Drug AbuseDeterrence
AbusePotential,Pharmacokinetics,Pharmacodynamics,andSafetyofIntranasallyAdministeredCrushedOxycodone
HClAbuse‐DeterrentControlled‐ReleaseTabletsinRecreationalOpioidUsers
TheJournal ofClinicalPharmacology54(4)468–477
©2013TheAuthors.TheJournalofClinicalPharmacologyPublishedby
WileyPeriodicals,Inc.onbehalfofTheAmericanCollegeofClinicalPharmacology
DOI:10.1002/jcph.235
StephenC.Harris,MD1,PeterJ.Perrino,MS1,IraSmith,MD2,MeganJ.Shram,PhD3,SalvatoreV.Colucci,MS1†,
CynthiaBartlett,MMath2,andEdwardM.Sellers,MD,PhD,FRCPC4‡
Abstract
Theobjective ofthisstudy was toevaluate abuse potential, pharmacokinetics,pharmacodynamics, and safetyofintranasallyadministered,crushedreformulatedOxyContin1(oxycodoneHClcontrolled‐release)tablets(ORF),relativetocrushedoriginalOxyContin1(OC),oxycodonepowder(OxyAPI),andOCplacebo.Thisrandomized,double‐blind,positive‐andplacebo‐controlledcrossoverstudyenrolledhealthy,adult,nonphysicallydependentrecreationalopioiduserswithrecenthistoryofintranasaldrugabuse(N¼27).Activetreatmentscontainedoxycodone(30mg).
Pharmacokinetics,pharmacodynamics(e.g.,OverallDrugLiking[ODL],TakeDrugAgain[TDA],andHighVisualAnalogScales[VAS];SubjectiveDrugValue [SDV];pupillometry;intranasal irritation),andsafety(e.g.,adverseevents,vitalsigns,laboratory tests)wereassessed to24hourspostdose.
CrushedORFadministrationyieldedreducedoxycodoneCmax andincreasedTmaxversuscrushedOCandOxyAPI.PeakeffectsforpharmacodynamicmeasuresweredelayedwithORF(1–2hours)versusOCandOxyAPI(0.5–1hour).ODL,TDA,HighVAS,andSDVEmaxvaluesweresignificantlylower
(P::;.05)andsomeintranasalirritationratingsweregreaterforORFversusOCandOxyAPI.Nosignificantorunexpectedsafetyfindingswereobserved.ComparedwithOCandOxyAPI,intranasallyadministeredORFwasassociatedwithloweranddelayedpeakplasmaconcentrations,decreaseddrug‐liking,anddecreasedintranasaltolerability.ThissuggeststhatORFhasadecreasedpotentialforintranasaloxycodoneabuse.Therewere
nosignificantorunexpectedsafetyfindings.Asistrueforallabusepotentialstudies,epidemiologicalorotherappropriatepost‐marketingstudiesare
requiredtoassesstheimpactofthereductioninintranasaloxycodoneabusepotentialobservedinthepresentstudyonreal‐worldpatternsofORF
misuse,abuse,anddiversion.
Keywords
oxycodone,OxyContin,reformulation,abusedeterrent,abusepotential,pharmacokinetic,pharmacodynamic,tamperresistant
ThedirectandindirectcostsofchronicpainintheUnitedStateshavebeenestimatedatmorethan$100billionannuallyinmedicalexpenses,lostwages,andlostproductivity.1Prescriptionopioidsareanimportanttreatmentoptionforthemanagementofchronicpain,buttheirmisuseandabuseconstituteasubstantialmedicalandpublichealthproblem.2While opioids are often abused via intact oraladministration,opioiddosageformsarealsofrequentlytamperedwithandthenabusedorallyorviaalternateroutesofadministration(predominantlyintranasaland
intravenousroutes)thatproviderapidopioiddeliverytothecentralnervoussystem.3–5Inanefforttoreduceabuseviaalternateroutes,opioidformulationshavebeencreated
withfeaturesdesignedtodetertampering,suchasphysicalbarriers(e.g.,excipientsthatresistmanipulation)andinclusionofantagonists(e.g.,naloxoneornaltrexone)thatblockopioideffects.6Itisrecognized thatnoopioidformulationisimmunetotamperingbyknowledgeabledrugabusers,6buttamper‐deterrentformulations mayservetodecreasethepublichealthburdenofopioidabuse
1PurduePharmaL.P.,Stamford,CT,USA
2INCResearchToronto,Toronto,Ontario,Canada3AltreosResearchPartners,Toronto,Ontario,Canada4DLGlobalPartners,Toronto,Ontario,Canada
ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution‐NonCommercial‐NoDerivsLicense,whichpermitsuseanddistributioninanymedium,providedtheoriginalworkisproperlycited,theuseisnon–commercialandnomodificationsoradaptationsaremade.
Submittedforpublication11July2013;accepted14November2013.
CorrespondingAuthor:
StephenC.Harris,MD,ClinicalPharmacology,PurduePharmaL.P.,OneStamfordForum,Stamford,CT06901,USA
Email:
†Mr.ColucciiswiththeBiostatisticsdepartmentatPurdue.
‡HonoraryFellowoftheAmericanCollegeofClinicalPharmacology.
bymakingabusemoredifficult,moretimeconsuming,andlesseffectivetotheabuser.
TheoriginalformulationofOxyContin1 (OC)was
approvedin1995bytheFoodandDrugAdministration(FDA)foruseinthetreatmentofmoderatetoseverepain.The originalformulation providedno inherentresistancetotampering,andthecontrolofoxycodonereleasecouldbeeasilydefeatedbycrushingthetabletintoafinepowder.By2001,OChadbeenidentifiedasonecomponentofthegrowingproblemofprescriptiondrug
abuse.7–9TheFDArespondedtothisproblem,inpart,by
workingwithindustrytodevelopproactiveriskmitigationstrategies.SuchstrategiesforOCincludedaddingablackboxwarningtoproductlabellingandinitiatingaproactivesurveillanceprogamforprescriptionopioidabuseanddiversion.7
Tofurtheraddresstheproblemofmisuse,abuse,anddiversionofOC,anabuse‐deterrentreformulationofOxyContin1(ORF)wasdeveloped.ORFwasdesignedto
bebioequivalenttoOCfollowingintactoraladministra-tionandtoresistphysicalandchemicalmanipulationsintendedtodefeatthecontrolofoxycodonerelease.InvitrotamperingstudiesdemonstratedthatORFresists
crushingandotherparticlesize reductionefforts.ORFis
commerciallyavailable.TheresultsofthisstudyapplystrictlytoORF.
Methods
EthicalConduct
Thisstudywasconductedat INCResearchToronto Inc.,Toronto,Canada,inaccordancewiththeDeclarationofHelsinkianditsamendmentsasoutlinedbytheInternationalConferenceonHarmonisation.Priortostudyinitiation,theInstitutionalReviewBoard,IRBServices,Aurora,Canada,approvedinformedconsentformsandthestudyprotocolinaccordancewithGoodClinicalPracticeandapplicableregulatoryrequirements.
Subjects
Thestudyenrolledeligiblehealthymaleandfemaleadults(aged18–55years,inclusive)whoreportedahistoryofnonmedicaluseofopioidsviatheintranasalroute,thoughreportsofotherroutes ofadministrationdidnotprecludeparticipation.Theabsenceofopioidphysicaldependencewasassessedbyinterviewandconfirmedbytheresultsof
analoxonechallenge.Subjects wereexcludediftheyhad
14
anticipated todiscouragetampering andintranasaloxyco-
anObjectiveOpiateWithdrawalScale(OOWS)
score3
doneabuse.Firstly,tamperingwithORFrequiressignifi-canttimeandeffort.Secondly,theparticlesproducedbytamperingwithORFmayretainsomecontrolled‐release
properties.Thirdly,thesizeoftheparticlesmayserveto
increaseboththelikelihoodofincompletedosingandtheseverityofnasalirritationassociatedwithinsufflation.Lastly,whenORFisdissolvedinsmallvolumesforintravenousadministration,itformsaviscoussolutionthatcannotbeeffectivelydrawnintoasyringe.10However,sinceORFisdesignedtodeliveroxycodoneovertimewhentakenasdirected,itcanbeabusedbytakingintacttabletsorallywithoutlegitimatepurpose.
Thisstudyofrecreationalopioidusersevaluatedtheabusepotential,pharmacokinetics,pharmacodynamics,andsafetyoffinelyandcoarselycrushed,intranasallyadministeredORFtabletsrelativetofinelycrushedOC,oxycodonepowder(OxyAPI),andOCplacebo.Itexaminedintranasaladministration(i.e.,snorting)ofcrushedORFandOCforthreereasons:becauseintranasaladministrationhasbeenfoundtobearoutepreferredamongabusersfordeliveryofopioids,includingoxyco-done5,11 and OC specifically12; because intranasal
administrationinvolvesthecrushingorpulverizingofORF,whichmaycompromiseitscontrolled‐releaseproperties13; and because the accelerated absorption
affordedbyintranasaladministrationmayposeagreaterrisktotheabuser.
ORFistheonlyavailablecontrolled‐releaseformulaofoxycodoneatpresent.Otherproductsareindevelopment
byothercompanies,butnonearecurrentlyapprovedor
orgreaterfollowingthenaloxonechallengetest,self‐
reporteddrugdependence(past2years),orapositive
urinedrugscreenorbreathalcoholtest.Keyrestrictionsincludedabstainingfromalcoholconsumptionfor48hourspriortoeachvisitandfromrecreationaldrugusefromscreeningthroughstudycompletion.Alsonotpermittedwerecaffeineconsumptionfor24hourspriortoclinicadmissionandnicotineconsumptionfrom11PMthenightbefore until 8hoursaftereachdoseadministration.
OverallStudyDesign
Thiswasarandomized,double‐blind,positive‐andplacebo‐controlled,five‐treatmentcrossoverstudythatevaluatedtheabusepotential,pharmacodynamics,phar-
macokinetics,andsafetyprofileoffinelyandcoarselycrushedORFversusOCandOxyAPIaccordingtocurrentguidelinesforstudiesofabuseliability.15,16Thestudyconsistedof:ascreeningphase,aqualificationphase,atreatmentphase,andafollow‐upvisit(2–4daysfollowingthelasttreatmentvisitorafterearlywithdrawal).Thescreeningphaseincludedanaloxonechallengetodeterminephysicaldependence.
Inthequalificationphase,subjectsself‐administeredintranasaldosesof30‐mgOxyAPIandvolume‐matchedlactose powder placebo in a randomized crossover
fashion,withapproximately24hoursbetweenadminis-trations.Subjectswereeligibletoenterthedouble‐blindtreatmentphaseiftheytolerated30‐mgOxyAPI.Additionally,thefulfillmentofoneofthefollowingthree
criteriawasrequired:(1)subjectshadbothapeakscore
forlactosepowderplacebo::;55ona0–100pointbipolarDrugLikingvisualanalogscale(VAS)where50representeda“neutral”response,ANDapeakscore
::;10ontheunipolar0–100HighVASwhere0representeda“noeffects”response;OR(2)subjectshadbothapeakDrugLikingVASscorefor30‐mgOxyAPIpowder
greaterthanOCplacebobyatleast15pointsANDapeak
HighVASscoregreaterthanOCplacebobyatleast30 points.Finally,subjectswereeligibletoenterthetreatmentphaseiftheirresponsestoOxyAPIandOCplacebo werejudged tobeacceptableby theinvestigatoronVASforDrugLiking,GoodEffects,BadEffects,andHigh.
In the double‐blind treatment phase, subjects self‐administeredintranasaldosesofthefivestudytreatments
inarandomizedcrossoverfashion,withawashoutperiodof at least 48hours between treatments. The five
treatmentswerelactosepowderOCplacebo,30‐mgfinelycrushedORF,30‐mgcoarselycrushedORF,30‐mgfinelycrushedOC,and30‐mgOxyAPIpowder.CoarselycrushedOCwasnottestedbecausesimplecrushingofOC
readilyproducesafinepowder.OCplaceboconsistedoffinelygroundOCplacebotabletsthatwerepreparedinthesamemannerastheactiveOCtablets.
Pharmacokinetic Assessments
Plasmaoxycodoneconcentrationswerequantifiedfromvenousbloodsamplescollectedviaanindwellingcannulaorbydirectvenipunctureatpredose,andat0.25,0.5,1,2,
3,4,6,8,and24hourspostdose.Asolid‐phaseextractionmethod was used to extract oxycodone from 200mL
plasmasamples.TheextractedsampleswereanalyzedbyLC‐MS/MS using a Phenomenex Luna Si, 5mm,2mmx100mm,normalphasecolumn.Themobilephaseusedwas85:15(0.1%formicacidinacetonitrile:0.2%formicacidin20mMammoniumformatebuffer,v/v).
Themassspectrometerwasoperatedinthemultiplereactionmonitoring(MRM)modewithpositiveiondetection.Thelower limitofquantitation (LOQ)foroxycodonewas0.1ng/mL.
Pharmacodynamic Assessments
Thevariouscomputer‐administered“100‐point”VASusedtoevaluatethedrugadministrationexperiencearedetailedinTable1,whichalsoincludestimepointsofVAS
assessments.SubjectiveDrugValue(SDV)wasadminis-teredat8and24hourspostdose.Pupillometrywasassessedpredoseand0.5,1,2,3,4,6,and8hourspostdose.Subjectswereinstructedtobasetheirresponses
Table1.BipolarandUnipolarVisualAnalogScales
0–100VAS
VASType
050100
DrugLikingaBipolarAtthismoment,mylikingforthisdrugis:
StrongDislikingNeutralStrongLiking
OverallDrugLikingbOverall,mylikingforthisdrugis:
StrongDislikingNeutralStrongLiking
TakeDrugAgainbIwouldtakethisdrugagain:
DefinitelyNotNeutralDefinitelySo
Alertness/DrowsinesscIamfeeling:
VeryDrowsyNeutralVeryAlert
HighcUnipolarIamfeelinghigh:
DefinitelyNotDefinitelySo
GoodEffectsaIcanfeelgooddrugeffects:
DefinitelyNotDefinitelySo
Bad EffectsaIcanfeelbaddrugeffects:
DefinitelyNotDefinitelySo
AnyEffectsaIcanfeelanydrugeffect:
DefinitelyNotDefinitelySo
VAS,visualanalogscale.SubjectscompletedVASendpointsviacomputerbyusingthemousetopositionacursorattheappropriateplaceoneachscaleandclicking“OK.”
aAdministered at 0.5,1,2,3,4, 6,8,and 24hourspostdose.
bAdministeredat8and24hourspostdose.
cAdministered predoseandat0.5,1,2,3,4,6,8,and24hourspostdose.
oncumulativeoroverallassessmentofdrugeffectsforOverallDrugLikingVAS,TakeDrugAgainVAS,andSDV.ForotherVAS,subjectsbasedtheirresponsesoneffects“atthismoment.”
TheSDVassessmentinvolvedaseriesofindependent,
hypotheticalforcedchoicesbetweenthestudydrugadministeredanddifferentmonetaryamounts.Subjectswereaskedtochoosebetweenreceivinganotherdoseofthesamedrugtotakehomeoranenvelopecontaininga
specifiedamountof money ($0.25–$50.00). Subjectsdidnotreceiveeitherthestudydrugorthemoneydescribedin
thechoices.ThistestwasadaptedfromasimilarprocedureextensivelyutilizedbyGriffithsetal.17,18
Pupillometry19 andintranasalphotographyservedas
twoadditionalmeasuresofpharmacologicandphysico-chemicaleffects.Anear,nose,andthroatspecialistassessedintranasalirritationusingendoscopyandintra-nasalphotography.Intranasalirritationwasassessedafterobservingthesubjectforatleast3minutes.Subjectratedassessmentofintranasalirritation(SRAII)assessedfivecategories (burning,needtoblow nose,runnynose/nasaldischarge,facialpain/pressure,andnasalcongestion)on
thesame6‐pointscale:0¼notobserved/noproblem;1¼very mild problem; 2¼mild/slight problem; 3¼
moderateproblem;4¼severeproblem;or5¼verysevereproblem/“asbadascanbe.”
Inapost‐hocanalysis,eachindividualstudysubject
wasassessedforpercentreductioninDrugLikingVAS
betweenOCandORF.AsimilaranalysisassessedpercentreductioninDrugLikingVASbetweenOxyAPIpowderandORF.
SafetyAssessments
Safetyassessmentsconsistedofadverseevents(AEs),vitalsigns,laboratoryassessments,and12‐leadelectro-cardiogram (ECG). AE reports and vital signs were
collectedfromthetimeofthesigningoftheinformedconsentformthroughtotheendofthefollow‐upphase.LaboratoryassessmentsandECGreadingswerecompleted
duringscreening,atadmissiontoeachtreatmentphasevisit,andatfollow‐up.
StatisticalAnalysis
Pharmacokineticanalyseswereconductedonthephar-macokineticpopulation(i.e.,allsubjectswhowererandomized,receivedactivestudydrug,andhadatleastonevalidpharmacokineticmetric).Pharmacokineticparameterswerederivedusingnoncompartmentalmeth-ods.Pharmacokineticmetricswere:maximumplasmaconcentration(Cmax),timetomaximumplasmaconcen-tration(Tmax),areaundertheconcentrationtimecurve
fromtimezerotoinfinity(AUCinf),andterminalhalf‐life
(t1/2).Abusequotient(AQ¼Cmax/Tmax),ameasureofthe
averagerateofincreaseinplasmaoxycodoneconcentra-
tionovertheintervalbetweentreatmentadministrationandthetimeofmaximum oxycodone concentration,wasalsocalculated.5,20
Abusequotientswerecalculatedasaposthocanalysisusinggenerallinearmodelwithtreatmentandsubjectasindependent variables.Pairwise comparisonsoftreat-mentswereperformed.
Meanscoresformaximumandminimumeffect(EmaxandEmin)werederivedforDrugLikingVAS;meanEmaxandEminwerealsomeasuredat8and24hoursforOverallDrugLikingVAS,TakeDrugAgainVAS,andSDV.EmaxwasderivedforHighVAS,GoodEffectsVAS,andSRAII.Eminwasderivedforpupillometry.TimetoEminandtimetoEmaxwerealsocalculatedforVASandpupillometrymeasures.Pharmacodynamicderivedparameterswereanalyzedusingamixed‐effectmodelforacrossoverstudy.Themodelincludedtreatment,period, sequence, andfirst‐order carryovereffectsasfixedeffects,baseline(predose)measurementsascovariate,whereappropriate,andsubjectnestedwithintreatmentsequenceasarandomeffect.Forthepurposesofstudyvalidation,asassessedbycomparisonof Oxy API versus OC placebo and OC versus OC
placebo,theprimary pharmacodynamic endpointswereEmaxofDrugLikingVAS,OverallDrugLikingVAS,andSDV.However,relativeabusepotentialconclusionswerebasedonresponsesonallpharmacody-namicmeasures.
Safetyanalyseswereconductedonthesafetypopula-tion (i.e., all subjectswho took atleastone doseofstudydrug in thetreatment phase).
Results
DispositionandDemographicData
Thirtysubjectsmetqualificationcriteriaandwererandomizedtothetreatmentphase.Ofthese,threesubsequentlywithdrewfromthestudy.Therefore,27metallprotocol‐specificproceduresandassessmentsandweredesignatedasstudy completers.
Subjects werepredominantlymale(86.7%)andwhite(86.7%).Themean(standarddeviation[SD])agewas
32.1(8.99)years,witharangeof18–48years,andthebodymassindexrangedfrom19.0to29.7kg/m2.All
subjectsreportedahistoryofrecreationalopioiduse(codeine,dihydrocodeine,heroin,hydromorphone,mor-phine, opium, OxyContin, oxycodone, oxycodone‐
acetaminophen, acetaminophen‐codeine). Recreational
use of other psychoactive drugs was reported by
86.7%ofsubjectsforcannabinoids(hashish, marijuana),53.3.%forstimulants(amphetamines,cocaine,MDMA),30.0%fordepressants(benzodiazepines,lorazepam,alprazolam), 30.0%fordissociative anesthetics(keta-mine),and23.3%forhallucinogens(LSD,psychedelicmushrooms).
Figure1.(a–d)Timecourseofpharmacokineticandpharmacodynamiceffects.(a)Meanplasmaoxycodoneconcentrationovertime(pharmacokineticpopulation).(b)Meanpupilsizeovertime(pharmacodynamicpopulation).
(c)MeanDrugLikingVASovertime(“atthismoment,mylikingforthisdrugis”)(pharmacodynamicpopulation).(d)MeanHighVASovertime(“Iamfeelinghigh…”)(pharmacodynamicpopulation).h,hour;OC,finelycrushedOC;ORF‐C,coarselycrushedORF;ORF‐F,finelycrushedORF;OxyAPI,oxycodonepowder;VAS,VisualAnalogScale.*Pupillometrywas
collected for8hours after dosing.
Pharmacokinetics
Dosing.Incompletedosingoccurredin9/28subjectsreceivingORF‐C(32%),10/29subjectsreceivingORF‐F(34%),2/28subjectsreceivingOC(7%),0/29subjects
receivingOxyAPI,and3/29subjectsreceivingOCplacebo(10%).
PharmacokineticParameters.Figure1aillustratesmeanplasmaoxycodoneconcentrationsovertime,andTable2summarizesderivedpharmacokineticparametersbyactivetreatment.CmaxvalueswerelowerforfinelyandcoarselycrushedORFthanforOCandOxyAPI.MedianTmaxvaluesforfinelyandcoarselycrushedORFwereapproximatelytwiceaslongasthoseobservedforOCandOxyAPI.MeanAUCinfvalueswerecomparableacrossallactivetreatments.Mediant1/2valuesweresomewhathigherandmorevariableforfinelyandcoarselycrushedORFcomparedwiththatofOCandOxyAPI.
AQ.AbusequotientswerefivefoldhigherforOxyAPIandOC(102.15and94.75ng/mL/h,respectively)comparedwithfinelyandcoarselycrushedORF(17.57and16.96ng/mL/h,respectively).AQforfinelyandcoarsely crushed ORF were significantly lower
(P.0001)thancrushedOxyAPIandOC.
Pharmacodynamics
Acrossallsubjectivepharmacodynamicmeasures,re-sponseswerelargestforthepositivecontrols,smallestforOCplacebo,andintermediateforfinelyandcoarselycrushedORF,withfinelycrushedORFgenerallyshowinglargerresponsesthancoarselycrushedORF.Thelargerresponsesseenforthepositivecontroltreatmentsupportedthevalidityofthestudydesign.
Pupillometry.IntranasaladministrationofOxyAPIandOCresultedinoxycodone‐inducedmiosis(i.e.,reducedpupil size)thatpeakedat 0.5–1hourpostdoseversusOCplacebo.Meanpupilsizethenincreasedslightlybeginning
at3hourspostdose(Figure1b).Nonotabledifferencesinpeak scores were observed between positive control
treatments.EminvaluesforOxyAPIandOCweresignificantlylowerthanOCplacebo(P.001foreach).Comparedwithpositivecontroltreatment,ORFadminis-trationshowedamoregradualonsetinpupil‐sizereduction,peakingatapproximately2–3hourspostdose.MeanEminvaluesweresignificantlylowerforbothfinely
andcoarselycrushedORFcomparedwiththatforOxyAPIandOCandsignificantlyhigherthanthatforOCplacebo (P.001 for all comparisons). No notable
differenceswereobserved inpupil‐size scores across
timewithOCplacebotreatment.
SubjectiveEffects
Qualificationphase.Duringthequalification phase,subjectsdemonstratedtheabilitytodistinguishbetweenOxyAPIandOCplacebotreatments.Mean(SD)EmaxvaluesforOxyAPIandOCplacebo,respectively,were,fortheprimary measures:94.3(11.0)and45.1(18.6)for
Table2.PharmacokineticandPharmacodynamicParameters(PharmacokineticandPharmacodynamicPopulations)
ORF‐F / ORF‐C / OC / OxyAPIPharmacokineticparameters
Cmax (ng/mL)Mean(SD) / 29.4 (7.71) / 29.8(12.2) / 59.6(16.2) / 52.1(13.0)
GeometricMean(%CV) / 28.4 (26.2) / 27.0(51.0) / 57.5(28.3) / 50.6(25.0)
Tmax(h)
Median(range)AUCinf(ng/mL/h)
Mean(SD) / 2.08(1.07–6.07)
339(101) / 2.62(0.25–8.1)
376(182) / 1.10 (0.25–3.13)
385(102) / 1.00 (0.25–4.10)
350(69.6)
Geometricmean(%CV) / 323(33.8) / 320(74.1) / 372(27.5) / 343(20.6)
t1/2(h)
Median(range)5.6(3.4–12.1)6.6(4.1–12.5)4.2(3.18–7.1)4.07 (3.39–5.99)AQ
Mean(SD)17.57(9.59)16.96(19.66)94.75 (91.87)102.15 (95.73)
ORF‐FORF‐COCOxyAPIOCPlacebo
Pharmacodynamic parameters
OverallDrugLikingVAS(“Overall,mylikingforthisdrugis…”)Emax
Mean(SD)69.7(29.4)61.1(25.8)87.4(22.2)84.8(18.9)48.9(14.8)
Take DrugAgainVASEmax
Mean(SD)64.0(38.2)52.8(37.4)89.6(20.7)86.6(23.5)28.2(24.3)
SubjectiveDrugValueEmax
Mean(SD)$17.01($16.39)$17.25 ($17.93)$27.95($16.03)$27.30 ($17.40)$0.37 ($0.60)
AUCinf,areaundertheconcentration timecurvefromtimezerotoinfinity;AQ, abusequotient(i.e., Cmax/Tmax); Cmax,maximumplasmaconcentration; CV,coefficientofvariation;Emax,maximumeffect;OC,finelycrushedOC;ORF‐C,coarselycrushedORF;ORF‐F,finelycrushedORF;OxyAPI,oxycodonepowder;SDV,SubjectiveDrugValue;Tmax,timetomaximumplasmaconcentration;t12,terminaleliminationhalflife;VAS,visualanalogscale.
DrugLikingVAS;90.0(16.30)and41.0(19.24)forOverallDrugLikingVAS;and$30.90($16.40)and$0.25
Table 3.Overall Subjective Drug Effects (PharmacodynamicPopulation)
($0)forSDV.
TreatmentPhase.ForbothDrugLikingandHighVAS,Emaxresponseswerehighestforthepositivecontrols,andtheseoccurredwithin1hourpostdose(Figure1c,d).Thepositivecontrolsshowedcomparablepeakscoresandtimecourses.LowerpeakresponseswereseenwithbothfinelyandcoarselycrushedORF,andtheseoccurredlaterthanforthepositivecontrols.ResponsesforthepositivecontrolsandforORFwereallhigherthanforOCplacebo.ThepeakresponseandtimecourseofcoarselycrushedORFwerelowerthanforfinelycrushedORF.
ForOverallDrugLikingVAS,TakeDrugAgainVAS,andSDV,responsesremainedrelativelyconsistentat8 and24hourspostdose(Table3).Thehighestresponseswereseenforthepositivecontrols,thelowestresponsewasseenforOCplacebo,andintermediateresponseswereseenforfinelyandcoarselycrushedORF,withcoarselycrushedORFshowinglowerresponsesthanfinelycrushedORF.
PharmacodynamicmeasureN
8hoursmean (SD)
24hoursmean(SD)
Table2presentsmean(SD)Emax valuesforOverallDrugLikingVAS,TakeDrugAgainVAS,andSDV.All
OC,finelycrushedOC;ORF‐C,coarselycrushedORF;ORF‐F,finelycrushedORF;OxyAPI,oxycodonepowder.
activetreatmentshadEmaxvaluesthatweresignificantlygreaterversusOCplacebo(P::;.003)exceptcoarselycrushedORF,whichdidnotdifferfromOCplaceboonOverallDrugLiking(P¼.07).FinelyandcoarselycrushedORFhadsignificantlylowerEmaxvaluesversuspositivecontrolsforallthreeglobalmeasuresofdrugeffect(P::;.002).Emax valuesforfinelyandcoarselycrushedORFdidnotdiffersignificantlyfromeachotheronTakeDrugAgainVASandSDV.TheEmaxvalueforOverallDrugLikingVASwassignificantlylowerforcoarselycrushedversusfinelycrushedORF(P¼.043).Similarly,OCandOxyAPIwereassociatedwithmean(SD)SDVEmax of$27.95(16.03)and$27.30(17.40),
respectively,whereasmeanSDVEmax forcoarselyand
finelycrushedORFwerelower($17.25[$17.93]and
$17.01[$16.39],respectively),andOCplacebowasthelowest($0.37[$0.60]).Positivecontrolsdidnotdiffersignificantlyfromeachother(P�.437)onallthreemeasures.
Thepattern of responsesfor High VAS,GoodEffectsVAS,andARCIMBG(datanotshown)provedsimilarforboth positive controls; both treatments demonstrated
prominent,statisticallysignificantresponsesversusOCplacebo(P.001forall).ORFscoreswereintermediate,andOCplaceboscoreswerethelowest.
Apost‐hocresponderanalysisofEmax21fordruglikingofORFcomparedtoOCfoundthat,amongsubjectswho
insufflatedbothfinelycrushedORFandfinelycrushedOC,acumulative57%(n¼16)hadsomereduction(i.e.,
0%)indrugliking,36%(n¼10)hadareductionofatleast30%,and29%(n¼8)hadareductionofatleast50%
(Figure2a).AsimilaranalysiscomparingORFtoOxyAPIfoundthatacumulative56%(n¼15)hadsomereductioninEmaxofdruglikingoffinelycrushedORFcomparedwithOxyAPI,33%(n¼9)hadareductionofatleast30%,and22%(n¼6)hadareductionof50%(Figure2b).
IntranasalTolerability.Overall,scoreswerelowforalltreatmentsonallmeasures(i.e.,themajorityofscoreswere1.0),butgreaternasalirritationwasseenwithcoarselyandfinelycrushedORF.ComparedtoOCplacebo,finelycrushedORFhadsignificantlyhigherEmaxonmeasuresofNeedtoBlowNose(P¼.017)andNasalCongestion (P¼.014), whereas Oxy API, OC, and
Figure2.(a)Responderanalysis:percentreductionprofilesfor EmaxofDrugLikingVAS(finelycrushedORFcomparedwithfinelycrushedOC).
(b)Responderanalysis:percentreductionprofilesforEmaxofDrugLikingVAS(finelycrushedORFcomparedwithOXYAPI).
coarselycrushedORFdidnot.ComparedtoOxyAPI,bothfinelyandcoarselycrushedORFhadsignificantly
higherEmaxonbothofthesemeasures(P0.01forallcomparisons).Compared toOC, finely crushed ORFhad
significantlyhigherEmaxonbothmeasures,andcoarselycrushedORFhad significantly higherEmaxforNasalCongestiononly(P¼0.001).
Safety
Nodeaths,severeTEAEs,orotherseriousAEsoccurred.TheoverallincidenceofreportedTEAEs,fromhighesttolowestincidence,was96.4%forfinelycrushedOCand89.7%forOxyAPI(positivecontrols),86.2%forfinelycrushedORF,75.0%for coarselycrushedORF,and41.4%forOCplacebo.MostTEAEswereofmildintensity.Only1subjectexperiencedamoderatelyintenseTEAE(respiratorydepressionfollowingfinelycrushedOCintranasaladministration).ThemostcommonTEAEswereconsistentwiththeknowneffectsofoxycodone
(Table4). Allmean laboratoryvaluesand vital signsfellwithinthenormalrangeatbaselineandfollow‐up,withno notablechangesfrombaseline observed.
Discussion
Theabuse‐deterrenteffectsofORFwereevident,inpart,inthepharmacokineticprofilesfortamperedORFversusOC,whichindicatedlesspotentialforabuse ofORFcompared
withOCbaseduponadecreaseintherateandextentofoxycodoneaborption in thefirsthoursfollowingadminis-tration.ThepharmacodynamicdatacollectedfollowingORFdemonstratedareductioninabusepotentialcomparedtoOC.ThesefindingsprovideevidencethatthedifferenceinformulationcharacteristicsbetweenOCandORFobserved in in vitro tampering experiments translated
intotheintendedabuse‐deterrenteffectsonpharmacoki-neticandpharmacodynamicpropertiesofORF.10 Safety
findingsprovedconsistentwiththeknowneffectsofopioiduseandnounexpectedsafetyfindingsemerged.
ConsistentwithrecentFDAdraftguidance,21thisstudy
ofabusepotentialwasvalidatedbycomparingtheresponsestothepositivecontroltreatmentswithresponsestotheOCplacebotreatment.Intranasaladministrationofbothpositivecontrols,OCandOxyAPI,resultedinsignificantincreasesinEmaxforDrugLikingVAS,OverallDrugLikingVAS,andSubjectiveDrugValue.
Theelementsofthisstudyareconsistentwiththoserecommendedinseveralpublishedguidelines,including:double‐blinding;theuseofactiveandOCplacebotreatmentsinapopulationofnondependentrecreationalopioiduserswhowereabletodiscriminatebetweenthemviatherelevantrouteofadministration;aqualification
phasethatincludedanaloxonechallenge;theuseofopaquevialsandparticlesofcrushedtreatmentsthatappearedsimilaracrossalltreatments;primarymeasuresofdrug‐likingcaptured onbipolarVASandexpressed intermsofEmax;appropriatepharmacokineticmeasures(includingtherateoftheriseofdrugconcentration);andappropriate
additionalpharmacodynamicmeasures(includingadequateassessmentsofintranasaltolerability).16,21–25Finally,thisstudywaspartofalargerprogramdevelopedtocharacterize
theabusepotentialofORF.
ThecomprehensiveanalysisoftheabusepotentialofORFincludesabatteryofinvitrotamper‐testingstudiesaswellasinvivopharmacokineticandabusepotentialstudies.10,26,27Italsoincludesasuiteofreal‐worldepidemiologicalstudiesthatcompareratesofmisuse,abuse,anddiversionoverthe2‐yearperiodsincetheintroductionofORFwitha15‐monthpre‐introductionbaselineperiodofOCrates.28 Recentlyreportedresults
Table4.TEAEsReportedby�5%ofSubjectsforAnyTreatmentatOnsetbyMedDRAPreferredTerm(SafetyPopulation)
TEAEs / Placebo(n¼29) / ORF‐F (n¼29) / ORF‐C (n¼28) / OC(n¼28) / OxyAPI(n¼29)AnyTEAE / 12(41.4) / 25(86.2) / 21(75.0) / 27(96.4) / 26(98.7)
Dizziness / 2(6.9) / 1(3.4) / 1(3.6) / 3(10.7) / 3(10.3)
Drymouth / 0 / 0 / 1(3.6) / 1(3.6) / 2(6.9)
Epistaxis / 1(3.4) / 0 / 1(3.6) / 2(7.1) / 1(3.4)
Euphoricmood / 1(3.4) / 17(58.6) / 12(42.9) / 23(82.1) / 24(82.8)
Fatigue / 0 / 2(6.9) / 0 / 1(3.6) / 0
Feelinghot / 0 / 1(3.4) / 1(3.6) / 2(7.1) / 3(10.3)
Feelingofrelaxation / 1(3.4) / 1(3.4) / 1(3.6) / 2(7.1) / 1(3.4)
Headache / 0 / 2(6.9) / 3(10.7) / 1(3.6) / 0
Nasalcongestion / 2(6.9) / 9(31.0) / 5(17.9) / 2(7.1) / 1(3.4)
Nausea / 1(3.4) / 0 / 0 / 3(10.7) / 1(3.4)
Pruritus / 0 / 6(20.7) / 4(14.3) / 4(14.3) / 8(27.6)
Pruritusgeneralized / 0 / 2(6.9) / 0 / 7(25.0) / 6(20.7)
Somnolence / 3(10.3) / 11(37.9) / 7(25.0) / 9(32.1) / 9(31.0)
Vomiting / 1(3.4) / 0 / 0 / 1(3.6) / 2(6.9)
MedDRA,MedicalDictionaryforRegulatoryActivities,version9.1;OC,finelycrushedoriginalOC;ORF‐C,coarselycrushedORF;ORF‐F,finelycrushedORF;OxyAPI,oxycodonepowder;TEAEs,treatment‐emergentadverseevents.
fromthesemultiple,ongoingepidemiologicstudiessupportthefindingspresentedhere.Theepidemiologicstudyresultsavailabletodatehaveshownreductionsinoverallandtamper‐relatedabuseofOxyContin sincetheintroductionofthereformulationofOxyContin(ORF)in
2010,29–31aswellasinitsstreetprice,32anddiversion.33Incommonwith limitations ofallabuse potential
studies,34theresultsofthisstudydonotprovideinformationrelatingtheintroductionofthisabuse‐deterrentformulationtochangesinreal‐worldabuse.Another limitation is that current recommendations
suggestthatcognitiveandpsychomotormeasuresbeincludedinopioidabusepotentialstudies,althoughitisacknowledgedthatspecifictestshavenotyetbeenidentifiedforrecommendation.35Anadditionallimitationisthat,despitemeasurestakentoreducetheopportunityforsubjectstomakephysicalcomparisonsamongthestudytreatments(e.g.,treatmentswereheldinopaquevialswithpreinsertedtubesforinsufflation),itwasnotpossibletofullypreventsuchcomparisonsbeingmade,whichmayhavecompromisedblindingtosomeextent.Finally,theoutcomemeasuresofthisstudyareacknowl-edgedtobemeasuresofrelativeabusepotentialandnotabsolutemeasurements.Whilethemethodsthemselvesappear tohave validity, they do nottake into accountthesocialcontextinwhichORFappears,includingculturalnormsandlegalstricturesonavailability.Therefore,theresults of this study should be interpreted in proper
context:astudythatcomparesanabuse‐deterrentreformulation of a product with a product that was
previouslysubjecttosignificantmisuseand abuse.
Conclusions
ReformulatedOxyContin(ORF)hasphysicochemicalpropertiesintendedtodetertamperingforthepurposesofintranasaloxycodoneabusebymakingcrushingbothmoredifficultandlesseffective,resultinginareductionintherateandextentofoxycodoneabsorptioninthefirsthoursafteradministration.ThepharmacokineticandpharmacodynamiceffectsofORFwereseeninthisstudyofhealthyadultswhowerenonphysicallydependent,recreationalopioidusers.IntranasaladministrationofcrushedORFwasassociatedwithreducedCmax,increasedTmax,andlowerabusequotientscorescomparedwithOxyAPIandcrushedOC.ComparedwithbothoriginalOxyContin(OC)andOxyAPI,peakeffectsoffinelyandcoarselycrushedORFweresignificantlyloweronmostsubjectiveandobjectivemeasures(includingOverallDrugLikingVAS,TakeDrugAgainVAS,HighVAS,SubjectiveDrugValue,andpupillometry),andthesepeakeffectsoccurredlatercomparedwiththepositivecontrols.SignificantincreasesinthesesubjectiveandobjectivemeasuresforOCandOxyAPIcomparedtoOCplaceboconfirmedthevalidityofthestudydesign.ORFexhibited
asafetyprofileconsistentwithintranasalopioiduseinthispopulation.ThereducedintranasaloxycodoneabusepotentialofORFindicatedbythefindingsofthepresentstudyareconsistentwiththefindingsofreductionsinintranasaloxycodoneabusereportedinepidemiologic
studiesofreformulatedOxyContin.28–33
Acknowledgments
TheauthorsthankMichaelL.Pucci,PhD,ofSCIScientificCommunicationsInformationandHudaAbdullah,PhD,formerlyofSCI, for preparing this manuscript on behalfof Purdue Pharma L.P., One Stamford Forum, Stamford,
Connecticut.FurtherwritingandeditorialassistancewasprovidedbyHenryAndrewCaporoso,MA,afull‐timeemployeeof PurduePharma L.P.
DeclarationofConflictingInterests
AllauthorsaffiliatedwithPurduePharmaL.P.arefull‐timeemployees.Dr.Smithwastheprimaryinvestigatorforthisstudy.
Dr.ShramandMs.Bartlettwereinvolvedindatainterpretationandpreparationoftheclinicalstudyreport.Dr.SellerswasaninvestigatorforthisstudyandisaconsultantforPurduePharma
L.P.Dr.ShramwasanemployeeofINCResearchTorontoatthetimethisstudywasconducted.
Funding
ThisstudywassponsoredbyPurduePharmaL.P.
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