Safety andEfficacyof Controlled-ReleaseOxycodone: ASystematicLiteratureReview
D.GaryRischitelli,M.D.,J.D.,M.P.H.,andSeanH.Karbowicz,Pharm.D.
Prescriptionsforcontrolled-releaseoxycodone,anarcoticanalgesic,recentlycontributedtoadramaticincreaseinpharmacycostsforalargeprivateinsurancecompany. Todeterminewhetherthisagentofferedclinicalbenefitsoverotheravailabledrugsthatwouldjustifyitssignificantlygreatercost,asystematicreviewof16clinicaltrialswasundertaken. Thereviewsuggestedthatimmediate-releaseandcontrolled-releasepreparationsofoxycodonehavesimilarefficacyandcomparablesideeffectprofiles. Controlled-releaseoxycodonehastheadvantageoflessfrequentdosingthanimmediate-releaseoxycodone;however,otheragentsmaybedosedinfrequentlyatmuchlowercosts. Forpatientsrequiringa controlled-release opioidtreatment, controlled-releasemorphineandmethadoneshouldbeconsideredbecausetheyappeartobeaseffectiveasoxycodoneandcostconsiderablyless. Controlled-releaseoxycodonemaybeappropriateforsomepatients,particularlyiftheycannottolerateothercontrolled-release orlong-actingopioidanalgesics.(Pharmacotherapy2002;22(7):898–904)
MethodsResults
Outline
revealedthatthegreatestcostincaringforpatientswithlowbackpainarose fromtreatmentwithnarcoticanalgesics.1,2 From1999–2001,a
Safety andEfficacyofOxycodoneforTreatmentofNoncancerPain
EffectofControlled-Release OxycodoneonQualityofLifeinPatients withNoncancerPain
Safety andEfficacyofImmediate-ReleaseversusControlled-Release Oxycodone
Safety andEfficacyofOxycodoneComparedwithOtherOpioids
DiscussionConclusion
A recentstudyconductedwithinalarge UnitedStatesuniversity-basedhealth caresystem
FromtheCenterforResearchonOccupationalandEnvironmentalToxicology(Dr.Rischitelli)andtheDepartmentofPharmacyServices(Dr.Karbowicz),OregonHealthandSciencesUniversity;LibertyNorthwestInsuranceCompany(Dr.Rischitelli);andRegenceBlueCrossBlueShield(Dr.Karbowicz), Portland, Oregon.
AddressreprintrequeststoGaryRischitelli,M.D.,J.D.,M.P.H.,CenterforResearchonOccupationalandEnvironmentalToxicology,OregonHealthSciencesUniversity,3181SWSamJacksonParkRoad,L606,Portland, OR97201-3011;e-mail: .
largeprivateworkers’compensationinsurance
company(LibertyNorthwestInsuranceCo.,Portland,OR)experiencedasharpupturninpharmacycoststhatwaslargelyattributabletoprescriptionsforcontrolled-releaseoxycodoneforoutpatientpaintreatment.Asaresult,therecentliteraturewasreviewedtodeterminewhethercontrolled-releaseoxycodoneofferedclinicalbenefitsoverotheravailabledrugsthatwouldjustifyits significantlygreatercost.
Methods
AnelectronicsearchoftheMEDLINEdatabasefromJanuary1994–October2000withthemedicalsubjectheading(MeSH)oxycodoneyielded69citations.Allclinicaltrialsthataddressedthesafetyandefficacyofoxycodone(immediate-orcontrolled-release)ortherelativesafetyandefficacyofoxycodonecomparedwithotheropioidswereselected.Ofthe69citations,15mettheinclusioncriteriaasprospectiveorretrospectiveclinicaltrials;theremaining
Table1. SafetyandEfficacyofOxycodonefor theTreatmentofNoncancerPain
StudyDesign / StudyPopulation / Comparison / OutcomeMeasure / ResultsRandomized, / Osteoarthritispain / CRoxycodone / Self-reportedpain / CRoxycodone 20mgsuperiorto
double-blind,placebo-controlled7 / (n=133) / vsplacebo / andinterferencewithmood, sleep, / placeboinpainrelief;meandosageaftertitration40mg/day;
andenjoymentof / typicalopiate adverse effects.
life
Randomized, / Osteoarthritispain / CRoxycodonevs / Self-reportedpain / CRoxycodone orIRoxycodone
double-blind,placebo-controlled6 / (n=107) / IRoxycodone+acetaminophen / andsleepquality / +acetaminophensuperiortoplacebo.
vsplacebo
Randomized, / Chronicbackpain / CRvs IR / Self-reportedpain / Painintensitydecreasedfrom
double-blind, / (n=47) / oxycodone / moderate-severetoslightinboth
active-controlled,twoperiodcrossover5 / treatmentgroups;CRandIRcomparableinefficacyand
safety; typicalopiate side effects.
Randomized, / Cancerpain(n=48) / CRvs IR / Self-reportedpain / 85%ofpatients withcancerpain
open-label,dosetitration8 / andchronic backpain(n=57) / oxycodone / and91%ofpatients withbackpainachievedstablepain
control; nodifference between
CRandIRinefficacyoradverse
effects.
Randomized, / Chronicbackpain / NSAIDvs IR / Self-reportedpainand / Bothopioidgroupssuperiorto
open-label,long-term4 / (n=36) / oxycodonevsCR morphine+ / emotionaldistress / NSAIDalone;titratedCRmorphine+ IRoxycodone
IRoxycodone / superiortoset-dosage
IRoxycodone.
Retrospectivecohort9 / Rheumatoidpain / Codeine or / Self-reportedpain / Patientstreatedwithopioidshad
(n=644) / oxycodonevs / andadverse effects / significantlylowerself-reported
nonopioid / painseverity thanpatients
treatment / treatedwithnonopioidsbasedon
0–10scale(3.6vs 8.2,p<0.001);
typicalopioidadverse effects.
Randomized, / Neuropathicpain / CRoxycodone / Self-reportedpain, / CRoxycodonesuperiortoplacebo
double-blind, / (n=50) / vsplacebo / disability,and / inreducingpainseveritybased
placebo-controlled,crossover10 / treatmentpreference / on0–10scale(2.9vs 1.8,p=0.0001)andpreferredby
patients(67%vs 11%,p=0.001).
CR=controlled-release;IR=immediate-release;NSAID= nonsteroidalantiinflammatorydrug.
citationswerereviews,editorials,letters,orotherwiseinappropriate.Anadditionalstudythatwascitedbythemanufacturer(PurduePharmaL.P.,Norwalk,CT)initsmarketingmaterialswasincludedintheanalysisforatotalof16clinicaltrials.3
Results
SafetyandEfficacy ofOxycodoneforTreatmentofNoncancerPain
Sevenstudiesaddressedthesafetyandefficacyofoxycodoneforthetreatmentof noncancerpain(Table1).4–10Allofthesestudiesdemonstratedthatoxycodoneandotheropioidanalgesicswereeffectiveforthisindication.Oxycodonewassuperiortoplaceboinrelievingself-reported
pain.6,7,10Comparisonsofoxycodonewithnonsteroidalantiinflammatorydrugsorothernonopioidtreatmentsdemonstratedthatopioid-treatedpatientshadsuperiorpainrelief.4,6,9However,comparisonsofcontrolled-releaseoxycodonewithimmediate-releaseoxycodoneshowednosignificantdifferencesbetweenthetwoformulations withregardtoanalgesicefficacyorsideeffectprofiles.5,6,8Thesestudiessuggestthatcontrolled-releaseoxycodoneofferednoclinicallysignificantadvantageoverimmediate-releaseoxycodoneinthemanagementofnoncancerpain.
EffectofControlled-ReleaseOxycodoneonQualityofLifeinPatients withNoncancerPain
Controlled-releaseoxycodoneiseffectivein
Table2. SafetyandEfficacyofImmediate-ReleaseversusControlled-ReleaseOxycodone
StudyDesign / StudyPopulation / Comparison / OutcomeMeasure / ResultsRandomized,double-blind6 / Osteoarthritispain(n=107) / IRvs CRoxycodone / Self-reportedpainandsleepquality / Painandsleepscores comparable;CRgrouphadlower frequencyof
nauseaanddrymouth.
Randomized,open-label14 / Postoperativepain(ACLrepair) / IRoxycodonescheduleddose / Self-reportedpain / CRgrouphadlesspainandsedationthanIRgroup,tookless
(n=60) / vs IRoxycodone / totaldrug,hadlower frequency
asneededvs / ofsleepdisturbancesand
CRoxycodone / vomiting, andreportedgreater
satisfaction.
Randomized, / Chronicbackpain / IRvs CR / Self-reportedpain / CRandIRcomparableinefficacy
double-blind, / (n=47) / oxycodone / andsafety; typicalopiate adverse
active-controlled,
two-periodcrossover5 / effects.
Randomized, / Cancerpain(n=48) / IRvs CR / Self-reportedpain / Nodifference betweenIRandCR
open-label,
dosetitration8 / andchronic back
pain(n=57) / oxycodoneinefficacyoradverse effects.
Randomized, / Cancerpain / IRvs CR / Self-reportedpain / IRoxycodone slightlysuperiorto
double-blind, / (n=111) / oxycodone / CRoxycodoneinefficacy;no
multicenter,parallelgroup13 / differenceinadverse events.
Randomized, / Cancerpain / IRvs CR / Self-reportedpain / CRandIRoxycodonecomparable
double-blind, / (n=164) / oxycodone / andtreatment / inefficacy;significantlyfewer
multicenter,parallelgroup12 / acceptability / adverse events withCR.
CR=controlled-release;IR=immediate-release;ACL=anteriorcruciate ligament.
reducingchronicnoncancerpainbutisaccompaniedbysignificantadverseeffects.Untilrecently,onlysurveysandopentrialsassessedtheefficacyandsafetyofopioidsforthetreatmentofnoncancerpain.Thesestudieshadinconsistentresults.10,11
Controlled-releaseoxycodonefailedtodemonstrateconsistentbenefitonqualityoflife,despiteshowingsuperiorityoverplaceboinself-reportedpainscores.7,10Typicalopioidadverse effects,suchasconstipation,nausea,vomiting,andsomnolence,weremorefrequentandsevereintheactivetreatmentgroupsthanintheplacebogroups.Inatrialevaluating50patientssufferingfrompostherpeticneuralgia,globaldisabilityscoresstatisticallyfavoredactivetreatment.10However,becauseanonvalidatedassessmenttoolwasusedandthedifferenceobservedwasquitesmall,theclinicalrelevanceofthisfindingisdifficulttodetermine.Furthermore,neithertheBeckDepressionInventorynortheProfileofMood Statesquestionnairedetecteddifferencesinaffectivestateandmoodfactorsbetweentheactivetreatmentgroupandplacebogroup.
Inalong-termexperimentwith133patientswhoexperiencedosteoarthritispain,several
parameters,includingself-reportedpain,wereexamined.7Inadditiontononvalidatedtests,themodifiedStanfordHealthAssessmentQuestionnairewasusedtoassesstheeffectofcontrolled-releaseoxycodoneonqualityoflife.Inthisstudy,activetreatmentdidnotimprovequalityoflife.7Thesedatasuggestthattreatmentwithcontrolled-releaseoxycodonedoesnotimprovequalityoflifeinpatientswithchronicnoncancerpain.
SafetyandEfficacy ofImmediate-Release versusControlled-ReleaseOxycodone
Sixstudiescomparedthesafetyandefficacyofcontrolled-releaseoxycodonewithimmediate-releaseoxycodoneincancerandnoncancerpain(Table2).5,6,8,12–14Onlyoneofthesestudiesfoundthatthe controlled-releaseformulationwassuperiortotheimmediate-releaseformulationintreatingpostoperativepain,withlowerdosages,improvedpaincontrol,andfewersideeffects.14Theremainingfivestudiesshowednosignificantdifferencesinanalgesiceffectbetweenimmediate-releaseandcontrolled-releaseoxycodone.5,6,8,12,13
Differencesinspecificadverseeffectsbetween
Table3. SafetyandEfficacyofOxycodoneComparedwithOtherOpioids
StudyDesign / StudyPopulation / Comparison / OutcomeMeasure / ResultsRandomized,double-blind16 / Postoperativepain(hysterectomy) / CRoxycodone
vs CR morphine / Self-reportedpain / CRoxycodone 20mgand40mgcomparabletoCR morphine
(n=169) / 45mgand90mg,respectively;
adverse effectssimilar.
Randomized, / Cancerpain / CRoxycodone / Self-reportedpain, / Nosignificantdifferencesin
double-blind,crossover15 / (n=32) / vs CR morphine / treatmentpreference,andadverse effects / efficacy,preference, oradverseeffects betweenCRoxycodone
andCR morphine.
Randomized,double-blind3 / Cancerpain(n=101) / CRoxycodone
vs CR morphine / Self-reportedpain,qualityof life, / CRoxycodoneandCR morphinesimilarinanalgesicefficacyand
treatment / adverse effects; hallucinations
acceptability,and / (n=2)associatedwithCR
adverse effects / morphinebutnotCRoxycodone;
fewercomplaintsofitchingwith
CRoxycodone.
Open-label, / Cancerpain / CRoxycodone / Self-reportedpain, / Comparable analgesia;
randomized / (n=45) / vs CR morphine / treatmentpreference, / CRoxycodone associatedwith
titrationphase / andadverse effects / more escapedoses andhigher
followedby / meanpainintensitythanCR
double-blind, / morphine;frequencyofadverse
randomizedcrossover18 / effectssimilar,butvomitingmorefrequentwithmorphineand
constipationmorefrequent
withoxycodone.
Randomized, / Cancerpain / CRoxycodonevs / Self-reportedpain, / Nosignificantdifferenceinpain,
double-blindcrossover17 / (n=44) / CR hydromorphone / treatmentpreference,andadverse effects / sedation,nausea,orpatientpreference.
CR=controlled-release;IR=immediate-release.
controlled-releaseandimmediate-releaseoxycodonewerenotconsistentamongtrials.Adverseeffectssuchasnausea,somnolence,dizziness,constipation,pruritus,andheadachewerereportedinbothtreatmentgroupsinallstudies.5,6,8,12–14 Inthreetrials,therewasno
SafetyandEfficacy ofOxycodoneComparedwithOtherOpioids
Fiverandomized,double-blindclinicaltrialscomparedtheefficacyofcontrolled-releaseoxycodonewithotherlong-actingopioids(Table
3, 15–18
statisticallysignificantdifferenceinadverse
3).
Fourofthemcomparedcontrolled-
effectsbetweencontrolled-releaseandimmediate-release oxycodone.5,8,13However,inatrialconductedin164patientswithcancer,thefrequencyofheadacheandgastrointestinaladverseeffectswaslowerwithcontrolled-releaseoxycodonethanwithimmediate-releaseoxycodone.12
Inanothertrialconductedin107patientswithosteoarthritispain,nauseawasreportedlessfrequentlybypatientstreatedwiththecontrolled-releaseproduct.6Thus,halfofthestudiescomparingimmediate-releaseoxycodonewiththecontrolled-releaseformulationshowednosignificantdifferenceinside effects.Controlled-releaseoxycodonehasnotdemonstratedaconsistentclinicalbenefitoverimmediate-release oxycodone.
releaseoxycodonewith controlled-release
morphine;nodifferenceinanalgesicefficacybetweenthetwotreatmentswasfound.3,15,16,18Onestudyreportedahigherfrequencyofitchingandscratching withmorphinethanwithoxycodone.3Anotherstudyshowedasimilarfrequencyofadverseeffectswiththetwodrugs,butvomitingwasassociatedmorefrequentlywithcontrolled-releasemorphine,andconstipationwasassociatedmorefrequentlywithcontrolled-releaseoxycodone.18Noincreaseinanyoneadverseeffectwasnotedinthesefourtrials.3,15,16,18
Inacomparisonofcontrolled-releaseoxycodoneandhydromorphone,nodifferenceinanalgesicefficacyoradverseeffectswasobserved.17Thesefivestudiessuggestneitheranadvantageinanalgesicefficacynoraconsistent
Table4. RelativeCostsofOpioidAnalgesics19
Drug / UnitCosta($) / Quantity/Unit / UsualFrequency / Cost/Day($) / Cost/30 Days($)Methadone5mg / 9.00 / 100 / b.i.d. / 0.18 / 5.00
Methadone 10mg / 14.00 / 100 / b.i.d. / 0.30 / 9.00
Methadone 40mg / 36.00 / 100 / b.i.d. / 0.72 / 22.00
MS Contin15mg / 100.00 / 100 / b.i.d. / 2.00 / 60.00
OxyContin10mg / 121.00 / 100 / b.i.d. / 2.42 / 73.00
MS Contin30mg / 190.00 / 100 / b.i.d. / 3.80 / 114.00
Fentanyl patch25µg / 59.00 / 5 / q3d / 3.93 / 118.00
OxyContin5mg / 27.00 / 100 / q2–4h / 4.32 / 130.00
OxyContin20mg / 231.00 / 100 / b.i.d. / 4.62 / 139.00
Fentanyl patch50µg / 96.00 / 5 / q3d / 6.40 / 192.00
MS Contin60mg / 370.00 / 100 / b.i.d. / 7.40 / 222.00
OxyContin40mg / 410.00 / 100 / b.i.d. / 8.20 / 246.00
Fentanyl patch75µg / 154.00 / 5 / q3d / 10.27 / 308.00
MS Contin100mg / 547.00 / 100 / b.i.d. / 10.94 / 328.00
Fentanyl patch100mg / 191.00 / 5 / q3d / 12.73 / 382.00
OxyContin80mg / 770.00 / 100 / b.i.d. / 15.40 / 462.00
MS Contin200mg / 1001.00 / 100 / b.i.d. / 20.02 / 601.00
aAveragewholesaleprice.
significantdecreaseinadverseeffectswithcontrolled-releaseoxycodoneversuscontrolled-releasemorphineorcontrolled-releasehydromorphone.3,15–18
Discussion
Areviewoftherecentliteraturesuggeststhatimmediate-releaseandcontrolled-releaseoxycodonehavesimilarefficacyinthetreatmentofnoncancerpain.Thetwopreparationsarealsocomparablewithregardtotypeandfrequencyofadverseeffects. Controlled-releaseoxycodone
offerstheadvantageoflessfrequentdosingthanimmediate-releaseoxycodone;however,otheravailablepreparationsallowinfrequentdosingatmuchlowercosts(Table4).19Datademonstratednosignificantclinicaladvantageforcontrolled-releaseoxycodoneoverothercontrolled-releaseopioids,suchascontrolled-releasemorphineorcontrolled-releasehydromorphone.
Equipotentdosagesofcontrolled-releasemorphineandcontrolled-releaseoxycodonehavenotbeenclearlyestablished,whichmakesacostcomparisondifficult. Inasingle-dosestudy,
1800
1600
1400
1200
$1338
$1796
140
120
100
$139
100080
800
60
600
40040
200
0
Methadone40mgb.i.d.
MSContin400mgb.i.d.
Fentanylpatch350g/hr
every3days
Oxycontin320mgb.i.d.
20
0
Methadone 10mg b.i.d.
Fentanyl patch
25g/hr every 3 days
Oxycontin 20mg b.i.d.
NarcoticRegimen
Figure1.Comparativemonthlycostsofhigh-dosagenarcoticregimens(calculatedfromaveragewholesaleprices).19Thisexampleisnotintendedtobeusedasaguideforequianalgesic dosing.
NarcoticRegimen
Figure2.Comparativemonthlycostsoflow-dosagenarcoticregimens(calculatedfromaveragewholesaleprices).19Thisexampleisnotintendedtobeusedasaguideforequianalgesic dosing.
controlled-releaseoxycodonewasapproximatelytwiceaspotentascontrolled-releasemorphine.16However,instudiesoflongerduration,thedifferenceinpotencywassmaller.3,15,18Using2001prices,apatientwithchronicpainwhoreceivesMSContin100mgtwice/daywouldpay
$328/month.19Anapproximatelyequianalgesicdosage(80mgtwice/day)ofOxyContinwouldcost$462/month(Table4).19
Althoughnopublishedstudiescomparemethadonewithoxycodone,severalreportssuggestthatmethadoneisanequallyeffective,lessexpensivealternativetocontrolled-releasemorphineandothernarcotics.20–24Therefore,methadoneshouldnotbeexcludedasapossiblealternativetocontrolled-releaseoxycodone.Thepharmacokineticandpharmacologicpropertiesofmethadonemakeitfavorablefortreatingpatientswithchronicpainwhorequirelargeamountsofnarcotics.24,25Methadonehasalongandvariableeliminationhalf-life(upto128hrs)andgoodbioavailability.ItisdispersibleinsolutionfororaladministrationandactsasanN-methyl-D-aspartate–receptorantagonisttoreducetolerancetoopioids.25Inaddition,whereasthedoserelationshipbetweenmorphineandoxycodoneislinearduringlong-termadministration,thedoserelationshipbetweenmethadoneandthesecompoundsisnonlinear.Atmorphinedosageslessthan100mg/day,theconversionratioformethadoneis3:1.Atmorphinedosageshigherthan800mg/day,theratioincreasesto15:1.24,25Thus,thepotentialeconomicsavingsofmethadonebecomedisproportionatelygreateraspatientsrequiremorenarcotic(Figures1and2).Thedistinctivecharacteristicsofmethadonemaycomplicateswitchingpatientstothisagentfromotheropioids;however,withclosemonitoring,appropriatepatientscanbesafelyswitched.23,25Forpatientsrequiringcontrolled-releaseopiates,methadoneandcontrolled-releasemorphineareestablishedtreatmentsforchronicpainandarelessexpensivealternativestocontrolled-releaseoxycodone.
Conclusions
Immediate-releaseandcontrolled-releaseoxycodoneareequallyeffectiveinthetreatmentofpainandhavesimilaradverseeffectprofiles.Controlled-releasepreparationsandproductswithalongdurationofactionareattractivebecausetheyoffertheadvantageoflongerdosingintervals,whichresultsinsustainedanalgesic
effectandgreaterconvenience.Thereviewedliteraturesuggestsnoclinicallysignificantadvantageofcontrolled-releaseoxycodoneoverotherlong-actingopioidstojustifyitsgreatercost.
Ifapatientisanappropriatecandidateforacontrolled-releaseopioid,controlled-releasemorphineandmethadoneshouldbeconsideredbecausetheyappeartobeequallyeffectiveandcost considerably less than oxycodone.Controlled-releaseoxycodonemaybeappropriateforsomepatients,particularlyiftheycannottolerateothercontrolled-releaseorlong-actingopioidanalgesics.
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