OriginalArticle

Controlled-ReleaseOxycodoneAloneorCombined withGabapentinforManagement ofMalignantNeuropathic Pain

Xiao-meiLi1*,Duan-qiLiu1,Hang-yuWu1,ChunYang2,LiYang3

1DepartmentofMedicalOncology,3DepartementofMedicalTraining,theBeijingMilitaryGeneralHospitalofPLA,Beijing100700,China

2DepartmentofAnatomy,CapitalMedicalUniversity,Beijing100069,China

CLCnumber:R730.5Documentcode:AArticleID:1000-9604(2010)01-0080-07

DOI:10.1007/s11670-010-0080-1

ChineseAnti-CancerAssociationandSpringer-VerlagBerlinHeidelberg2010

ABSTRACT

Objective:Toevaluatetheanalgesicefficacyofcontrolled-release(CR)oxycodoneandgabapentininmalignantneuropathicpain(NP).

Methods:PatientswithmalignantNPwereenrolledandbaselinepainintensity(PI)wasrecorded.TheyinitiallytookoneweekCRoxycodoneandwereallocatedtotwodifferentgroupsatday8byreevaluatedPI.PatientswithmildpainwenttoCRoxycodonemono-therapygroup(OOgroup)andtookanothertwoweeksCRoxycodone.Otherswentto(CRoxycodonecombinedgabapentingroup(OGgroup)andreceivedadditionalgabapentin.Dailydosesandsideeffectswererecorded.

Results:Fifty-eight(92.06%)ofthe63enrolledpatientscompletedtheinitialweek’stherapy. Twenty-two(37.93%)wenttoOOgroupandPIsignificantlyreducedatday15(2.00vs.2.62,P=0.004),butnotimprovedatday22(1.90vs.2.00,P=0.54).Thirty-six(62.07%)patientswenttoOGgroupandPIwassignificantlyreducedatday15(4.47vs.2.94,P<0.001), butnotimprovedat day 22 (2.94vs. 2.75,P=0.136).Meandaily dose (MDD) of CRoxycodoneatday8was62.64mg.Itwassignificantlyincreasedatdays15and22(71.43mgvs.62.64mg,P=0.021;

81.90mgvs.71.43mg,P=0.004)inOOgroup.MDDofgabapentinwassignificantlyincreasedatday22comparedtoday15(862.50mgvs.993.75mg,P<0.001).Constipationwasoccurredin13.64%ofthepatientsinOOgroupand

14.26%inOGgroup.

Conclusion:MalignantNPmaybewellcontrolledbyoxycodonemono-therapy.Earlycombinationwithgabapentinissensible when painisnotsatisfactoryrelievedbyoxycodonealone.The side effectsofthem aremanageable.

Keywords:CRoxycodone;Gabapentin;Malignantneuropathicpain; Analgesicefficacy

INTRODUCTION

CancerpaincanbeeffectivelyandsafelycontrolledinmajorityofcancerpatientsaccordingtotheguidelinesofWorldHealthOrganization(WHO).However,somecancerpaincanbeintractableinwhichneuropathicpain(NP)isacommonreason.NPhasbeendefinedbytheInternational Association for the Study of Pain

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Received20090723; Accepted20091124

*Correspondingauthor.

E-mail:

(IASP)aspainthatisinitiatedorcausedbyaprimarylesionordysfunctioninthenervoussystem[1].Withfeweffectivepharmacologicoptions,itstreatmentremainsaclinicalchallenge.UnsatisfactorytherapyofNPoftenleadstochronicdisability,psychosocialdysfunctionandfamilialfinancialdisruption.Oxycodoneandgabapentinhavebeenidentifiedastwoeffectiveanalgesicsinthetreatment of nonmalignant NPinsomerandomizedstudies[1, 2],buttheywerenotwellstudiedintreatingmalignantNPandveryfewdataarecurrentlyavailable.InChina,opioidshavebeencommonlyusedtorelievemostmoderatetosevere

cancerpainsincludingcancer-relatedNP.Thecontrolledrelease(CR)oxycodone(OxyContintablets®,BeijingMundipharma PharmaceuticalCo.,Ltd)wasnotapprovedtotreatmoderatetoseverecancerpainbyChineseStateFoodandDrugAdministration(SFDA)untilSeptember2003,butnowithasalreadywidelyusedinhospitalsincentralcitiesinChinaduetoitsmoretolerablesideeffectsthanmorphine.Uptonow,however,nodataofoxycodoneinthetreatmentofmalignantNPisavailableinourcountry.GabapentinisaneffectiveanalgesicforbothnonmalignantandmalignantNP.InChina,ithasnotyetbeencommonlyusedtorelievemalignantNP.Toprovidetheevidence-basedoptionsfortherapy,wedesignedthisopen-label observational study to evaluate the

efficacyandsafetyofCRoxycodonealoneorcombinedwithgabapentinforthemanagementofmalignantNP.

MATERIALSANDMETHODS

Thisopen-labelobservationalstudywasconducted at the inpatientdepartmentofMedicalOncology,theBeijingMilitaryGeneralHospitalofPLA.Eachpatientgavewritteninformedconsentbeforeparticipatinginthestudy.

FromJune2005toNov.2008,atotalof63consecutivecancerpatients with malignant NPwereenrolledintothestudy.Figure1presentstheflowofthe63patientsthroughoutthestudy.

Figure1.Flowofpatientsthroughthestudy.

Patients’Characteristics

Patientswithmoderateorseverecancerpainwereenrollediftheyhad anactivecancerlesioncausingpain byinfiltrationor compressionofnervousstructures, oraneuropathycausedbychemotherapy. Patients had at least one of the

followingsymptomsorsignsreferredto thepainarea:burning,shooting,tingling,electrical,stabbing,pinsandneedlesorallodynia.Imagingdiagnosis(computedtomography,magneticresonanceimaging,ultrasound,orothersasjudgedappropriatebytheinvestigator)wasrequiredexcept for patients with chemotherapy-induced

peripheralneuropathy(CIPN).Tothesepatients,adetaileddescriptionofchemotherapydirectlyleadstoperipheralNPshouldbeconfirmed.

InclusionandExclusionCriteriaoftheCases

Inclusioncriteriawere:aged18tolessthan80years;PI4onanumericalratingscalefrom0to10inthe24hperiodprecedingthescreeningvisit,suffered fromneuropathic cancerpainasdefinedabove;lifeexpectancy30days;andKarnofskyperformancestatus(KPS)40.

Exclusioncriteriawere:unabletotakemedicationsorally;plasma creatinine >1.5 mg/mlorcreatinineclearance<60ml/min;currentopioid,gabapentin,nonopioidanalgesics and otheradjuvantdrugsuse;chemotherapyfrom7dbeforescreeningthroughoutthestudy;andradiotherapytothepain-producinglesionfrom15dbeforescreeningthroughout the study. Hormonetherapycouldbestartedbeforethestudy,butthedosecouldnotbechangedafterwards.Patientswerewithdrawnfromthestudywhenanewpaindevelopedorwhenintolerablesideeffectsoccurredduringthecourseofthestudy.

StudyDesign

Thestudywasdividedintotwoconsecutivephases.Abaselinepainintensity(PI)wasassessedbythenumericalratingscale(NRS)atthescreeningvisit(day0)andwasreevaluatedatdays8,15and22.Inthefirstphase,allpatientsenrolledinitiallytookoneweekCRoxycodone.Theinitialdosewas10mg,q12h(20mg/day)anditwascarefullytitratedaccordingtopatients’PI. Afteroneweek’smono-therapy,patientswentontothesecondphasestudyinwhichtheywereallocatedtotwodifferentgroupsaccordingtotheirreevaluatedpainscoresatday8andcontinueanothertwoweekstherapythereafter.Patientswhose painscoreswerelessthan4atday8wereassignedtoCRoxycodonemono-therapygroup(OOgroup)inwhichtheycontinuedtotake another two weeksCRoxycodoneandgraduallytitratedtheirdosesaccordingtotheirpainscores.Patientwhosepainscores4wereassignedto CR oxycodonecombinedgabapentingroup(OGgroup).Inthisgroup,CRoxycodonedoseswerekeptconstant,whilegabapentindoseswereadministered300mgthreetimesdailyforpatientsyoungerthan60yearsold.Initialgabapentindosewere100mgthreetimesdailyforpatientsolderthan60yearsold.Thesedoseswerereachedslowlyinthreedaysandcouldbetitratedtoamaximumdoseof3200mg.

SideeffectsofCRoxycodoneandgabapentinwerealsorecordedinthestudy.Instantreleasemorphinetabletswereallowedevery24hasneededforbreakthroughpain.Therescuemorphinedoseshouldnotexceededhalfofthetotaldailyopioiddose.Prophylacticbowelregimens andanti-emeticswerestartedsimultaneouslywithinitiationofCRoxycodonetherapy.

Statistical Analysis

Patientswhocompleted at least one phasestudywereincludedintotheefficacyanalysis.Patientsreceivingatleastonedoseofstudymedicationswereincludedintothesafetyanalysis.Patientswereexcludediflosttofollowup.SPSS

17.0programwasusedfortheanalysisof data.Datawerepresentedasxs.Pairedt-testswereusedforthecomparisonsofthepainscalesandanalgesicdosesatdifferentobservationaldays.StatisticalsignificancewasdefinedasP<0.05foratwo-tailedhypothesis.

RESULTS

Duringthefirstobservationalweek,3(4.92%)patientsdiscontinuedduetointolerablesideeffectsofCRoxycodone.Two(3.17%)patientswerelosttofollow-up.Sixty-one(96.83%)patientswereevaluableforthesafetyanalysis.Atotalof58(92.06%)patientscompletedthefirstweekstudy.Duringthefollowingtwoweeksstudy,3(8.57%)patientsintheOGgroupand1(4.55%)patientintheOOgroupwerediscontinuedduetointolerablesideeffects.One(2.78%)patientintheOGgroupwaslosttofollow-up.Atotalof53(84.13%)patientscompletedthewholestudy(32patientsinOGgroupand21patientsinOOgroup).Patients’characteristicsareshowninTable1.

PainIntensity

BaselinePI ofthe58evaluablepatientswere7.91(SD=1.29).It’ssignificantlydecreasedto3.74(SD=1.11)atday8whentheycompletedtheinitialweek’sCRoxycodonemono-therapy(P<0.001).

Twenty-twopatientswhosepainscales werelessthan4wereallocated to OO group.Twenty-one(95.45%)patientscompletedthefollowingtwoweekstherapy.Atday15,theirmeanPIsignificantlydecreasedcomparedtoday8(2.00vs.2.62,P=0.004).However,ithadnosignificantdecreaseatday22comparetoday15(1.90vs.2.00,

P=0.54).

Thirty-six(62.07%)patientswhosePIwere4atday8wereenrolledintotheOGgroupand32patientscompletedthefollowing two weekstherapy.Atday15,theirmeanPIweresignificantlyimproved(4.47vs.2.94,P<0.001)comparedtoday

8.Theywerecontinuedtodecreasemildlyatday22butwithoutstatisticaldifference(2.94vs.2.75,P=0.14).ChangeinPIthroughoutthewholestudyperiodisdepictedinTable2.

AnalgesicDoses

Mean daily dose (MDD) of CR oxycodone of

all58completingpatientsatday8was62.64mg

(SD=32.35), and 66.67 (SD=26.08) and60.00 mg

(SD=35.56)forOGgroupandOOgrouprespectively.InOOgroup,MDDofCRoxycodoneatday15was71.43mg(SD=26.51)anditwassignificantlyincreasedcomparedtoday8(P=0.021).Atday22,itfurtherincreasedto81.90mg(SD=32.80)whichisstatisticallyhigher thanday15(P=0.004).

MDD ofgabapentinsignificantlyincreasedatday 22(993.75,SD=279.33)comparedtoday 15(862.50 mg, SD=282.56, P<0.001). MDDs of CR

oxycodoneandgabapentinat differentobservationaldaysarelistedinTable3.

Table1.Summaryofdemographyandbaselinecharacteristics-fullanalysispopulation

aLosttofollow-up;bWithdrawn;SD:Standarddeviation

Table2.ChangeinmeanPIthroughoutthethreeweeksstudyperiod

OverallOOgroupOGgroup
Dayn=53Pvaluen=21(SD)Pvaluen=32(SD)Pvalue
Baseline(SD)7.91
Day8(SD)3.74 / (1.29)7.81(1.25)7.97(1.33)
(1.11)<0.0012.62(0.59)<0.0014.47(0.67)<0.001
Day15(SD) / 2.00(0.71)0.0042.94(0.67)<0.001
Day22(SD) / 1.91(0.44)0.542.75(0.76)0.14

PI:Painintensity;SD:Standarddeviation.

Table3.Dailyanalgesicdosesthroughoutthethreeweeksstudyperiod

Dailyoxycontindose
Day / Overalln=58 / OGgroupn=32 / OOgroupn=21 / DailyGabapentinDoseOGgroupn=32
Day8
Mean(mg) / 62.64 / 60.00 / 66.67
SD / 32.35 / 35.56 / 27.08
Min(mg) / 20 / 20 / 20
Max(mg) / 180 / 180 / 120

Day15

Mean(mg) / 71.43a / 862.50
SD / 26.51 / 282.56
Min(mg) / 40 / 600
Max(mg) / 120 / 1800

Day22

aP=0.021;bP=0.004;cP<0.001.SD:standarddeviation;Min:minimum;Max:maximum.

SafetyAnalysis

Of the 63 patients enrolled, 2 (3.17%) lost tofollowupduringthefirstweek’sstudyperiod.So,atotalof 61(96.83%) patients wereevaluable for thesafetyanalysis.Inaddition,3(4.92%)patientswerewithdrawnduetointolerablesideeffectsinthisphase.As a result, 58 (92.06%) patients went on to thesecondphasestudyinwhich1(2.86%)patientlosttofollowupintheOGgroup,57(98.28%)patientswere

evaluableforthesafetyanalysis.One(4.55%)patientintheOOgroupand3(8.57%)patientsintheOGgroupwerewithdrawnduetointolerablesideeffects.Noseveresideeffectswereobservedinallevaluablepatients.Themostcommonsideeffectofallpatientsenrolledwasconstipation.Itoccurredin13.64%patientsintheOOgroup.ThemainsideeffectsofOGgroupwereconstipationandnausea(14.26%and8.57%respectively).ThesideeffectsobservedarelistedinTable4.

Table4.Incidenceofsideeffects

1stweek’soxycontinOOgroupOGgroup

Sideeffectn=61(%)an=22(%)n=35b (%)

Constipation6(9.84)3(13.64)5(14.26)

Nausea5(8.20)c2(9.09)3(8.57)

Vomiting3(4.92)c1(4.55)c1(2.86)c

Dizziness1(1.64)c02(5.71)c

Sedation2(3.28)03(8.57)

Sweating1(1.64)01(2.86)

Pruritus1(1.64)00

Drymouth1(1.64)02(5.71)

Asthenia1(1.64)1(4.55)1(2.86)

Ataxia002(5.71)c

aExceptedtwolosttofollowup;bExceptedonelosttofollowup;cWithdrawnduetointolerablesideeffect.

DISCUSSION

Ofthe63enrolledpatientsinourstudy,58(92.06%)patientscompletedtheinitialweek’sCRoxycodone mono-therapy. Among these patients,

22(37.93%)gotasatisfactorypaincontrol(PIdecreasedtomild).Twenty-one(95.45%)ofthesepatientseventuallycompletedthewholestudyandgainedfurtherpainimprovement.Thisresultindicatesthatsomemalignantneuropathicpainisresponsivetooxycodonemono-therapy.Ifsatisfactorypainreliefisobtainedintheinitialweek,ongoingtitrationofthesamemedicationmaybereasonableandabetterpainimprovementcouldbeobtained.Inaddition,theanalgesicdosesdatashowedthateventhedailydoseofCRoxycodonesignificantlyincreasedatday22comparedtoday15inthestudy,patients’meanPIwerenotdecreasedaccordingly.ItindicatestheetiologicalcomplexityofNPandsuggestscoanalgesicsshouldbeconsideredinthisphaseforfurtherpaincontrol.

Ofthe58patientsinourstudywhocompletedoneweekCRoxycodonemono-therapy, 36(63.03%) patients got a significantly painimprovementcomparedtothebaselineatday8,buttheirmeanPIdidnotreachtomildwhichindicateda combinational therapy should be taken.Accordingtoourstudydesign,thesepatientswenton to the second phase study in which theyreceived gabapentin as a coanalgesic. Our resultssuggestthatthiscombinationisobviouslyeffective.Asignificant difference in pain scores at day 15comparedtoday8wasobserved.Itindicatesthatthis combination may be a potential effectiveregimen to patients whose NP were notsuccessfully controlled by CR oxycodonemono-therapy. The early combination may beadopted and further investigation is necessary todefine which type of malignant NP should betreated by the combinational therapy. Othercombinationsshouldalsobestudiedinthefuture.

Astothedoseofgabapentin,thetitrationwascontinuedonthethirdweekandthedailygabapentindoseincreasedsignificantlyatday22comparedtoday15,nostatisticallysignificantdifferenceinmeanPIwasobservedthoughitcontinuedtodecreasemildly.Wethinkitmayduetothefactthateventheaveragedailygabapentindosekeptincreasingduringthetwoweekstitration,

itwas still farless than thatofother studies[46].

Maybea higherdoseismoreeffective.However,racialdifferencesshouldbeconsideredaswefoundthefrequencyofitssideeffectsinourstudyissimilar to other studies[4, 7, 8]. Side effectscan be

anotherreasonwhichlimitsitsdoseescalation.Inaddition,inourcountry,currentlyonly100mgcapsulegabapentinisavailable,thismayalsobeanimportantobstacleofdosetitration.Asit is notonlyinconvenientforpatientswhoneedrelativelyhigherdosesbutalsocausingthefearoftakingsomanycapsules.

Intermsofsafety,wefoundthat95.08%ofthe61evaluablepatientscompletedtheinitialweekofCRoxycodonemono-therapyandonly34.92%patientshadintolerablesideeffects.Anoteworthyfactisthat4patientsreceivingCRoxycodonemono-therapy(3inthefirst and1inthe secondstageofthestudy)withdrewduetonausea,vomitinganddizziness.Itindicatesthateventhetolerancetothesesideeffectsdevelops within afewdaysofconsistentdosing,aneffectiveregimeofsymptomscontrolshould be taken untiltolerancereallydevelops.Opioidrotationmaybeanalternativeforthesepatients.

Inourstudy,themainsideeffectobservedwasconstipation.Itoccurredin9.84%ofallthe61evaluablepatientsinthefirstweek’sCRoxycodonemono-therapyand13.64%intheOOgroup.ThefrequencyofconstipationinourstudyissimilartoFanBFandYuSY’sreports[9,10].Themainside effects ofOG group were constipationandnausea.ThefrequencyofthesesideeffectswassimilartoHannaM’sstudy[11]andwasalsosimilartotheOOgroupinthisstudy.Unfortunately,thesefigureswerenotbigenoughtodofurtherstatisticalcomparisons.WealsofoundahigherfrequencyofsomnolenceanddrymouthintheOGgroupevenwecannotcomparethemduetothesamereasonmentionedabove.Wethink that the higherfrequencymaybetheresultofthesideeffectsoverlapbetweenthetwodrugs.Ingeneral,bothofthesetwoanalgesicsaresafeandmostoftheirsideeffectsaremanageableinourstudy.

Inconclusion,CRoxycodoneiseffectivetomalignantNPcontrol.Somepatientsmaygainasatisfactorypainreliefbyitsmono-therapy.Topatientswhosepainisnotwellcontrolledbyitalone,anearlycombinationwithgabapentiniseffective.Bothofthetwodrugsaresafeandmostofthesideeffectsarereadilymanageable.

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