pharmacoepidemiologyand drugsafety(2014)
PublishedonlineinWiley OnlineLibrary(wileyonlinelibrary.com)DOI:10.1002/pds.3658
ORIGINALREPORT
Reductionsinreporteddeathsfollowingtheintroductionofextended- releaseoxycodone(OxyContin)withanabuse-deterrentformulation†
NelsonE.Sessler1,JerodM.Downing1,HrishikeshKale1,HowardD.Chilcoat1,3,ToddF.Baumgartner4
andPaulM.Coplan1,2*
1DepartmentofRiskManagementandEpidemiology,PurduePharmaL.P.,Stamford,CT,USA
2DepartmentofClinicalBiostatisticsandEpidemiologyUniversityofPennsylvaniaPerelmanSchoolofMedicine(Adjunct)Philadelphia, PA,USA
3DepartmentofMentalHealth,JohnsHopkinsBloombergSchoolofPublicHealth(Adjunct),Baltimore,MD,USA
4DepartmentofRegulatory Affairs,PurduePharmaL.P.,Stamford,CT,USA
ABSTRACT
Purpose Abuseofopioidanalgesicsfortheirpsychoactiveeffectsisassociatedwithalargenumberoffatalities.Theeffectofmakingopi- oid tabletshardertocrush/dissolveonopioid-relatedfatalitieshasnot beenassessed.Theobjectiveofthisstudywastoassesstheimpactof introducingextended-release oxycodone(ERO[OxyContin®])tabletscontainingphysicochemicalbarrierstocrushing/dissolving (reformulatedERO)ondeathsreportedtothemanufacturer.
Methods AllspontaneousadverseeventreportsofdeathintheUSreportedtothemanufacturerbetween 3Q2009and3Q2013 involving EROwereused.Themeannumbersofdeaths/quarterinthe3yearsafterreformulatedEROintroductionwerecomparedwiththeyear before.Changesintheslopeoftrendsindeathswereassessedusingsplineregression.Comparisongroupsconsistedofnon-fatalreports involvingEROandfatality reportsinvolvingERmorphine.
Results Reportsofdeathdecreased82%(95%CI: 89, 73)fromtheyearbeforetothethirdyearafter(131to23deathsperyear) reformulation;overdosedeathreportsdecreased87%(95%CI: 93, 78)andoverdosedeathswithmentionofabuse-relatedbehavior decreased86%(95%CI: 92, 75).Incontrast,non-fatalEROreportsdidnotdecreasepost-reformulation,andreportedERmorphinefa- talitiesremainedunchanged.The ratioof EROfatalitiestoalloxycodonefatalitiesdecreasedfrom21% to8%intheyearpre-reformulation tothesecondyearpost-reformulation.
Conclusions Thesefindings,whenconsideredinthecontextofpreviouslypublishedstudiesusingothersurveillance systems,suggestthat theabuse-deterrentcharacteristicsofreformulatedEROhavedecreasedthefatalitiesassociatedwithitsmisuse/abuse.©2014TheAuthors.PharmacoepidemiologyandDrugSafetypublishedbyJohnWiley &Sons,Ltd.
keywords—OxyContin; extended-releaseoxycodone;abuse-deterrent;overdosedeath; pharmacovigilance;pharmacoepidemiology
Received11September2013;Revised1May2014;Accepted12May2014
INTRODUCTION
Opioidanalgesicsarerecommendedforthetreatment of serious,persistentpain after non-pharmacologic therapies and non-opioid medications have been
*Correspondence to:P.Coplan,ExecutiveDirector, Department ofRisk ManagementandEpidemiology,PurduePharmaL.P,OneStamford Forum, Stamford,CT06901,USA.E-mail:
†PriorPresentation:Aportion of thesedatawaspresentedat PAINWeek2012in LasVegas,NV,USA2012;thesecondInternational ConferenceonOpioids Boston,MA,USA2012;the29thInternational ConferenceonPharma- coepidemiologyand TherapeuticRiskManagementinMontreal,Canada2013.
used.1–5 Extended-release(ER)andimmediate-release (IR)opioidanalgesicsaredispensedtoover4million and56millionpatients intheUSAperyear,respec- tively(IMShealth). However,overthelastdecade, prescription opioidabuse(forpsychoactiveeffects) has increasedgreatly,resultingin increaseddeaths andburdentopublichealth.6–9 Theaddictionpotential andsequelae ofabuseincreaseexponentiallywhen tabletsarecrushed/dissolved fornon-oraladministra- tion(e.g.,snorting,injecting, andsmoking)toobtain rapidabsorptionoftheopioidexperienced asa “high.”10–12 Initial oral abuse often progresses to
©2014TheAuthors.PharmacoepidemiologyandDrugSafetypublishedbyJohnWiley &Sons,Ltd.
ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution-NonCommercial-NoDerivsLicense,whichpermitsuseand distributioninanymedium,providedtheoriginalworkisproperlycited,theuseisnon-commercialandnomodificationsoradaptationsaremade.
non-oralabusebythetimeofadmissiontoasubstance abusetreatmentfacility.11,13–15
Scientificinnovation ofabuse-deterrentformulations topromotesafeprescriptionopioiduseisafocusofre-
searchanddevelopmentamongpharmaceutical compa- nies.16,17 Pharmacologicalapproachesto incorporate
characteristics designedtodeterabusehaveincluded: (i)addinganopioidantagonist(e.g.,buprenorphine andnaloxone[Suboxone®],ERmorphine andseques- terednaltrexone[Embeda®], aswellaspentazocine andnaloxone[Talwin®NX]);(ii)addingagentsthatin- duceunpleasant symptomswithexcessiveintake(e.g., IRoxycodoneandaversive agent[Oxecta®]);and(iii) incorporatingphysicochemicalbarriersintendedtocon- ferresistancetotablettampering(e.g.,ERoxycodone [OxyContin®], ERoxymorphone[Opana® ER],and ERtapentadol[Nucynta® ER]).
OxyContin(ERO)isER-formulated oxycodoneap- provedintheUSA in 1995forthetreatmentof moder- ate-to-severechronicpain,18 whichhasbeenwidely abused,19–21 especiallybysnorting/injecting,requiring tabletcrushing/dissolving.22–25 InApril2010, theFood andDrugAdministration (FDA)approvedare- formulatedEROcontainingphysicochemical barriers tobreaking,crushing/dissolving todeterabuse,which remainsthe only availableER form of oxycodone availablein the USA. Pre-approvalstudies demon- stratedthatreformulated EROisbioequivalentto,is moredifficult toextractoxycodonefrom,andisless liked by abusersthan the originalformulation.26–28
AllshipmentsoforiginalEROtowholesalersstopped on 5 August, and shipments of reformulatedERO startedon9August2010.Thetransitiontothereformu- lationwasconductedwithoutnotificationofthegeneral public. Post-marketingstudies have demonstrateda
reductioninreportedEROabuseindrugtreatmentcen- terpopulationsandcallstopoisoncenters.29–32InApril
2013,EROreceivedFDA-approved labeling,indicat- ingthatitisexpectedto beabuse-deterrentviaintrana-
sal and intravenous routes of administration.33
However,theeffectsonfatalityhavenotbeenreported.
Thisreportfocusesontheimpactofreformulated
ERO on reports of US fatalities submitted to the
manufacturer’spharmacovigilancedatabase.Mortality databases,suchastheNationalDeathIndexandstate
medicalexaminerdatabaseswerenotusedbecause
theydonotdifferentiate betweenIRandERoxyco- done,andonly5%ofpatientsprescribedoxycodone
intheUSAreceivedERoxycodone(IMSHealth).
However,theratioofdeathsassociatedwithEROre- ported to the manufacturer versus all oxycodone
deathsreportedtotheFDA’sAdverseEventReporting
System(AERS)wasassessed toprovideadditional contexttothefindings.
METHODS
Manufacturersreceive,archive,andsubmitspontane- ousreportsofadverseeventsonmarketed drugsto nationaldrug-regulatoryauthorities,suchastheFDA intheUSA.34,35Searchingthemanufacturer’sadverse eventreporting databaseidentifiedallreportsoffatal eventsoriginatingintheUSAinvolvingEROfrom
3Q2009–3Q2013.Individualcasereportnarrativede- scriptionswerereviewedandcategorizedasmention- ing an opioid overdose-related event and/or drug
abuse-related behavior using criteria developed a
priori (Table1).Thisreviewwasconductedbythe twoprimaryauthorswithanydisagreementsresolved
byconsensus.
Table 1. Criteriatoidentifyoverdose-relatedeventandabuse-relatedbehaviormentions
Overdose-relatedevent •Reporterdescribedeventusingverbatimterm“overdose”oramedicallyrelatedterm(e.g.,drugpoisoning,polydrug toxicity,drugintoxication,andovermedicated);or
•Circumstancessurroundingdeathsuggestanoverdose-relatedevent(e.g.,ingestedmanypills,dosingmistake,tampering/
snorting/injectionofdrug,anddrugobtainedandingestedataparty);or
•Coronerorphysician deemedfatalitywasassociatedwithopioidoverdoseorpolydrugoverdose (with orwithout toxicology evidenceofoxycodoneoropioidingestion).
Abuse-relatedbehavior •Subjectcurrentlyorpreviouslymanipulatedextended-releaseoxycodone withintentionofabuse(e.g.,crushedand
snorted,dissolvedandinjected);or
•Extended-releaseoxycodonewasnot prescribedto thesubjectand/orsubjectwasobtainingdrugviaunlawfultransfer
(e.g.,stolen,ataparty,fromparentssupply,andfromthestreet);or
•Subjectwasobtainingextended-releaseoxycodoneprescriptionsfromapillmill,multiplehealthcareproviders,and/or multiplepharmacies;or
•Reporterstates subjecthashistoryofaddictiondisorderand/ordrugrehabilitationorindicatesthatsubjectiscurrently addicted;or
•Reporterstatessubjecthadbeenusingillicitdrugsoralcoholincombinationwithextended-releaseoxycodone
(e.g.,heroin,cocaine,marijuana,andamphetamines),or
•There wasevidenceofsubjectexposure toabenzodiazepine,anopioidother thanoxycodone,and/ormusclerelaxant/
hypnoticinabsenceofmentionofprescription.Forthispurpose,anexposurewas definedas:theindividualwas observed takingdrug,orreportedtohavetakenthedrug,ordrugwasrevealedintoxicologicalresults.
Theanalysisfocusedonspontaneousfatalityreports thatincludedmonth/year ofdeath,astimetrendsin mortalitycannotbeascertainedwherethisinformation isunknownandthedatewhenthereportwasreceived bythemanufacturerdoesnot necessarilycorrelatewith thedate ofdeath.Reportsassociatedwithpost-market- ingstudies(includingthemanufacturer’sindividualpa- tientassistanceprogram),litigation(becausethesewere not spontaneousreports),and those lacking a core reportingelement(patient,reporter,suspectproduct, oradverseevent)wereexcluded.Allreportscontaining month/year ofdeathfrom3Q2009–2Q2013wereana- lyzedusingSASv9.2(SASInstitute,Inc,Cary,NC).
Fatalitiesweredividedintofourperiodscorresponding to1yearpre-reformulation(3Q2009–2Q2010)andthe first (3Q2010–2Q2011), second (3Q2011–2Q2012),
andthird(3Q2012–2Q2013)yearpost-reformulation.
The mean fatalitiesper quarterandchangesin theslope oftrendsinfatalitieswerecalculatedbysplineregression
usingaPoissonmodelwiththeinflection pointcorre- spondingtothetimeofEROreformulation.36,37
Severalsensitivity analyseswereconductedtoas- sesstherobustnessoftheresults.Toassesstheimpact ofprescription changesonfatalities,countswere adjusted for 100,000 ERO prescriptionsdispensed (IMSNationalPrescriptionAuditdatabasesystem).38
Becausereporting accuracy variesbysource,cases reportedby healthcareprofessionalswereanalyzed separately. Toassesstheimpactofintentionalharm, fatalitiesexcluding suicide/homicidewere analyzed separately.Theimpactofcaseswithoutdateofdeath wasassessedbycombiningallcasesandusingreport receiptdateasaproxyfordateofdeath.Toassess theimpact ofcasescontainingmissingornonspecific formulationinformation, fatalitychangeswerecalcu- latedforcasesinwhichthereporter mentionedbrand name “OxyContin.”A sensitivityanalysisassessed theimpactofdelayedreportingbyremovingcasesthat werereportedmorethan3months(or6months)after eachquarterinthestudyperiod.
TheratioofdeathsassociatedwithERO reportedto themanufacturerversusalloxycodonedeathsreported totheFDA’sAERSsystem(dataavailablethrough
4Q2012)wascalculated.Dateofdeathisnot included
intheFDAAERSdatabecauseofprivacyregulations;
therefore,reportreceiptdatebytheFDAwasusedin theanalysis.
RESULTS
Populationcharacteristics
Atotalof326uniquefatalities involvingERO,origi- natingintheUSA,werespontaneouslyreportedto
themanufacturerwitha month/yearofdeathfrom
3Q2009–2Q2013(Table2).Overdosewasmentioned
in240reports,andabuse-related behaviorwasmen- tionedin206reports.Reportsinvolvingfatalover-
doses were most frequently received from a
healthcareprofessional,morefrequently involvingan adult (age 18–64years) and often involving
polysubstance use.
Overall,therewerenolargedifferences inreport characteristics between the pre-reformulation and
post-reformulation periodsintermsofreportsource,
gender,age,reportsource/type,andsourceoftoxicol- ogyinformation.However,forfataloverdoses,nota-
ble decreases in the proportion of reports from
southernregions(40% to29%) andthosewith mentionsofbenzodiazepines(42%to33%)orother
opioids(37%to24%)wereobserved.
Decreaseinreportsoffatalities
Therewas a reductionin reportsoffatalitiesinvolving EROinthepost-reformulationperiods,particularlyfor thesubsetofcases ofoverdose andoverdosewith mentionofabuse(Figure 1).Thesereductionsbegan thefirstyearpost-reformulation andweremorepro- nouncedinsubsequentyears.Specifically,themean ofall reportsoffatalitiesintheyearpre-reformulation was32.8perquarter,whichdecreased by82%(95% CI: 89%to 73%)to5.8reportsperquarterinthe thirdyearpost-reformulation;themeanoffatalityre- portsinvolvingoverdosein theyearpre-reformulation was26.0perquarter,whichdecreased by87%(95% CI: 93%to 78%)to3.3reportsperquarterinthe thirdyearpost-reformulation;andthemeannumber offatality reports involvingbothoverdoseandabuse- relatedbehavior in the year pre-reformulationwas
23.3perquarter,decreasingby86%(95%CI: 92% to 75%)to3.3reportsperquarterinthethirdyear post-reformulation(Table3).
Increasing trendsinmeanquarterlyfatalityreports wereobservedinthepre-reformulationyear.Incon- trast,inthepost-reformulationyears,theslopeofthe
3-yeartrendforallEROfatalreportsdecreased an average of15.6%(95%CI: 18.7%, 12.3%)per quarter,representingachangeof 20.7%(95%CI:
31.3%to 8.5%) frompre-reformulationtopost-re- formulation, which was statistically significant (p=0.0015).Similarstatisticallysignificantchanges inquarterlyslopeswereobservedforreportsoffatali- tiesinvolvingoverdose( 22.9%;CI: 34.7 %to
8.9%,p=0.0022)andoffatalitiesinvolvingboth overdoseandabuse( 22.2%;CI: 34.9%to 7%, p=0.0058).Changesfornon-overdosefatalities (e.g.,
Table2. Characteristicsofextended-releaseoxycodonefatalityreportsreceivedbymanufacturerwithdateofdeathduring 1-yearperiod beforeand3-year periodafterintroductionofreformulatedextended-releaseoxycodone
Allfatalcases(N=326) Subsetoffatalcases ofoverdose (N=240)
Oxycodonemention
*Oxycodonenototherwisespecified.Reportsinvolvingoxycodonetabletsthatdonotspecifyformulation(e.g.,immediate-release orextended-release formulation)areimpliedtohaveinvolvedextended-release oxycodone(OxyContin)becausethereporterhastakenthetimetospecificallytransmitthe informationtothemanufacturer.Duringtheevaluationperiodofthisstudy,onlyextended-releaseoxycodonewassoldbythemanufacturer,andnogeneric extended-releaseoxycodone productwasapprovedorsold.
†Illicitdrugsincludemarijuana,cocaine,amphetamines,andheroin.
deathnototherwise specified,suicide/homicide,and cancer) were not statistically significant ( 15.8%; CI: 36.8%to12.3%,p=0.2421)buttrendeddown.
Trendsincomparators
Nosubstantialchangeinadverseeventcasehandling orpharmacovigilanceprocedures weremadebythe manufacturer duringthestudyperiod.Non-fatalre- portstothemanufacturerforEROwere384perquar- terintheyear pre-reformulationcomparedwith 3129,
395,and294perquarterinthefirst,second,andthird yearpost-reformulation,respectively.Thesecompara- tor results suggest that the reductions in fatalities
involvingEROpost-reformulationwerenotdueto temporalchangesinreportingpatterns.
Aspikeinadverse eventreportsappearedshortly afterreformulation,mostofwhichoccurredwithin
3monthsofthemarketplacetransition.Asurveyof
1967subjectswhoreportedadverseeventsatthattime indicatedthat93%werefromindividualswhohad
usedEROforsometimeandwerereportingchanges
fromwhattheywereaccustomedto.Thetransitionto thereformulationwasconductedwithoutnotification
ofthegeneralpublic.
ReportsoffatalitiestothemanufacturerforERmor- phine(MSContin®)were toofewtoprovideastatisti- calcomparatortrend(2.7,1.5,2.5,and 2.0perquarter
Figure1. Number ofextended-releaseoxycodone(ERO)fatalityreportsperquarter.Categoriesentitledoverdose andoverdosewith mention ofabuse- related behavioraredefinedinmethods.DistributionofreformulatedEROtowholesalerswasinitiated 9August2010(indicatedbythearrow).
intheyearpre-reformulation, andfirst,second,and third year post-reformulation,respectively),though therewasnosubstantialdecrease.
Fatalityreportsforextended-releaseoxycodone versusalloxycodone
Theratioofthenumbersoffatalities involvingERO reportedtothemanufacturerrelativetofatalitieswith anyoxycodonecategorizedassuspectdrugreported to FDA decreased significantly (p0.0001) from
21%(131/637)intheyearpre-reformulationto22% (122/551),8%(50/616),and10%(12/120)inthefirst, second,andfirst6monthsofthirdyearpost-reformu- lation, respectively.
Sensitivityanalyses
Toassesstherobustnessoftheprimaryresults, sensi- tivityanalyseswereconductedadjustingforthenum- berofdispensedEROprescriptions,missingdateof deathinformation, reportertype,reportersource,for- mulationspecificity,andreportingtimelag(Table 3). Relativetothepre-reformulationyear,thenumber
ofEROprescriptions dispensedinretail,long-term care, and mail-orderpharmaciesdecreasedby 2% from1.72millionto1.69millionperquarterinthe
first,by9%to1.57millionperquarterinthesecond,
andby12%to1.51millionperquarter inthethird post-reformulationyear(Figure2).Decreasing trends infatalitycountsweredetectably, butnotsubstan- tially,altered whenadjustedforEROprescription numbers.Theprescription-adjustedrateofallfatality reportsdecreasedby80%(95%CI: 87%to 69%) comparingtheyearpre-reformulationtothethirdyear post-reformulation. Significantdecreasesinreported fataloverdosecases andfataloverdosecases thatalso mentionedabuse-relatedbehaviorwerealsoobserved.
Limiting theanalysistoreportsreceived from healthcareprofessionals, confiningtheanalysistofa- talitycaseswherebrandname “OxyContin”was men- tioned,removingfatalityreports withtextualmention of suicideor homicide(42 cases),or inclusionof post-marketing studies(82cases)didnotchangethe resultssubstantially. Imposingaconsistentreporting lagperiodof3or6monthsforallquartersacrossthe studyperiodshowedsimilardecreases infatalityre- portspost-reformulation,suggestingthattheobserved decreaseswerenotaffectedbyareportinglag.
Duringthestudyperiod,themanufacturerreceived
376fatalitycasesmissingthedateofdeath.Incompar- isonwithreportsthatincludedthisinformation,these
reports,ingeneral,lackeddetailedinformationregard- ingautopsyfindings,toxicologyresults,patientage,
and concomitant drugs. Analysis combining the
Table3. Changesinthe numberofextended-releaseoxycodonefatalityreportsperquarterreceivedbythe manufacturerfrom1yearbeforeto3yearsafter introductionofreformulatedextended-releaseoxycodone
1-yearpre-reformulation
(3Q2009–2Q2010)
Firstyear post-reformulation
(3Q2010–2Q2011)
Secondyearpost- reformulation(3Q2011–
2Q2012)
Third yearpost- reformulation(3Q2012–
2Q2013)
%change / %change / %changeMean* / Mean / (95%CI) / Mean / (95%CI) / Mean / (95%CI)
Caseswith dateofdeathreported(n=326) Allfatalreports
All
O
Non-overdose 6.8 9.5 41( 14,130) 2.8 59( 80, 18) 2.5 63( 82, 23) Allfatalreports,per100000prescriptionsofOxyContin†
All 1.903 1.802 5( 26,21) 0.794 58( 70, 42) 0.380 80( 87, 69)
Overdose1.516 1.241 18( 38,10) 0.619 59( 72, 41) 0.213 86( 92, 75) Abuse-relatedbehavior 1.359 1.033 23( 44,5) 0.475 65( 77, 47) 0.213 84( 91, 72)
Non-overdose 0.387 0.561 43( 12,135) 0.176 55( 78, 10) 0.167 58( 80, 13)
Subsetofallfatalreportsfromhealthcareprofessionals
All19.8 15.8 20( 43,11) 6.0 70( 81, 52) 2.8 86( 93, 74) Overdose 15.8 11.3 29( 51,5) 5.0 68( 81, 42) 2.0 87( 94, 74) Abuse-relatedbehavior 14.8 11.0 25( 50,10) 4.0 73( 84, 53) 2.0 86( 94, 72)
Non-overdose 4.0 4.5 12( 43,121) 1.0 75( 92, 25) 0.8 81( 95, 36)
Subsetofallfatalreportsmentioning brandname“OxyContin”
All17.0 15.8 7( 34,31) 6.5 62( 76, 40) 3.0 82( 90, 67) Overdose 12.0 9.0 25( 51,16) 4.3 65( 80, 38) 1.3 90( 96, 74) Abuse-relatedbehavior 10.5 7.8 26( 54,17) 3.3 69( 83, 42) 1.3 88( 95, 70)
Non-overdose 5 6.8 35( 24,141) 2.3 55( 80, 1) 1.8 65( 85, 17)
Subsetofallfatalreportswithdataconfinedtocasesreceivedduring3-monthperiodfollowingdateofdeath
All11.5 18.0 57(8,127) 4.0 65( 80, 39) 4.0 65( 80, 39) Overdose 9.5 10.5 11( 29,71) 3.3 66( 82, 36) 2.0 79( 90, 55) Abuse-relatedbehavior 9.0 8.5 6( 41,51) 2.8 69( 84, 40) 2.0 78( 90, 52)
Non-overdose 2.0 7.5 275(72,718) 0.8 62( 90,41) 2.0 0( 62,166)
Subsetofallfatalreportswithdataconfinedtocasesreceivedduring6-monthperiodfollowingdateofdeath
All17.3 21.5 25( 9,71) 7.3 58( 73, 35) 5.0 71( 82, 52) Overdose 13.8 13.5 2( 33,43) 5.3 62( 77, 37) 2.5 82( 91, 64)
Abuse-relatedbehavior 12.8 11.0 14( 42,29) 4.8 63( 78, 37) 2.5 80( 90,61) Non-overdose 3.5 8.0 129(22,328) 2.0 43( 76,36) 2.5 29( 68, 61)
Caseswith dateofdeathreported(n=326)andnotreported(n=376)
Fatalreportswithdateofdeath+fatalreportswithoutdateofdeath(usingmanufacturerreceiptdateasproxy) All
Overdose
Abuse-relatedbehavior 31.8 29.0 9( 29,17) 16.3 49( 62, 31) 11.3 65( 75, 50)
Non-overdose 22.3 26.5 19 ( 10, 58) 11.0 51 ( 66, 29) 10.5 53 ( 67, 32)
*Meannumberoffatalitycases perquarterwithvaluesroundeduptoonedecimal.
†IMSNationalPrescriptionAuditdatabase(includesretail, mailorderandlong-termcarepharmacyprescriptions).
fatality reports withoutdateofdeath,usingmanufac- turerreport-receipt dateasaproxyfordateofdeath, withthosereportscontainingdateofdeath,showeda
47%(95%CI: 58%to 34%)decreaseinallfatality
reportsinthethirdyearpost-reformulation. Significant decreasesinthenumberofoverdosefatalities,over-
dosefatalitieswithmentionofabuse-relatedbehavior,
andnon-overdose fatalitieswerealsoobserved.
DISCUSSION
Thenumberofspontaneousreportsofdeathinvolving
ERO reported to the manufacturerdecreasedafter
introductionofareformulatedEROthatwasdesigned tobeabuse-deterrent. Asvoluntaryspontaneousad- versereportsdonotcaptureallevents,temporaltrends in thesereportsmaynotbea reliablesourceforcausal interpretation.39–41 However,thelargemagnitudeof thedecreaseinreportedfatalities, whilenon-fatality adverseeventsremainedunchangedorincreased,sug- geststhedecrease wasnotduetochangingprocesses forreporting/collecting ofEROadverseevents.The relativestability ofdeathreportsforanother opioid productduringthesame period,thoughmuchfewer (becauseoffewerprescriptions), suggeststhatthere wasno systematicprocesschangeforreportingor
Figure2. OxyContinprescriptions perquarter.Retail,mailorder,and long-term care pharmacy dispensing of OxyContin prescriptions for
3Q2009–2Q2013extractedfromIMSNationalPrescriptionAuditdata-
base.DistributionofreformulatedOxyContintowholesalerswasinitiated
9August2010(indicatedbythearrow).
collectingreportsofdeathsbythemanufacturerduring thisperiod.Furthermore,analysesconductedtoassess whethermethodologicalartifactsmightberesponsible forthedeclineshowedlittleimpactofpotential arti- facts,suchaschangesinprescription numbers,re- portertypeorsource,formulationspecificity,missing dateofdeath,andreportingtimelag.Therefore,these resultssuggestadecrease inthenumberoffatalities associatedwithEROabuse/misuseasaresultofitsre- formulationwithphysicochemicalpropertiesthatdeter crushing/dissolving.
Other studieshave reportedsimilardecreasesin abuse/misuse of ERO post-reformulation. Cicero etal.29 reportedthatinpatientswithopioiddepen- dence who were enteringtreatment,the choice of EROastheprimarydrugofabuseanduseofERO togethighatleastonceinthelast30days,decreased significantlypost-reformulation(SurveyofKeyInfor- mantsPatients’ ProgramoftheRADARS® System). Butleretal.30 reportedthatforindividualsassessed forsubstanceabusetreatment,oraland non-oralabuse ofreformulated EROwere17%and66%lower,re- spectively, thanhistoricabuseoforiginalERO (NAVIPPROSurveillanceSystem), whereasabuseof ERoxymorphoneandERmorphineincreased or remained relativelyunchanged,respectively. Severtsonetal.31 reportedthatEROabuseexposure callsto poisoncentersand reportsofdiversionof ERO,onaper-catchment areapopulationbasis,de- creased38%and53%,respectively,andthatthestreet priceforreformulated EROwassignificantlylower thanoriginal ERO(PoisonCenterStudyandDrug Diversion Program of RADARS System). Coplan etal.32 reportedthatpoisoncenterEROabuse,suicide, therapeuticerrorsamong patients,accidentalexpo- suresamongchildren,andadversereactionexposures
decreasedsignificantlypost-reformulation butin- creasedorremainedsteadyforothersingle-entityoxy- codoneproducts(National PoisonDataSystem). Havensetal.42 reported thatexperiencedopioid abusersin a ruralKentuckycountyself-reporteda lowfrequencyofabuseofreformulated EROwhile maintainingaconsistentlyhighfrequencyofabuseof IRoxycodone.TheFloridaMedicalExaminersCom- missionReportshowedadecreaseindeathsdueto allformsofoxycodone,bothER andIR formulations, from apeakof1516in2010to735in2012.43 How- ever,duringthisperiod,astatelawwasenactedtoim- posestricterrequirementsfordispensingofcontrolled substancestargetedspecificallyatpillmillsthatwere primarilyprescribingordispensingIRoxycodone.50
Nationally,theratiooffatalitiesinvolvingEROversus anyoxycodone morethanhalved(from21%to8%) afterreformulation,furtherendorsingthespecificity oftheeffectofthereformulation.
Otherresearchers haveusedspontaneousadverse eventreports toassesstheeffects ofopioidformula- tionsintendedtodeterabuse.Post-marketingadverse
eventreportsreceivedforanERmorphinecapsule
combined with naltrexone(anopioidantagonist)indi- catedalownumberofproducttamperingreportsand nocasesofconfirmedtamperingresultinginfatality.44
Therearelimitationstocausalinferencefromvolun- taryspontaneousfatalityreports. However,whenthe results ofthisstudyareconsideredinthecontextof thefiveadditionalpublishedarticlesandtheonestate surveillance reportthatdemonstrateanabuse-deterrent impactofreformulated ERO,theBayesianpriorthat theobservedchangeinreportedfatalitiesiscaused bythereformulationisincreased.45
Alternateexplanations for the declinein fatality reporting wereconsidered.AreductioninEROdis- pensingoccurredduringthestudyperiod.However,
combined prescription reductions of original and
reformulatedERO(2%,9%,and12%in thefirst, second,andthirdyearpost-reformulation,respectively)
were insufficienttoaccountforthemuchlargerreduc-
tioninfatalities.DispensingoforiginalERO gradually decreasedinthe18monthsafterwholesaleshipments
stopped.Ofnote,reportsreceivedbythemanufacturer
post-reformulationincludedexposurestobothoriginal andreformulatedEROandthereforeaportionofthe
fatalreportsinthepost-periodlikelyinvolvedoriginal
ERO,whichmayaccountforthegradualdecrease in fatalitiespost-reformulation.
Severalinitiativestodeteropioidabuse/overdose
commenced orwereongoingduringthestudyperiod. TheFDA’sRiskEvaluationandMitigationStrategy
forERandlong-actingopioidswasapprovedinJuly
2012.46 However,itsprimarycomponentiscontinuing educationofprescribers,whichbeganinMarch2013, subsequentto the reductionin ERO deaths.State prescriptiondrugmonitoringprogramswereoperating orinitiatedduringthe study period.47 Preliminary evaluationoftheseprograms indicateapositive impactonopioidabuse/misuse,48 buttheireffect on fatalities isnotclear.49,50 Community-basedopioid overdosepreventionprogramshavereduceddeaths inthefewlocalregionswhereimplemented but cannotaccountforlargenationalchanges.51,52 Drug disposalprogramshavebeenestablishedbuthave notfocusedspecifically onEROandhavenotbeen showntoimpactdeathsassociated withopioids.53,54
Theseinitiativesmayhavecontributedtodecreases in opioid-relatedfatalities;however, they are un- likelytoaccountforthelevelofdecrease inERO fatalities. The ratio of fatalities involving ERO versusanyoxycodonemore thanhalvedafter reformulation.
Someauthorsattributedanincreaseinheroinabuse tothereformulation ofEROwhenitwasfirstintro- duced,29 andthishasledtowidespreadattribution of thecauseoftherapidlyescalating heroinabuseto EROinmediareports.55 However,currently,1.7%of individualsdispensedopioidanalgesics intheUSA receiveERO,and2.5%ofopioidprescriptions dis- pensedareforERO.Theseproportionshaveremained roughlyconstantoverthepast5years(IMSHealth, unpublisheddata).Furthermore, approximately4.3% ofdiagnosedoverdoseeventsininsuranceclaimsdata- basesin2011wereamongpeopleprescribed ERO (MarketScan,unpublisheddata)andtheprevalence ofreformulatedEROabuseamongprescriptionopioid abusersindrugtreatment centersis12.1%.22 There- fore, itisunlikelythatreducedabuseofERO,which occurredinasingle,abruptinterventionbeginningin August2010,couldaccountforspikesinheroinabuse
3½yearslater.
Inconclusion,thenumberofspontaneousreports of fatalities involving ERO has significantly de-
creasedafteritsreformulation, whereasnon-fatal reports involving ERO remained unchanged or
increased.Thesefindings,whenconsideredin the
contextofpreviouslypublishedstudies usingother surveillancesystems,suggestthatthe abuse-deterrent
characteristicsofreformulatedEROhavedecreased
fatalitiesassociatedwith its misuse/abuse.Abuse- deterrent formulations may be a valuable risk
management tool, such that innovation, policing,
regulation,carefulprescribing,andeducationcanbe combinedtomitigate serious riskandimprovethe benefit-riskbalance ofopioidanalgesics.56
CONFLICTOFINTEREST
NelsonSessler, JerodDowning,HrishikeshKale, Howard Chilcoat, Todd Baumgartner, and Paul Coplanarefull-timeemployeesofPurduePharmaL.P.
KEYPOINTS
•Abuseofprescriptionopioidanalgesicsforthepsy-
choactiveeffectsisassociatedwithalargenumberof
fatalities. However,theeffectofmakingopioidtablets
hardertocrushordissolveinordertodeterabuseon opioid-relatedfatalitieshas notbeenassessed.
•Themanufacturer’spharmacovigilancedatabase
wasusedtoassesschangesinfatalitiesassoci-
ated with extended-releaseoxycodone (ERO, OxyContin)aftertheproductwasreformulated
tobehardertocrushordissolve.
•Alargedecreaseinthenumberoffatalityreports
associatedwithEROoccurredfollowingintro-
ductionofreformulatedOxyContin,especially reportsof fatalitiesinvolvingoverdose-related
eventsandinvolvingabuse.
•Thesefindings,whenconsideredinthecontextof
previouslypublishedstudiesusingothersurveillance
systems,suggestthattheabuse-deterrentcharacteris-
tics of reformulated ERO have decreased the fatalitiesassociatedwithitsmisuseandabuse.
ETHICSSTATEMENT
Theauthors statethatnoethicalapprovalwasneeded. ACKNOWLEDGEMENTS
CasereviewassistancewasprovidedbyBarbaraHar- ding.Manuscriptpreparationassistancewasprovided byMelindaPhilbrook.Writingassistance waspro- videdbyLouisAlexander. Thisstudywassponsored byPurduePharmaL.P.
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