TheUseofHighDosesofOxycodone inanAcutePalliativeCareUnit
SebastianoMercadante,MD1,2,PatriziaFerrera,MD1,FabrizioDavid,MD1,andAlessandraCasuccio,BS3
AmericanJournal of Hospice
PalliativeMedicine®28(4)242-244
ªTheAuthor(s)2011
Reprints and permission:sagepub.com/journalsPermissions.navDOI:10.1177/1049909110381378
Abstract
Aretrospectivestudyofpatientswhowereprescribedcontrolled-releaseoxycodone(CRO)inaperiodof3years(2006-2008)wasperformed.Atotalof212patientswereprescribedatdischargeCROforbackgroundanalgesia;129,43,and40patientswereprescribeddosesofoxycodoneoflessthan120mg/day(groupL),120to240mg/day(groupM),andmorethan240mg/day(groupL),respectively.Nodifferencesingender,primarydiagnosis,andpainmechanismswerefound,butdosesweresignificantlylowerinolderpatients(P.0005).Atdischarge,adverseeffectsweremildandonlyaminorityofpatientswereswitchedtootheropioids.ThisstudydemonstratedthatCROadministeredinlargerdoseswassafeandeffective,showingversatilityandflexibilitysimilartomorphine.
Keywords
oxycodone,cancerpain,opioids,palliativecare,supportivecare,adverseeffects
TheanalgesicladderrecommendedbytheWHOhasbeenshowntoprovideefficientpainreliefforalargenumberofcan-cerpatients.Opioidadministrationistheprimarytherapeuticmodalityinthemanagementofmoderate-to-severecancerpain.Morphineisconsideredthepreferreddrugbecauseofitswideavailability,variedformulations,andwell-characterizedpharmacologicproperties.1Efficaciousdosesofmorphinehaveawiderange,duetoindividualdifferences.Sometimemor-phinedosestitratedindividuallytoachieveadequatepainreliefcanrequireextremelyhighdoses.Oralmorphinehasbeenshowntobeasafeanalgesicdrugeveninthehigh-doserange(morethan300mg/day).2-4
Oxycodonewasoriginallyformulatedincombinationwithnonopioids.Subsequently,oxycodonewasshowntobeasver-satileand flexibleas oralmorphine in themanagementofcan-cerpain.5Controlled-releaseoxycodone(CRO)iswidelyacceptedasanalternativetomorphine,resultingassafeandeffectiveascontrolled-release morphine.6TheuseofrelativelyhighdosesofCRO(meandailydoseofabout230mg)inter-minalcancer patientswassafe,efficient,andunrelatedtoshortersurvivaltimes.7
Thisarticlecharacterizespatientsadmittedtoanacutepainreliefandpalliativecareunitwhoreceivedevenlargerdosesof CROforthemanagementofcancerpain.
PatientsandMethods
AretrospectivestudyofaconsecutivepopulationofpatientswhowereprescribedCROduringadmission at an acutepainreliefandpalliativecareunitinaperiodof3years
(2006-2008)wasperformed.Foreachpatientincludedinthestudy,demographicparameters,siteoftumor,characteristicsofpain,hospitalstay,anddosesofCROprescribedatdischargewererecorded.
Painintensitywasassessedbyanumericalscale0to10andsymptomsassociatedwithopioidtherapyorcommonlypresentinpatientswithadvancedcancer,suchasnauseaandvomiting,drowsiness,confusion,constipation,dry-mouth,andsoon, usingascalefrom0to3(notatall,slight,alot,awful),wererecorded.Symptomswereassessedbythepatient.Discress score(DS)wascalculatedfromthesumofsymptomintensity.Duringhospitalization,decisionsregardingtheadministrationofopioidsandadjustmentofdosagewerebasedonassessment,patient’sdailyreport,andrescuedosesgivenduringthepre-ceding24hours.Patientsaredischargedhomewhenpaindoses arepresumablystabilizedandpaincontrolhasbeenachieved.ThestudysoughttoestablishwhetherprescriptionoflargedosesofCROwassafeandeffective.Forthispurpose,patientswere divided in 3 groups: L (dose less of 120 mg/day),
1PainReliefandPalliativeCareUnit,LaMaddalenaCancerCenter,Palermo,Italy
2PalliativeMedicine,DepartmentofAnesthesia,andIntensiveCare,University
ofPalermo,Palermo,Italy
3Department ofClinical Neuroscience,University ofPalermo,Palermo, Italy
CorrespondingAuthor:
SebastianoMercadante,PainReliefandPalliativeCareUnit,LaMaddalenaCancerCenter,ViaSanLorenzo312,90146Palermo, Italy
Email:
Mercadanteetal243
M(dosesintherangeof120-240mg7day),andL(doses higherthan240mg/day).
StatisticalAnalysis
DatawereanalyzedbytheEpiInfosoftware(version6.0, CDC,Atlanta,Georgia)andtheSPSSSoftware14.0version(SPSS,Inc,Chicago,Illinois).Frequencyanalysiswasper-formedwithchi-squaretest.Theone-wayanalysisofvariance(ANOVA)wasperformedtoevaluatedifferenceinparametricvariables.Moreover,toexplorearelationshipamongdosesof CROandpatients’characteristics,aseriesoflogisticregressionanalyseswereconducted.Independentvariablesincludedage,gender,andcharacteristicsofpain.AllPvalueswere2-sidedandPvalueslessthan.05wereconsideredtoindicatestatisticalsignificance.
Results
Of1526patientsadmittedin3yearsforpainandsymptomcon-trol,998patientsweredischargedhomewithastrongopioidprescription.Globally,234patientswereprescribedCROdur- ingadmission.Twenty-twopatientswereswitchedtotheopioids,and34patientswereswitchedtoCRO.Wecollected212patientswhowereprescribedatdischargeCROforback-groundanalgesia(patientswhoinitiatedCROandcontinueduntildischargeorwhowereswitchedtoCRO).Themeanagewas62.4(13.2)yearsand118patientsweremales.Primarydiagnoseswereinarankorder:gastrointestinal(54),lung (52),urogenital(46),breast(27),others(33).Overall,themeandoseofoxycodonewas141mg(+167,range10-960mg).Inall,129,43,and40patientswereprescribeddosesofoxyco-doneoflessthan120mg/day(groupL),120to240mg/day(groupM), and morethan 240 mg/day (groupL),respectively.Themeandosesinthe3groupswere48.4+25,156.5+30.5, and435+ 196,respectively.Nodifferencesingender,pri-marydiagnosis,andpainmechanismswerefound(P¼.067,
P¼.43,andP¼.783,respectively).Dosesweresignificantly
lowerinolderpatients(P.0005).Themeanadmissiontime
was4.8(+3.2)days.Athospitaldischarge,meanpaininten-sitywas2.9(+1.9),adverseeffectsweremildinintensity(DS¼3.5+1.7)andwerenotrelatedtoCROdoses(P0.19).
United Kingdom.8Although recentdata suggestedthatoxycodoneisefficaciousandwelltoleratedasafirst-lineopioidindosesof20to40mg/dayafter3weeks,9fewreportshaveassessedpatientsreceivinghighdosesofoxycodone.In anearlyexperience,themeanhighestdosesofCROwere160mgafter12weeksoftreatment.10Inamorerecentstudy, themaximummeandosewasabout230mg/dayinpatientswithveryadvancedcancerwithameansurvivalof12days. Highdoseswereunrelatedtosurvivaltime.7Finally,inamixedItalianpopulationrecruitedindifferentsettings,dosesofCRO achievedafteranaveragetreatmentdurationof37dayswere221mg/day.11
Inourexperience,suchdosesarenotconsideredparticularlyhigh,possiblyduetotheselectionofpatientsadmittedinour unit,whoarealreadyreceivingopioidsatrelevantdoses,andhavealong-termsurvival.Mostpatientswerereceivingopioidsandweretitratedorswitchedtooxycodonetoobtainthebestbalancebetweenanalgesiaandadverseeffects.AccordingtoexistingstudiesreportingonhighdosesofCRO,wedividedpatientswhoweredischargedhomewithaprescriptionofoxy- codonein3groups,andconsideredhighdosesonlythose superior to the mean maximumdoses administeredin previousstudies.Accordingtodepartmentpolicy,patientsaredis- chargedhomeonlyonstabledosescapabletomaintainanacceptablepainrelief(painintensityof::;4onanumerical
scale0-10and2-3dosesofopioidsasneededforbreakthrough
pain)andtolerableadverseeffects.ThisstudydemonstratedthatCROadministeredinveryhighdosescomparedtothoserecordedinpreviousstudieswiththesamepurposeswassafeandeffective,showingversatilityandflexibilitysimilartomor-phine,withdosestitratedagainstintensityofpain.
Asmorphine,CROshowedatypicalinterindividualvaria-bilityindoses.Althoughinanhospiceexperienceageandgen-derdidnotinfluencetheCROdose,7 inthisstudy,olderpatientsreceiveddosessignificantlylowerinolderpatients.Thedifferencemayberelatedtothedifferentpopulationexam-ined.Ofinterest,mostofthepatientsexaminedwerestillon oncologictreatmentandhadaprolongedsurvival,differentlyfrompatientswithaveryshortsurvivaltypicallyobservedinhospicepatients.7Survival,althoughpresumablylonger,wasnotaddressed,andpatientswhodiedintheunitwerenotaccountedforthestudy.ThelowerdosesofCROfoundinolderpopulationreflectsimilarobservationreportedwithother
12
Discussion
opioids
andarelikelytoberelated towell-knownpharmaco-
Effectivenessandsafetyofhighdosesofopioidshavebeenpoorlyreportedinliterature.Inhospiceandhomecareseriesofpatientsreceivingoralmorphine,9%to12%ofpatientsrequireddoseshigherthan300mg/day.Suchrelativelyhighdosesdidnotinfluencethesurvival,attestingthesafetyofhighdosesofopioidsinpatientswithadvancedcancerwhowereresponsive.3,4Similarly,dosesintherangeof720to1100mgoforalmorphineweretoleratedinveryadvancedcancerpopulation.2
Oxycodonehasbeenfoundtobeaseffectiveasmorphine6andisthepreferreddrugforswitchingfrommorphinein
kineticsofopioidsinagedpopulation.13,14PainmechanismsdidnotinfluenceCROdoses,remarkingthepotentialefficacyofoxycodoneinthedifferenttypesofpain,includingneuro-pathicpain.15Giventheretrospectivenatureofthisstudy,adju-vantswerefreelyadministered.However,theconsumptionof
adjuvantswasnotdifferentfromthatreportedwithotheropioids.TheroleofCROinpatientswithneuropaticpainshouldbebetteraddressedinappropriatestudywithspecificdesignsandisbeyondtheaimofthecurrentstudy.
Adverseeffectswererarelydose-limiting,andsafetywas witnessedattimeofdischarge,which,asperprotocol,requiredtheachievementofanacceptablebalancebetweenanalgesia
244AmericanJournalofHospicePalliativeMedicine®28(4)
andadverseeffects.PatientsweredischargedwithanacceptableDS,whichhasbeenusedtogloballymonitortheintensityofopioid-relatedsymptoms.16Itisexpected,however,thatafterstartingtitrationwithCRO,15%ofpatientsmaydiscontinuethedrugforadverseeffects.9,10Inthisstudy,onlyaminorityofpatientswereswitchedtootheropioidsduringadmission(9.4%).Theprincipallimitsofthissurveyistheretrospectiveanalysis,which,however,hasalittleinfluenceontheresultsreported,accordingtowhichhigh doses of CRO, over240mg/day,aresafeandeffective.
DeclarationofConflictingInterests
Theauthor(s)declarednopotentialconflictsofinterestwithrespecttotheresearch,authorship,and/orpublicationofthisarticle.
Funding
Theauthor(s)receivednofinancialsupportfortheresearch,authorship,and/orpublicationofthisarticle.
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