiccoverageisnolongerguaranteedoncesedationsubsides.Intercept-freelinearregression(r2=0.74,Figure5)suggestthatthedurationofantinociception(relativeNWRthresholds>1.5)approximates80%ofthedurationofsedation(sedationscore≤3).Antinociceptionwasrapidlyreversedbyatipamezoleatthedosagerecommendedbythemanufacturer.ThecontinuousNWRthresholddeterminationtrackedpreciselytheonsetofantinociceptionreversal,whichwasapproximately6minafteratipamezoleadministrationforbothmedetomidineanddexmedetomidine.Thisimpliesthatappropriateanalgesianeedstobeconsideredwheneverthisantagonistisadministeredtoanimalsexperiencingpain.4.2.LimitationsThecomparisonbetweenMEDandDEXfollowedacrossoverdesignwitheightsubjects(paired)forthefirst45minonly.Thereafter,theoutputvariables(i.e.,NWRthresholdandsedation)inabsenceofreversalwerecomparedbetweentwogroupsoffourdogseach(subgroupsMED/SALandDEX/SAL,nocross-over).TheobservationsresultingfromthiscomparisonseemtoindicatethatDEXandMEDmaydifferindurationofactionmorethanintheirpotency,butthisfindingrequiresfurthervalidation.Twofemaleandsixmaleintactdogswereusedinthestudy.Anequalsexdistributionwouldhavebeenpreferable,assexisknowntopotentiallyaffectsensitivitytopainandthusnociceptivethresholds[45].Onefemaledogpresentedsignsofproestrusduringthesecondsessionofthetrial.Forthisindividualnodifferencewasobservedbetweenthebaselinevaluesrecordedduringthetwosessionsbutacertaininfluenceonthenociceptivethresholdcourseafterdrugadministrationcannotbeexcluded.Inthepresentstudy,antinociceptionwasinvestigatedusingthenon-invasiveNWRmodel.Adrug-relatedincreaseintheNWRthresholdcannotbedirectlyinterpretedasclinicalanalgesia,asthecomplexityofclinicalpaingoesclearlybeyondaspinalnociceptivereflex.Nevertheless,inhumanstheNWRthresholdisknowntocorrelatewelltothethresholdforpainperception[46],justifyingtheuseofthismodeltoassesspharmacologicallyinducedanalgesiainpain-freesubjectsinexperimentalsettings.4.3.HarmNoadverseeventsotherthanonefemaledogvomitingafterbothalpha-2-agonistinjectionswasobserved.Vomitingiscommonafteradministrationofalpha-2agonistsasaresultoftheiractionatthechemoreceptortriggerzone[9,47,48].5.ConclusionsAlthoughsedationappearedtobeslightlylongerlastingaftermedetomidine,sedationqualityandantinociceptiveefficacyweresimilarfordexmedetomidineandmedetomidine.Antinociceptiondidnotoutlastsedation,andatipamezolewasabletorapidlyreversebothsedationandantinociception. 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Figure1. Median(interquartilerange)sedationscores(from0to21)recordedin8beaglesafteradministrationinacrossoverdesignof(a)intravenousmedetomidine(MED,0.02mgkg−1,n=8)ordexmedetomidine(DEX,0.01mgkg−1,n=8)atT0,and(b)intramuscularatipamezole(ATI,0.1mgkg−1)oranequivalentvolumeofsaline(SAL)atT45.Dataarepresentedslightlyapartfromtheactualmeasurementtimepointstoeasereadability. Figure1. Median(interquartilerange)sedationscores(from0to21)recordedin8beaglesafteradministrationinacrossoverdesignof(a)intravenousmedetomidine(MED,0.02mgkg−1,n=8)ordexmedetomidine(DEX,0.01mgkg−1,n=8)atT0,and(b)intramuscularatipamezole(ATI,0.1mgkg−1)oranequivalentvolumeofsaline(SAL)atT45.Dataarepresentedslightlyapartfromtheactualmeasurementtimepointstoeasereadability. Figure2. Median(interquartilerange)relativenociceptivewithdrawalreflex(NWR)thresholdsrecordedin8beaglesafteradministrationinacrossoverdesignof(a)intravenousmedetomidine(MED,0.02mgkg−1,n=8)ordexmedetomidine(DEX,0.01mgkg−1,n=8)atT0,and(b)intramuscularatipamezole(ATI,0.1mgkg−1)oranequivalentvolumeofsaline(SAL)atT45.Dataarepresentedonlyforrepresentativetimepoints(whileactuallyrecordedeveryminute)toeasereadability. Figure2. Median(interquartilerange)relativenociceptivewithdrawalreflex(NWR)thresholdsrecordedin8beaglesafteradministrationinacrossoverdesignof(a)intravenousmedetomidine(MED,0.02mgkg−1,n=8)ordexmedetomidine(DEX,0.01mgkg−1,n=8)atT0,and(b)intramuscularatipamezole(ATI,0.1mgkg−1)oranequivalentvolumeofsaline(SAL)atT45.Dataarepresentedonlyforrepresentativetimepoints(whileactuallyrecordedeveryminute)toeasereadability. Figure3. Median(interquartilerange)sedationscores(from0to21)recordedfromT45toT210in8beaglessedatedatT0witheitherintravenousmedetomidine(MED/SAL,0.02mgkg−1,n=4)ordexmedetomidine(DEX/SAL,0.01mgkg−1,n=4).Dataarepresentedslightlyapartfromtheactualmeasurementtimepointstoeasereadability. Figure3. Median(interquartilerange)sedationscores(from0to21)recordedfromT45toT210in8beaglessedatedatT0witheitherintravenousmedetomidine(MED/SAL,0.02mgkg−1,n=4)ordexmedetomidine(DEX/SAL,0.01mgkg−1,n=4).Dataarepresentedslightlyapartfromtheactualmeasurementtimepointstoeasereadability. Figure4. Median(interquartilerange)relativenociceptivewithdrawalreflex(NWR)thresholdsrecordedfromT45toT210in8beaglesafteradministrationatT0ofeitherintravenousmedetomidine(MED/SAL,0.02mgkg−1,n=4)ordexmedetomidine(DEX/SAL,0.01mgkg−1,n=4).Dataarepresentedonlyforrepresentativetimepoints(whileactuallyrecordedeveryminute)toeasereadability. Figure4. Median(interquartilerange)relativenociceptivewithdrawalreflex(NWR)thresholdsrecordedfromT45toT210in8beaglesafteradministrationatT0ofeitherintravenousmedetomidine(MED/SAL,0.02mgkg−1,n=4)ordexmedetomidine(DEX/SAL,0.01mgkg−1,n=4).Dataarepresentedonlyforrepresentativetimepoints(whileactuallyrecordedeveryminute)toeasereadability. Figure5. Intercept-freelinearregressionbetweenthetimetorecoverfromsedation(sedationscore≤3)andthedurationofantinociception(relativenociceptivewithdrawalreflex(NWR)threshold≤1.5)in8beaglesafteradministrationatT0ofeitherintravenousmedetomidine(MED/SAL,0.02mgkg−1,n=4)ordexmedetomidine(DEX/SAL,0.01mgkg−1,n=4). Figure5. Intercept-freelinearregressionbetweenthetimetorecoverfromsedation(sedationscore≤3)andthedurationofantinociception(relativenociceptivewithdrawalreflex(NWR)threshold≤1.5)in8beaglesafteradministrationatT0ofeitherintravenousmedetomidine(MED/SAL,0.02mgkg−1,n=4)ordexmedetomidine(DEX/SAL,0.01mgkg−1,n=4). ©2020bytheauthors.LicenseeMDPI,Basel,Switzerland.ThisarticleisanopenaccessarticledistributedunderthetermsandconditionsoftheCreativeCommonsAttribution(CCBY)license(http://creativecommons.org/licenses/by/4.0/). Animals, EISSN2076-2615, PublishedbyMDPI Disclaimer Thestatements,opinionsanddatacontainedinthejournalAnimalsaresolely thoseoftheindividualauthorsandcontributorsandnotofthepublisherandtheeditor(s). MDPIstaysneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations. 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