ORIGINALARTICLE
SustainedSafetyandEfficacyof Once-Daily HydromorphoneExtended-Release(OROS®
hydromorphoneER)ComparedwithTwice-DailyOxycodoneControlled-ReleaseOver52WeeksinPatientswithModeratetoSevereChronicNoncancerPain
UteRicharz,MD*;SandraWaechter,PhD*;RainerSabatowski,MD†;LeszekSzczepanski,MD,PhD‡;HeinrichBinsfeldMD§
*Janssen-Cilag,Baar,Switzerland;†ComprehensivePainCenter,UniversityHospitalCarlGustavCarus,TechnicalUniversity,Dresden,Germany;‡WyzszaSzkolaSpoleczno-Przyrodnicza,Lublin,Poland;§Schmerz-ZentrumamSt.FranziskusHospital,Ahlen,Germany
AuthorCorrespondenceandreprintrequeststo:UteRicharz,MD,JanssenGlobalServices,LLC,Sihlbruggstrasse111,6340Baar,Switzer-land.E-mail:.
Disclosures:Dr.RicharzdisclosesthatsheisanemployeeofJanssenGlobal ServicesLLC and isalsoastockholderinJohnson& Johnson. Dr.SandraWaechterdisclosesthatsheisanemployeeofJanssen-CilagandisalsoastockholderinJohnson &Johnson.Dr.RainerSabatowskidisclosesthatheisaconsultantforCephalonInc.andGru¨nenthalandhasreceivedpaymentforlecturesfromMerckSharpDohmeLimited.Dr.LeszekSzczepanskihasnodisclosurestoreport.Dr.HeinrichBinsfelddisclosesthatheisaconsultantforJanssen-Cilag,hasservedasanexpertwitness,andhasreceivedpaymentforlecturesfromJanssen-Cilag,PfizerInc,AWDPharmaDresdenGmbH,andGru¨nenthal.
Submitted:October11,2011;Accepted:March5,2012DOI.10.1111/j.1533-2500.2012.00553.x
©2012JanssenGlobalServices
PainPractice©2012WorldInstituteofPain,1530-7085/13/$15.00PainPractice,Volume13,Issue1,201330–40
nAbstract:Once-dailyhydromorphoneextended-release(OROS® hydromorphone ER) and oxycodone controlled-
release(CR)aresemisynthetic,ERopioidanalgesicswithestablishedefficacy.Anopen-label,randomized,24-week,parallelgroup,flexible-dosestudydemonstratednoninferi-orityofOROShydromorphoneERvs.twice-dailyoxycodoneCRinpatientswithchronicnoncancerpain.Intotal,112patientswereenrolledina28-week,open-labelextensionstudy;60patientsreceivedOROShydromorphoneERand
52receivedoxycodoneCR.TheprimaryefficacymeasurewasthechangefrombaselinetoWeeks38and52inBriefPainInventoryitem‘‘painrightnow.’’Globalassessmentsofefficacy,dosingconvenience,andtolerabilityweresec-ondaryendpoints.Meanchangein‘‘painrightnow’’frombaselinetoWeek38was)3.0(OROShydromorphoneER)vs.)2.8 (oxycodone CR),and from baseline to Week52 was
)2.9vs.)2.8;thesechangesweresimilartothechangesinthecorephase()2.1vs.)2.1).Similarimprovementsweredemonstratedforsecondaryassessments,includingpain,paininterference,andqualityoflife.AtWeek52,globalassessmentofefficacywasratedas‘‘verygood’’or‘‘good’’bythemajorityofpatients(OROShydromorphoneER,91.7%;oxycodoneCR,86.5%).MorepatientsintheOROShydromorphoneERgroup(35.0%vs.21.2%)assessedmodeofdrugintakeas‘‘veryconvenient.’’ThemajorityofpatientsreceivingOROShydromorphoneER(88.3%)andoxycodoneCR(88.5%)ratedtolerabilityas‘‘good’’or‘‘verygood’’atWeek52;fewpatientsdiscontinuedtreatmentbecauseofanadverseevent(1.6%vs.0.4%,respectively).
TheeffectivenessofOROShydromorphoneERandoxyco-doneCRwasmaintainedthrough1year. n
KeyWords:chronicpain, long-term safety,sustainedefficacy,OROS,hydromorphoneextended-release
INTRODUCTION
IntheUnitedStates,approximately14%ofpersonsexperiencechronicpain,1,2definedaspainthatpersistsbeyondtheexpectedperiodofhealingand forextendedperiodsoftime.3Additionally,about19%ofadultEuropeansexperiencemoderateorseverechronicpain.4Inadditiontothephysicalburden,chronicpaincanaffectnumerousaspectsofpatients’lives,substan-tiallyimpactingoverallqualityoflife.5Chronicpaincanalsoaffectsleep,aspatientsmayexperiencediffi-cultyfallingandstayingasleepormayhavelessrestfulsleep.6Wakefulnessisoftenaffectedaswell,asopioid-inducedsedationisapossibleadverseeffectofchronicopioidtherapy.7Theoverallobjectiveofpharmacolog-icalpainmanagementistoimprovequalityoflifebybalancingacceptableefficacyandtolerability.8 Whenotherinterventionshaveprovedunsuccessfulforthemanagementofchronicpain,opioidanalgesicsmaybeanappropriatetreatmentoption.9TheAmericanPainSocietyandAmericanAcademyofPainMedicineagreethatopioidscanbeeffectiveforcarefullyselectedandmonitoredpatientswithchronicnoncancerpain.9Useofopioidanalgesicsforthetreatmentofchronicnon-cancerpainisalsosupportedbyguidelinesissuedbytheEuropeanFederationofChaptersoftheInterna-tionalAssociationfortheStudyofPain.10
Once-dailyhydromorphoneextended-release(OROS®hydromorphoneER)andtwice-dailyoxyco-donecontrolled-release(CR)aresemisynthetic,ERopioidanalgesicswithestablishedefficacy.11,12Hydro-morphone is a potent oral opioid analgesic, with
approximately4:1to8:1morphine:hydromorphoneequianalgesicpotency.13 Hydromorphone has beenusedextensivelyinthetreatmentofchronicpain.14,15Originallyavailableasanimmediate-releaseformula-tion,hydromorphoneisnowavailableasanERfor-mulation (OROS® hydromorphone ER).16 Oxycodone
CRisapproximatelytwiceaspotentasmorphineandisalsousedextensivelyinthetreatmentofchronicpain.12,17Arecentlypublishedopen-label,randomized,24-week,flexible-dosestudydemonstratednoninferior-ityofOROShydromorphoneERvs.oxycodoneCRforthetreatmentofchronicnoncancerpain.18Theobjectiveofthisreportwastoevaluateresultsfromthe28-weekextensionphaseofthisstudy,whichwasdesignedtodeterminethesustainedsafetyandefficacyofOROShydromorphoneERandoxycodoneCRinpatientswithchronicnoncancerpain.
METHODS
Thiswasanopen-label,international,multicenter,randomized(1:1),comparative,parallel-groupnoninfe-rioritystudywith a 28-week extension phase inwhichpatientsreceivedtreatmentthrough52weeks(clinicaltrials.govidentifier:NCT00261495).Theresultsofthe24-week,open-labelstudyhavebeenpublishedelsewhere.18Ofthe64centersthatparticipatedinthecorephase,20participatedintheextension;manycenterswithdrewforadministrativereasons.WritteninformedconsentwasobtainedatthescreeningvisitinaccordancewiththeprinciplesoftheDeclarationofHelsinki.Allcentershadreviewboardapproval.
Patients
Patientsaged‡18yearswithchronicnoncancerpain(defined as pain occurring ‡20days/month for
3months) whorequiredcontinuousopioid therapywereenrolled.Chronicpainconditionsincludedlowback,musculoskeletal,andneuropathicpainandotherconditions.Thestudyincludedopioid-naı¨vepatients,patientsreceivingtreatmentwithweakopioids,patientstaking£60mgoralmorphineoranequiva-lentofanotherstrongopioid,andthosepatientsusingtransdermalfentanyl25mcg/hourortransdermalbu-prenorphine35mcg/hour.Patientsprovidedwrittenconsenttocontinuetreatmentfor28weeks.
Patientswhoseprevioushydromorphoneoroxyco-donetherapywasunsuccessfuland patients withknownhypersensitivitytoeitherdrugwereexcluded.
Patientswithahistoryofsignificantcardiac,nervoussystem,orgastrointestinalconditions,moderate-to-severehepaticimpairment,severerenalimpairment,orhereditaryproblemsofgalactoseintolerance,Lapplac-tasedeficiency, orglucose-galactosemalabsorptionwereexcluded.Womenwhowerepregnantorbreast-feedingwereexcluded.
StudyDesignandTreatments
PatientswereenrolledfortreatmentfromWeek0toWeek56,withWeeks53to56includedforafollow-upvisit.Thelastdoseofstudymedicationwasadmin-isteredduringWeek52.Primaryandsecondaryeffi-cacymeasureswereassessedatWeeks38and52intheextensionstudy.Inthecorephaseofthestudy,treatmentwasinitiatedwith8mgOROShydromor-phoneERoncedailyor10mgoxycodoneCRtwicedaily,followedbyindividualtitrationover4weekstoamaximumdailydoseof32mgor80mg,respec-tively.
Useofsupplementalanalgesics(acetaminophen,upto2g/d)waspermittedbutwasnotdocumentedinpatientdiaries.Investigatorswerepermittedtoadmin-isterbisacodyl5mgtwicedailytopreventconstipa-tion.Ifpatientsremainedsymptom-free,investigatorscoulddecreasethedosageordiscontinuebisacodyl.Anti-emeticscouldalsobeprescribedatthediscretionoftheinvestigators.
Mostconcomitantmedicationswereallowediftheyhadbeeninitiated‡2weekspriortostudyinclusionandweremaintainedatastableorreduceddosage.Concomitantmedicationsnotpermittedduringthestudyincludedotheropioidanalgesics;neuroleptics,excludinghaloperidolordroperidol,up to 2mg/dayfor£30daysduringthecourseofthestudytotreatnauseaand/orvomiting;hypnotics,excludingshort-actinghypnoticstakenfor£30daysduringthecourseofthestudy;sympathomimeticdrugs;monoamineoxi-daseinhibitors;andtetrabenazines.
EfficacyMeasures
TheprimaryefficacymeasurewasthechangeinBriefPainInventory(BPI)painseverityitem‘‘painrightnow’’frombaselinetoWeeks38and52.Scoresrangefrom0to10,withlowervaluesrepresentinglesspain.TheBPIincludesothermeasuresofpainintensity,aswellasinterferencewithfunction.Secondaryefficacyendpoints included BPI items ‘‘pain at its worst,’’
‘‘painrelief,’’andindividualpain-interferenceitems.Paininterferenceassessestheimpactofpainonseveralareasofphysicalandemotionalfunctioning.Globalassessmentsofefficacy,tolerability,andconvenienceofthestudydrugwereperformedatWeek52.
SleepwasassessedusingtheBPIsleepinterferenceitemandtheMedicalOutcomesStudy(MOS).TheMOSassessesseveralaspectsofsleep,includingqual-ity,disturbance,andsomnolence.LowerMOSsleepsubscalesscoresindicatedbettersleepquality.PatientsweregivenaShortForm-36(SF-36)questionnairetoassessqualityoflifeatWeeks38and52.TheSF-36scaleisusedtoassessphysical,emotional,andsocialfunctioningandincludesamentalhealthindexandameasureofgeneralhealthperception.SF-36scoresrangefrom0to100,withahighscoreindicatingbet-terqualityoflife.
SafetyEvaluations
Adverseevents(AEs)wereassessedfromtheadminis-trationofthefirstthroughthelastdoseofmedication.AglobalassessmentoftolerabilitywasperformedatWeek52.
StatisticalAnalysis
Demographicandbaselinecharacteristicswereana-lyzedfortheperprotocol(PP),intent-to-treat(ITT),andsafetypopulations.PrimaryandselectedsecondaryendpointanalyseswereperformedinthePPpopula-tion,definedasallpatientsincludedintheITTpopula-tionwhodidnotviolateanymajorprotocol.EfficacyanalyseswereperformedintheITT population,definedasrandomizedpatientswhoreceived‡1dose
ofthestudymedicationandhad‡1postbaselineeffi-
cacyassessment.Safetyanalyseswereperformedinthesafetypopulation,definedasallrandomizedpatientswhoreceived‡1doseofthestudymedication.
Summarystatisticsarepresentedbywayofn,mean,
andstandarderrorofthemean(SEM)forcontinuousvariables andbywayofgroupfrequenciesandper-centagesforcategoricalvariables.Percentageswerecalculatedusingthetotalnumberofpatientsineach treatmentgroup.Summarystatisticsforthevaluesobservedateachvisitarepresentedforallefficacyend-pointsdescribedaschangefrombaseline.Analysisofobserved caseswascarried out fortheprimaryend- pointandselectedsecondaryefficacyendpoints.Test-ingfornoninferioritybetweentreatmentswithrespect
totheprimaryendpoint,thatofchangeinBPI‘‘painrightnow’’frombaseline,wasconductedinaconfir-matorysense.Ifapatientrecordedanearlytermina-tionvisit,theearlyterminationdatewasusedastheenddateofthatlastvisitinterval.
RESULTS
PatientDisposition
Overall,112patients(40.4%)whocompletedthe24-
morphoneERandoxycodoneCRwere17.1mgand
44.6mg,respectively.ThemeanequianalgesicdoseratioofOROShydromorphoneERtooxycodoneCRwasapproximately2.5:1.
DemographicsandBaselineCharacteristics
Patientswhoenteredtheextensionphasetended tohavelowerpainseverity,greaterpainrelief,andgreaterimprovementsinsleepqualitycomparedwith
18
weekcorephaseofthestudywereenrolledinthe28-weekopen-labelextensionphase(Figure1).SixtypatientshadbeenreceivingOROShydromorphoneER(maximaldailydosage,32mg)and52hadbeenreceiving oxycodone CR (maximal daily dosage,80mg).Fifteenpatients(13.4%)discontinuedtreat-mentduring theextensionphase;ofthese,5(4.5%)discontinuedduetoAEsand6(5.4%)duetootherreasons(eg,dispensingofstudymedicationnotaccordingtotheprotocol).
Patientsintheextensionphasehadameandurationofexposureof371.0days(OROShydromorphoneER)and380.5days(oxycodoneCR).Meandoseanddistributionofpatientsattheendoftitration,mainte-
thosewhodidnotcontinuepastWeek24.
Intheextensionphase,theOROShydromorphoneERandoxycodoneCRtreatmentgroupswerecompa-rablewithregardtodemographics(Table2),disease-relatedbaselinecharacteristics,andmedicalhistories.The mostcommon underlyingdiseaseswere chroniclowbackpain(59.8%),musculoskeletalpain(23.2%),andneuropathicpain (9.8%). Fourteen patients(23.3%)randomizedtoreceiveOROShydromorphone
Table1.MeanDoseandDistributionofStudy TreatmentatWeek4,Week24,andWeek52inPatientsWhoEnrolledintheExtensionPhase
OROSHydromorphone
ER(n=60)OxycodoneCR(n=52)
nance,andextensionphasesaredescribedinTable1.AtWeek52,themeandailydosesofOROShydro- / Mean / Doseper / Mean / Doseper
Dose / Day / Dose / Day
StudyPeriod / (mg) / (mg) / n(%) / (mg) / (mg) / n(%)
Week4,endof / 16.1 / 8 / 19(31.7) / 40.4 / 20 / 15(28.8)
titrationphase / 16 / 31(51.7) / 40 / 29(55.8)
32 / 10(16.7) / 80 / 8(15.4)
Week24, endof / 17.5 / 8 / 19(31.7) / 43.5 / 20 / 11(21.2)
maintenance / 16 / 26(43.3) / 40 / 31(59.6)
phase / 32 / 15(25.0) / 80 / 10(19.2)
Week52, endof / 17.1 / 8 / 20(33.3) / 44.6 / 20 / 10(19.2)
extension / 16 / 26(43.3) / 40 / 31(59.6)
phase / 32 / 14(23.3) / 80 / 11(21.2)
CR, controlledrelease;ER, extendedrelease;OROS,oralosmotic drug deliverysystem.
Table2. DemographicCharacteristics
Characteristic
OROS
HydromorphoneER(n=60)
OxycodoneCR(n=52)
Total(N=112)
Age(years),mean(SD)58.4(10.1)57.9(12.3)58.1(11.1)
Gender,n(%)
Female33(55.0)27(51.9)60(53.6)
Race,n(%)
Caucasian60(100.0)52(100.0)112(100.0)
Country,n(%)
CzechRepublic21(35.0)8(15.4)29(25.9)
Germany18(30.0)18(34.6)36(32.1)
Poland19(31.7)21(40.4)40(35.7)
Slovakia2(3.3)5(9.6)7(6.3)
Figure1. Studydesign.
CR,controlledrelease;ER,extendedrelease;OROS,oralosmoticdrugdeliverysys-tem;SD,standarddeviation.
ERand9patients(17.3%)randomizedtoreceiveoxy-codoneCRwereopioidnaı¨veatthestartofthecorephaseofthestudy;46(76.7%)and43(82.7%)patientsineachgroup,respectively,hadreceivedpriorweakopioidtherapy(eg,codeine,dihydrocodeine,ortramadol).Themajorityofpatientsincludedinthisextensionphaseweretaking‡5concomitantmedica-tions(65%intheOROShydromorphone ER groupand 67.3%inthe oxycodoneCRgroup).Almostallpatientsweretaking‡1concomitantmedication(98.3%in theOROShydromorphoneERgroupand98.1%intheoxycodoneCRgroup).
Efficacy
AmongpatientsreceivingOROShydromorphoneER,mean(SEM)overallpainseveritydecreasedfrom6.3(0.1)atbaselineto3.9(0.2)atWeek52.InpatientsreceivingoxycodoneCR,painseveritydecreasedfrom
6.5(0.2)atbaselineto4.0(0.2)atWeek52.
PrimaryEfficacyMeasure
Mean(SEM)changeinBPIitem‘‘painrightnow’’frombaselinetoWeek38was)3.0(0.3)forOROShydromorphoneERvs.)2.8(0.3)foroxycodoneCR,andfrombaselinetoWeek52was)2.9(0.3)forOROShydromorphoneERvs.)2.8(0.3)foroxyco-
doneCR(Figure2A).Inthe OROS hydromorphoneERgroup,mean(SEM)‘‘painrightnow’’decreasedovertimefrom6.8(0.2)atbaselineto3.9 (0.3) atWeek52.Similarly,intheoxycodoneCRgroup,mean(SEM)‘‘painrightnow’’decreasedfrom6.9(0.2)atbaselineto4.1(0.3)atWeek52.
SecondaryEfficacyMeasures
Atbaseline,mean(SEM)‘‘painatitsworst’’scorewas
8.1 (0.2)inboth the OROS hydromorphoneERandoxy-codoneCRgroups(Figure2B).AtWeek52,mean(SEM)‘‘painatitsworst’’scorewas5.3(0.3)and5.7(0.3)intheOROShydromorphoneERandoxycodoneCRgroups,respectively.IntheOROShydromorphoneERgroup,mean(SEM)‘‘painatitsleast’’decreasedfrom
4.5(0.2)atbaseline to 2.6(0.2)atWeek52(Figure2C).IntheoxycodoneCRgroup,‘‘painatitsleast’’decreasedfrom4.8 (0.3)atbaselineto2.4(0.2)atWeek52.
Mean(SEM)paininterferencescoresatbaseline,Week24,Week38,andWeek52fortheOROShydro-morphone ER group were 6.6 (0.24), 4.2 (0.3), 3.9
(0.3),and4.2(0.3),respectively.IntheoxycodoneCRgroup,meanscoreswereslightlyhigheroverall:baseline(7.0[0.3]),Week24(4.3[0.2]),Week38(4.7[0.3]),
andWeek 52(4.4 [0.3]).Similarfindings wereobservedinbothtreatmentgroupswhenpaininterferencewithgeneralactivity(Figure3A),walkingability(Figure3B),
Figure2.Mean(SEM)BriefPainInventorypainseverityscoresfor(A)‘‘painrightnow’’,(B)‘‘painatitsworst’’,and(C)‘‘painatitsleast’’.Adecrease inpain severity scoreindicates lesspain. Darkbarsrepresent OROS hydromorphoneextended-release, andlightbarsrepresentoxycodonecontrolled-release.OROS,oralosmoticdrugdeliverysystem;SEM,standarderrorofthemean.
normalworkactivity(Figure3C),andsleep(Figure3D)wasevaluated.Additionally,foremotionaldomainsmeasuredbypaininterferencescores(ie,mood[Fig-ure4A],relationshipswithothers[Figure4B],andenjoymentoflife[Figure4C]),improvementsweresustainedovertimeinbothtreatmentgroups.
AccordingtotheSF-36questionnaire,mean(SEM)scoresforpainindexatbaselinewere20.6(1.6)intheOROShydromorphoneERgroupand16.4(1.6)intheoxycodoneCRgroup.AtWeek52,painindexscoresimprovedto 46.0(3.6)and41.9(2.9)in theOROShydromorphone ER and oxycodone CR groups,
Figure3.Mean(SEM)BriefPainInventoryphysicalpaininterferencescoresforgeneralactivity(A),walkingability(B),normalworkactivity(C),andsleep(D).Adecreaseinpaininterferencescoreindicateslessinterference.DarkbarsrepresentOROShydromor-phoneextended-release,andlightbarsrepresentoxycodonecontrolled-release.OROS,oralosmoticdrugdeliverysystem;SEM,stan-darderrorofthemean.
Figure4.Mean(SEM)Brief PainInventory emotional pain interferencescoresfor mood(A),relationshipswith others(B),andenjoy-mentoflife(C).Adecreaseinpaininterferencescoreindicateslessinterference.DarkbarsrepresentOROShydromorphoneextended-release,andlightbarsrepresentoxycodonecontrolled-release.OROS,oralosmoticdrugdeliverysystem;SEM,standarderrorofthemean.
Figure5.Changeinqualityoflifeaccordingtomean(SEM)SF-36domainscoresforgeneralhealthperception(A),mentalhealthindex(B),physicalfunctioning(C),socialfunctioning(D),andvitality(E).Anincreaseindomainscoresindicatesanimprovementinqualityoflife.DarkbarsrepresentOROShydromorphoneextended-release,andlightbarsrepresentoxycodonecontrolled-release.OROS,oralosmoticdrugdeliverysystem;SEM,standarderrorofthemean.
respectively.Improvementswerealsodemonstratedacrossallotherdomainsinbothtreatmentgroups(ie,generalhealthperception[Figure5A],mentalhealthindex [Figure5B], physical functioning [Figure5C],
Table3.Mean(SEM)Valuesof MOS EfficacyParameters forOROS Hydromorphone ER andOxycodoneCR
OROS
social functioning [Figure5D], and vitality [Fig-
EfficacyMeasure
Hydromorphone
Oxycodone
ure5E])inbothgroups.
SleepqualityissummarizedinTable3.Improve-ment(meanchange[SEM])insleepqualityfrombaselinetoWeek38was)12.5(2.7)forOROShydro-morphoneERvs.)12.4(3.0)foroxycodoneCR.Simi-larly,improvementinsleepquality(meanchange[SEM])frombaselinetoWeek52wasalsocomparablebetweentreatmentgroups()10.7[2.4]forOROShydromorphoneERvs.)11.5[2.7]foroxycodoneCR).TreatmentwithOROShydromorphoneERwasassoci-atedwithsubstantiallylesssomnolencethanoxycodoneCR.Thiswasalsotrueinthecorephaseofthestudy,
wheretherewasasignificantdifference(P=0.020)forsomnolenceintheOROShydromorphoneERgroup.18
AtWeek52,themajorityofpatientsratedtheglo-balassessmentofefficacyas‘‘verygood’’or‘‘good’’(OROS hydromorphoneER,n=55[91.7%];oxyco-doneCR,n=45[86.5%]).MorepatientsintheOROShydromorphoneERgroupthanintheoxyco-doneCRgroupassessedmodeofdrugintakeas‘‘very
convenient’’ (21 [35.0%] vs. 11 [21.2%]). Ten
(16.7%) and 15 (28.8%) patients receiving OROS
Score,mean(SEM)ER(n=60)CR(n=52)
SleepqualityBaseline / 48.1(2.1) / 51.9(2.2)
Week24 / 34.0(2.7) / 37.2(2.4)
Week38 / 35.4(2.6) / 40.3(3.1)
Week52 / 38.0(2.7) / 40.4(2.3)
Sleepdisturbance
Baseline53.4(2.5) / 60.8(2.8)
Week2434.2(3.0) / 35.9(3.1)
Week3836.1(3.2) / 42.5(3.8)
Week5237.3(3.2) / 40.7(3.0)
SleepsomnolenceBaseline / 40.9(2.2) / 39.9(2.7)
Week24 / 37.4(2.2) / 40.1(3.0)
Week38 / 32.8(2.2) / 41.4(2.4)
Week52 / 34.8(2.5) / 41.7(2.8)
Lowerscoresindicatebettersleepquality.
CR,controlledrelease;ER,extendedrelease;MOS,MedicalOutcomesStudy;OROS,oralosmoticdrugdeliverysystem;SEM,standarderrorofthemean.
hydromorphoneERandoxycodoneCR,respectively,assessedmodeofdrugintakeas‘‘convenient.’’
Safety
Overall,42patientsreceivingOROShydromorphoneER(84%)and43receivingoxycodoneCR(91%)reported
Table4.Summary of Adverse Events During theExtensionPhase
OROS
phoneERcomparedwithtwice-dailyoxycodoneCRinpatientswithchronicnoncancerpain.Patientswhocompleted an initial open-label 24-week trial were
Variable
MostcommonAEs,n(%)
HydromorphoneER(n=50)
OxycodoneCR(n=47)
Total(N=97)
allowedtocontinueinthe28-weekopen-labelexten-
sionphase,resultinginupto52weeksofactivetreat-ment.Paincontrolwasmaintainedinbothgroupsfor
Nasopharyngitis1(2.0)3(6.4)4(4.1)
Vertigo1(2.0)3(6.4)4(4.1)
Weight decreased3(6.0)1(2.1)4(4.1)
Anorexia3(6.0)0 (0)3(3.1)
upto1year,withOROShydromorphoneERdemon-stratingasimilarefficacyandsafetyprofiletooxyco-
Drugwithdrawalsyndrome
0(0)3(6.4)3(3.1)
done CR. Improvements in pain severity were
observed across a number of outcome measures,
Hypertension3(6.0)0 (0)3(3.1)
Nausea1(2.0)2(4.3)3(3.1)AEs,n(%)
Possiblyrelatedtostudydrug Probablyrelatedtostudydrug
Verylikelyrelatedtstudydrug Resultedinwithdra / 10(20.0) / 4(8.5) / 14(14.4)
1(2.0) / 0(0) / 1(1.0)
o0(0)6(12.8)6(6.2)
wal4(8.0)1(2.1)5(5.2)
Severity,n(%)
Mild / 14(28.0) / 7(14.9) / 21(21.6)
Moderate / 23(46.0) / 31(66.0) / 54(55.7)
Severe / 5(10.0) / 5(10.6) / 10(10.3)
AE,adverseevent;CR,controlledrelease;ER,extendedrelease;OROS,oralosmoticdrugdeliverysystem.
AEs.ThemostcommonlyreportedAEswerenasopharyn-gitis(4.1%),vertigo(4.1%),andweightdecrease(4.1%)(Table4).Intotal,investigatorsdeterminedthat20.0%ofAEswerepossiblyrelatedtotreatmentwithOROShydromorphoneER,and2.0%ofAEswereprobablyrelatedtothistreatment.ThemajorityofAEs(74%)intheOROShydromorphoneERgroupweremildtomod-erateinseverity.IntheoxycodoneCRgroup,investiga-torsdeterminedthat8.5%ofAEswerepossiblyrelatedtostudymedication,with12.8%ofAEsverylikelyrelatedtostudymedication.ThemajorityofAEs(80.9%)intheoxycodone CRgroup were mild to moderatein severity.
SeriousAEsoccurredin6patients(12%)receivingOROShydromorphoneER and4patients(8.5%)receivingoxycodoneCR.ThemostcommonseriousAEsweregastrointestinaldisorders(2[2.1%])andsur-gicalandmedicalprocedures(3[3.1%]).Nodeathsoccurredduringthecourseofthestudy.
ThemajorityofpatientsreceivingOROShydromor-phoneER(88.3%)andoxycodoneCR(88.5%)ratedtolerability as‘‘good’’or ‘‘verygood’’atWeek52; fewpatientsdiscontinued due to an AE (1.6% vs.0.4%,respectively).
DISCUSSION
Theobjectiveofthisstudywastoassessthelong-termsafety and efficacy of once-daily OROS hydromor-
includingBPIitems‘‘painrightnow,’’‘‘painatitsworst,’’and‘‘painatitsleast.’’Sustainedimprove-mentswerealsoobservedforpaininterferencewithfunctioning,qualityoflife,andindicesofsleep.Over-all,changesinefficacyendpointsfrombaselinetoWeek38andWeek52weregenerallycomparabletochangesreportedfrombaselinetotheendpointofthecorephase(Week24).18OROShydromorphoneERandoxycodoneCRweregenerallywelltoleratedforupto1year.Theseresultsextendthefindingsofpreviousshort-termstudiesinpatientswithchronicnoncancer andcancerpain,18,19and alsolong-termstudies inpatients with chronic cancerpain,20anddemonstratesustainedefficacyandtolerabilityofbothdrugsthrough1year.
Overall,91.7%ofpatientsratedtheefficacyofOROShydromorphoneERas‘‘verygood’’or‘‘good.’’IntheoxycodoneCRgroup,86.5%ofpatientsratedthedrugas‘‘verygood’’or‘‘good.’’MorepatientsreceivingOROShydromorphone ER rated the modeofintakeas‘‘veryconvenient’’(35.0% vs. 21.2%).Thedifferenceinglobalassessmentofconveniencebetweentreatmentgroupsmaybeareflectionoftheonce-dailydosingofOROShydromorphoneER.Once-dailydosingmayresultinhighertreatmentcom-plianceandfewerepisodesofend-of-dosefailurerela-tivetoformulationsthatrequiremultipledailydoses.Once-dailydosingmayalsodecreaseoverallpillbur-den,whichisparticularlyimportantforchronicpain
patients,whooftentakeseveralconcomitantmedica-tions.21
AtWeek52,themeanweighteddailydoseofoxy-codoneCR(44.6mg)wasrv2.5timesmorethanthatofOROShydromorphoneER(17.1mg)andwassimi-lartostudymedicationdosesattheendofthetitration(Week4)andcorephases(Week24).ThatneithertreatmentgrouprequiredsubstantialincreasesindailydosageafterWeek4suggeststhatnoadditionaltoler-ancetoanalgesiceffectsoftheopioidsdeveloped.Theratio of mean daily doses used in the present study
(2.5:1forOROShydromorphoneER:oxycodoneCR)isconsistentwiththe5:1equianalgesicdoseratioformorphinetohydromorphonefrompreviousreports.19,20,22
OROShydromorphoneERandoxycodoneCRhadcomparablesafety and tolerability profiles through1year.Intotal,84%ofpatientsreceivingOROShy-dromorphoneERand91%receivingoxycodoneCRexperiencedAEsduringtheextensionphase.ThemostcommonAEswerenasopharyngitis(5.2%),vertigo(4.1%),andweightdecrease(4.1%),whichisincon-trasttoAEsreportedinthecorephase.18Inthecore phase,themostcommonAEsweretypicalofthoseassociatedwithpotentopioids(eg,nausea,constipa-tion,vomiting,andfatigue).18Itisimportanttonotethatonly40%ofthepatientswhocompletedthecorephasecontinuedintotheextensionphase.Thesub-groupofpatientswhocontinuedintotheextensionphasemayhaveexperiencedmorefavorabletolerabil-ityofOROShydromorphoneERoroxycodone CRthanthosewhochosenottocontinue.Forexample,itispossiblethatthosepatientswhoexperiencedconsti-pationevenwhiletakingconstipation prophylaxis inthecorephaseofthestudychosenottoparticipateintheextensionphase;thismayhavecontributedtothelowincidenceofconstipationreportedintheextensionphase(2.1%).Also,constipationandothergastrointes-tinalAEswereconsideredAEsintheextensionphaseonlyiftheywerenewonsetorworsenedfromthecore
phase. The resultssuggestthat theseAEswere wellmanagedwithlong-termtreatment.Itisalsopossiblethatsometolerancedevelopedtocertainopioid-relatedAEsthroughoutthecourseofthestudy.However,tol-erancetotheanalgesiceffectsdidnotappeartooccur,asthedailyopioiddosesandreportsof pain reliefwerequitestable.Furthermore,tolerancetoopioid-mediatedconstipationisbelievednottooccur.ThemajorityofAEswereconsideredtobemild-to-moder-ateinseverity.SeriousAEsoccurredin12%ofpatientsreceivingOROS hydromorphone ER and8.5%ofpatientsreceivingoxycodoneCR;nodeathswerereported.Thepercentagesofpatientswhoratedtolerabilityas‘‘verygood’’or‘‘good’’were88.3%forOROShydromorphoneERand86.5%foroxycodoneCR.
Intheclinicalsetting,thepracticeofopioidrotationisoftenemployedwhentreatingpatientswithchronicpain.8Opioidrotation,achangeintheopioiddrugorrouteofadministrationwiththegoalofimprovingoutcomes,hasbeenshowntoimprovepaincontrol
andreducetoxicity.8,23 Ideally,physicianswillselectopioidswithestablishedefficacyandtolerability.Thepresentdata,andthatofotherstudiesemployingOROShydromorphoneERandoxycodoneCR,estab-lishtheefficacyandsafetyprofileofbothformulationsinpatientswithchroniccancerandnoncancerpain.11,18–20,24–33
Thereareseverallimitationsofthisstudythatmayaffectthegeneralizabilityofthesefindings.Theopen-labeldesign,whileincludinganactivecomparator,doesnottakeintoaccountthepercentageofpatientswhomayhaveimprovedwithnoactivetreatment.Thefactthatinferentialstatisticswerenotappliedtothedatarepresentsanotherlimitation.Astheprimaryobjectiveofthestudywastoassessthesustainedsafetyoftheopioidformulations,datawerepresentedonlyinadescriptivefashion.Finally,therelativelylowper-centageofpatientswhocompletedthecorephaseofthestudyandcontinuedintotheextensionstudymayrepresentasubsetthatexperiencedaparticularlyfavorabletolerabilityandefficacyprofile.
Overall,theresultsofthislong-term,28-weekextensionphaseindicatethatOROShydromorphoneERandoxycodoneCRareeffectiveandwelltoleratedinpatientswithchronicnoncancerpain.ChangesinefficacyendpointsfrombaselinetoWeek38andtoWeek52weregenerallycomparabletothechangesfrombaselinetotheendpointofthecorephase,indi-catingaconsistentanalgesiceffect.Thelong-termsafety,efficacy,andconvenienceofOROShydromor-phoneERmayaffordarationaltreatmentoptioninappropriatepatients.
ACKNOWLEDGMENTS
ThisstudywassupportedbyJanssenCilagEMEA.Technicaleditorialandwritingsupportfortheprepa-rationofthisarticlewasprovidedbyAmandaMcGe-ary,SynchronyMedical,LLC,WestChester,PA.Fundingforthissupportwasprovided by Mallinck-rodtInc.,aCovidiencompany,Hazelwood,MO.
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