RevBrasAnestesiol.2014;64(3):169---172
REVISTA
BRASILEIRA
DE
ANESTESIOLOGIA
OfficialPublicationoftheBrazilianSocietyofAnesthesiology www.sba.com.brSCIENTIFIC
ARTICLE
Ondansetron
reducing
pain
on
injection
of
etomidate:
a
controlled
randomized
study
夽
Omid
Azimaraghi
a,
Yasaman
Aghajani
a,
Maziar
Molaghadimi
a,
Malihe
Khosravi
a,
Kobra
Eslami
b,
Fatemeh
Ghadimi
b,
Ali
Movafegh
c,∗aDr.AliShariatiHospital,TehranUniversityofMedicalSciences,Tehran,Iran
bDevelopmentResearchCenter,Dr.AliShariatiHospital,TehranUniversityofMedicalSciences,Tehran,Iran
cDepartmentofAnesthesiologyandCriticalCare,Dr.AliShariatiHospital,TehranUniversityofMedicalSciences,Tehran,Iran
Received9April2013;accepted10June2013 Availableonline23October2013
KEYWORDS
Etomidate; Ondansetron; Pain
Abstract
Introduction:Etomidatecausespainwheninjectedintravenously.Inthisstudywesought to determineifpretreatmentbyondansetronreducesthepainoninjectionofetomidate. Methods:Inthisrandomized,doubleblinded,placebo-controlledclinicaltrial,20patientsof bothsexesagedbetween18and50yearsofAmericanSocietyofAnesthesiologists(ASA)physical statusclassIorII,whomwerecandidatesforvariouselectivesurgicalproceduresandneedmore thanoneintravenousaccesswereenrolledinthestudy.Onarrivaltotheoperatingroomtwo 22gaugecannulaswereinsertedintoveinsonthedorsumofbothhands.Followingtheinfusion of100mLnormalsalineintobothintravenouslines,usinganelasticband,venousdrainageof handswasoccluded atmidarm.The patientswereadministered 8mg(2mL)ofondansetron intoonehandand2mLof0.9%salineintotheotherhandatthesametime.Theelasticband was removed after 1min and2mg(1mL)ofetomidatewas administered atthe same rate simultaneouslyintointravenouslines.Thepatientswereaskedtogiveascoreofpainbasedon averbalanalogscale(VAS)toeachhand.
Results:Atotalnumberof20patientswerestudied(male=55%,female=45%).Themeanage oftheparticipantswas37.5±13.1yearsoldandthemeanweightwas67.7±7.3kg.Themean VASforinjectionpainofetomidateafterpre-administrationofintravenousondansetronwas 1.5±1.2whichwaslowercomparedtopre-administrationofplacebo(3.2±2.8,p<0.05). Conclusion: Thisstudyillustratesthatpre-treatmentwithintravenousondansetronsignificantly reducesthepainoninjectionofetomidate.
© 2013SociedadeBrasileirade Anestesiologia.Publishedby ElsevierEditoraLtda.Allrights reserved.
夽 Trialregistration:Irct.iridentifier:IRCT201106125140N4.
∗Correspondingauthor.
E-mail:[email protected],[email protected](A.Movafegh).
170 O.Azimaraghietal.
Introduction
Variousagentshavebeenusedforintravenousinductionof anesthesia,yetsomeofthesideeffectsinducedbydifferent drugslimittheiruse.1
Etomidateis oneofthepopularintravenousanesthetic agents, which can be administered during induction of general anesthesiaor sedation for shortprocedure.1 Pro-pyleneglycol formulated etomidatemay damagevascular endothelium and produce pain.2 Etomidate is famous for itscardiovascularstability,neverthelessinjectionpainand postoperativevomitingaretwounpleasantadverseeffects attributabletothisdrug.3
Thebroaddistributionoffivehydroxytryptamine(5-HT3) receptorsinhumanbodyhasprovidedthebasisfor investiga-tionofondansetron,asaselectiveserotonin5-HT3receptor antagonistinnovelapplications,althoughtheresultshave notalwaysbeenconsistent.4,5
Theprimaryoutcomeofthepresentstudywasto deter-minetheeffectofondansetron onpreventionofinjection paincausedbyetomidateduringinductionofanesthesia.
Methods
Ethics
ThistrialwasreviewedandapprovedbytheInstituteof Eth-icalCommitteeandIranianRegistryofClinicalTrials(IRCT ID:IRCT201106125140N4).
The study protocol was approved by the Institutional ethics committee of Tehran University of Medical Sci-ences. Ethical approval for this study (Ethical Committee N◦91/
2/201/22501)wasprovidedbytheEthicalCommittee ofTehranUniversityofMedicalSciences(ChairpersonProf. Sh.Akhondzade) on15January2013.Aninformedwritten consentwasobtainedfromalltheparticipants.
Patient’spopulation
Inthisrandomized,doubleblinded,placebo-controlled clin-icaltrial,20patientsofbothsexesagedbetween18and50 yearsofAmericanSocietyofAnesthesiologists(ASA)physical statusclassI or II, whowerecandidates for various elec-tivesurgicalproceduresrequiringmorethanoneintravenous accesslineswereenrolledinthestudy.
Exclusioncriteriaconsistedofpatientswithahistoryof thrombophlebitisorvasculardisease,chronicpain,diabetes mellitus, history of tumors or burns in either hands, his-tory of addiction or any contraindications to injection of ondansetronoretomidate.
Inthepreoperativevisitthenightbeforesurgeryallthe patientswerethoroughlyexplainedthevisualanalogscale (VAS)for pain(0=nopain,10=mostsevere pain).No pre-medicationswereadministered.
Intervention
Onarrival totheoperatingroom,all patientswere moni-toredwithan electrocardiogram(ECG), noninvasiveblood pressureand pulse oximetry. All the required drugs were
prepared intoopaque syringesby an anesthetist whowas notinvolvedineithertheadministrationofdrugstopatients orthepatients’assessment;thus,boththeanesthesiologist andthepatientswereblindedtopatientsgroups.
Two22gaugecannulaswereinsertedintotheveinsonthe dorsum of both hands.One hundredmillimeters of saline wasadministered over 10min fromeach of the cannulas. Using an elasticband asatourniquet,venous drainage of both handswasoccluded midarm. Eight milligrams (2mL) of ondansetronwasadministeredfromonehandand 2mL of0.9% salinefromtheother handat thesametime.The elasticbandwasremovedafter1minand2mg(1mL)of eto-midate wasadministeredatthe sameratesimultaneously at both hands. The patients were asked to give a score from0to10(0=nopainand10=mostseverepain)toeach hand. Adverse effectswerealso recorded.The choicefor the technique used for induction of anesthesia was left fortheanesthesiologisttomakebasedoneveryindividual. Endotracheal intubation was facilitated with 0.5mgkg−1 atracurium.Aftertrachealintubation,anesthesiawas main-tained by isofluranandN2O (50%); 0.1mgkg−1 atracurium and1gkg−1.Fentanylwereadministeredhalfhourly.
Ven-tilation was adjusted to maintain normocapnia (end-tidal carbondioxidepartialpressure4.7---5.3kPa).
Statistics
Itwasestimatedthatasamplesizeof20patients(40hands) wouldbesufficienttodetecta3scoredifferenceinpainon injectionofetomidate,estimatingaSDof3.5,powerof95% andsignificantlevelof0.05.
Statistical analysis of the results was performed using SPSSforwindows,release17.5(SPSSInc.).Theintensityof painwasanalyzedbytwosamplet-test.p-Value<0.05was consideredstatisticallysignificant.Thepowerofstudywas considered20%.
Results
Threepatientsweredeeplysedatedafterinjectionof etomi-dateandunabletoansweranyquestions.Wereplacedthese threepatientswithnewcases.Atotalnumberof20patients wereenrolledinthestudy(male=55%,female=45%).The meanageoftheparticipantswas37.5±13.1yearsandthe meanweightwas67.7±7.3kg.ThemeanVASforinjection pain ofetomidate after pre-administrationof intravenous ondansetron was 1.5±1.2 which was lower compared to pre-administration of placebo (3.2±2.8, p<0.05). Six patients developed urticaria following administration of ondansetron andbeforeetomidate administration. Nolife threateningormajorcomplicationswereobserved.
Discussion
Inthisstudytheeffectofintravenousondansetronon injec-tionpainofetomidatewasevaluated.Itwasobservedthat administrationof ondansetron prior toetomidate reduces theinjectionpainsignificantly.
Ondansetron has been shown to bind to opioid
Ondansetronandpainoninjectionofetomidate 171
pathways.Fivehydroxytryptaminereceptorsplaya prono-ciceptiveroleandmediatedescending excitatorycontrols thatallow spinalneurons tofullycodeperipheral stimuli. Ondansetron decreases chronic benign neuropathic pain, thiseffectseemstobeproducedbyanaction onthe neu-rons in the spinal cordthat codeand transmitperipheral nociceptivestimuli.7
Five hydroxytryptaminereceptors are alsoa targetfor localanesthetics.Theabilityofondansetrontoblocksodium channels and5-HT3receptorhas putforward the hypoth-esisthatondansetron possessesantinociceptive properties probably in a similar way to local anesthetics. Although localanestheticscontainhydrophilicandhydrophobic struc-turesseparatedbyanintermediateamideoresterlinkage, astructurewhichondansetrondoesnothave.8,9
Reducing injection pain of intravenous anesthetics has beenthesubjectofvariousstudies.Manydrugshavebeen previously used to attenuate injection pain of propofol and rocuronium. Lidocaine or fentanyl with local anes-thetic and sedative properties are the most commonly useddrugs.10---13When comparedtotramadol,ondansetron wasequallyeffectiveinpreventingpainofpropofol injec-tion, holding the analgesic properties of ondasetron, and was superior due to prevention of post operative nau-seaandvomiting.14Metoclopramide,andflurbiprofenaxetil, granisetron and ketamine effect on attenuating pain on injectionhaveallbeenpreviouslystudied.15---19
Quantificationofpainisagreatchallengetoresearchers. Visual analog scale is one of the most popular methods usedfor painassessment, butit is subjectiveand is diffi-culttoevaluatequantitativelyorstatistically.Reportedpain levelsbyindividualsusingVASarebasedonevery individ-uals painthreshold,which is unknown, making the whole resultsdefectivewhencomparedbetweenindividuals.Not only a different definition of pain exists in different cul-turesaroundtheworldbutalsoindividualvariabilityexists inperceptionofpain.Eveneveryindividual’spainthreshold may change basedon theunderlying emotional state and environmentalsituationinwhichthepainisassessed.
Therefore,whenpainisstudiedbetweendifferent indi-viduals,fromdifferentregions andin differentconditions theresultsareneithertrustworthyordependablenor con-sistent.A‘‘PainVision’’systemhasbeenrecentlyproposed forquantitativeassessmentofpaincausedbytheremovalof adhesivewounddressingmaterialswhichtakesintoaccount everypatient’spainthreshold.20
We believe that in this study a new way of pain assessment has been put forward. In this method, every individual’s hand is used as the case and control groups forpainperception,thereforereducingoreveneliminating thementionedintervariabilityinpainperceptionand con-foundingfactors.Inourpreviousworkinwhichweassessed theeffectofdexamethasoneoninjectionpainofdiazepam hydrochloride,21weusedthethismethodtoo.
Itshouldbenotedthattoourknowledgeinallthe previ-ouslyinjectionpainassessmentstudiesthemethodusedto assesspainwasdifferenttoourstudyandpainoninjection wasassessedbetweendifferentindividuals.Thiscouldlead tolessreliableresults.
Weproposethemethodusedinthisstudyasanoveland effectivewayofassessinginjectionpainofvariousdrugs.We arecurrentlyconductingaseriesofclinicaltrials,usingthe
mentioned method, evaluating the effect of ondansetron andgranisetrononthepainoninjectionofetomidateand propofol.
Thequestionthatwhatdosageofondansetronisrequired toprevent injection pain of various drugs remains unan-swered. Urticaria which developed in 6 patients was the negative aspect of ondansetron administration, although this was very short lasting and was probably related to thepreservativesusedandnomajorcomplicationoccurred in any of the individuals.2 It should also be noted that ondansetron’s antiemetic effect can help attenuate the postoperativenauseaandvomitingeffectofetomidate.We could not measure this variable because all the patients were administered ondansetron and we had no control group.
Inconclusion,theresultofthisstudydemonstratedthat ondansetroncould effectivelyreduce painon injectionof etomidate.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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