Factors Contributing to the Rise of Buprenorphine Misuse: 2008-2013

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Nova Southeastern University

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Faculty Scholarship

9-1-2014

Factors Contributing to the Rise of Buprenorphine Misuse:

2008-2013

Theodore J. Cicero

Washington University in St. Louis, [email protected]

Matthew Ellis

Washington University School of Medicine in St. Louis, [email protected]

Hilary L. Surratt

Nova Southeastern University, [email protected]

Steven P. Kurtz

Nova Southeastern University, [email protected]

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NSUWorks Citation

Cicero, T. J., Ellis, M., Surratt, H. L., & Kurtz, S. P. (2014). Factors Contributing to the Rise of Buprenorphine

Misuse: 2008-2013. Drug and Alcohol Dependence, 142 (2014), 98-104.

https://doi.org/10.1016/

j.drugalcdep.2014.06.005

This Article is brought to you for free and open access by the Faculty Scholarship at NSUWorks. It has been

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[email protected]

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ContentslistsavailableatScienceDirect

Drug

and

Alcohol

Dependence

jo u r n al h om ep age :w w w . el s e v i e r . c o m / l o c a t e / d r u g al c d e p

Factors

contributing

to

the

rise

of

buprenorphine

misuse:

2008–2013

Theodore

J. Cicero

a,∗

_,

_Matthew

_S.

_Ellis

a

_,

_Hilary

_L.

_Surratt

b

_,

_Steven

_P.

_Kurtz

b a_Washington_University,_Department_of_Psychiatry,_Campus_Box_8134,₆₆₀_S._Euclid_Avenue,_St._Louis,_MO_63110,_United_States b_Nova_Southeastern_University,_Center_for_Applied_Research_on_Substance_Use_and_Health_Disparities,₂_NE_40th_Street,_Suite_404,_Miami, FL33137,UnitedStates

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received31March2014

Receivedinrevisedform2June2014 Accepted3June2014

Availableonline18June2014 Keywords:

Buprenorphinemisuse,Heroin,Opioid misuse,Self-treatmentofopioid dependence

a

b

s

t

r

a

c

t

Objective:Thepurposeofthepresentstudywastoexaminethemotivationsunderlyingtheuseof buprenorphineoutsideoftherapeuticchannelsandthefactorsthatmightaccountforthereportedrapid increaseinbuprenorphinemisuseinrecentyears.

Methods:Thisstudyused:(1)amixedmethodsapproachconsistingofastructured,self-administered survey(N=10,568)andreﬂexive,qualitativeinterviews(N=208)amongpatientsenteringsubstance abusetreatmentprogramsforopioiddependenceacrossthecountry,centeredonopioidmisusepatterns andrelatedbehaviors;and(2)interviewswith30lawenforcementagenciesnationwideaboutprimary diverteddrugsintheirjurisdictions.

Results:Ourresultsdemonstratethatthemisuseofbuprenorphinehasincreasedsubstantiallyinthe last5years,particularlyamongstpastmonthheroinusers.Ourquantitativeandqualitativedatasuggest thattherecentincreasesinbuprenorphinemisusearedueprimarilytothefactthatitservesavariety offunctionsfortheopioid-abusingpopulation:togethigh,managewithdrawalsickness,asasubstitute formorepreferreddrugs,totreatpain,managepsychiatricissuesandasaself-directedefforttowean themselvesoffopioids.

Conclusion:Thenon-therapeuticuseofbuprenorphinehasrisendramaticallyinthepastﬁveyears, par-ticularlyinthosewhoalsouseheroin.However,itappearsthatbuprenorphineisrarelypreferredforits inherenteuphorigenicproperties,butratherservesasasubstituteforotherdrugs,particularlyheroin, orasadrugused,preferabletomethadone,toself-medicatewithdrawalsicknessorweanoffopioids.

1. Introduction

Buprenorphine is a dose-dependent, mixed opioid ago-nist/antagonistwithveryhighafﬁnityforthemu-opioidreceptor, butwithlimitedintrinsicactivitycomparedtoother,more com-monlyusedopioidanalgesics(Walshetal.,1994).Moreover,ithas averylowdissociationconstantfromtheopioidreceptor, generat-ingaverylonghalf-lifeandlimitingdosingfrequency(Bickeletal., 1988;DonaherandWelsh,2006;Greenwaldetal.,2003).These propertieshavemadethisdrugaparticularlyattractiveagentfor opioidsubstitutiontherapyprogramsacrosstheworld(Donaher andWelsh, 2006;Johnsonet al.,1992;Ling etal.,1998; Fiellin and O’Connor, 2002; Degenhardt et al.,2009; Bell et al., 2009; Sullivanetal.,2008;Alfordetal.,2011).Whileitismaintainedthat theseprogramshavebeensuccessfulinreducinguseofillicit opi-oids,buprenorphineitselfhasbecomealeadingdrugofchoicefor

∗ Correspondingauthor.Tel.:+13143624516;fax:+13143625630. E-mailaddress:[email protected](T.J.Cicero).

non-therapeutic purposes (e.g., produce euphoria/get high) in manycountrieswhichhavesuchprograms(Bell,2010;Auriacombe etal.,2004;Carrierietal.,2006;Aaltoetal.,2007;Yokelletal.,2011; Guichardetal.,2003;Vidal-Trecanetal.,2003;Lavonasetal.,2014). Recognizingthisfact,themanufacturerreformulated buprenor-phinewithlowdosesofnaloxonepriortoitsreleaseintheUnited States for opioid treatment (Reckitt Benckiser Pharmaceuticals Inc.,2014).Itwasassumedthatnaloxonewouldantagonizethe euphoricpropertiesofbuprenorphine,orprecipitatewithdrawal inopioidtolerantindividuals(Chiangetal.,2003;Mendelsonand Jones,2003;WalshandEissenberg,2003;Stolleretal.,2001).Thus, itsriskofmisusewasconsideredtobequitelow(MammenandBell, 2009;Alhoetal.,2007;Comeretal.,2010;Schuster,2006).Based onearlyassessmentsofthedrug,theFoodandDrugAdministration notonlyapprovedbuprenorphineandbuprenorphine/naloxoneas partof comprehensiveopioid harmreduction programin 2002, buttherewassufficientconfidencewiththesedrugsthattheywere approvedtobeprescribedforhomeuseratherthanmadeavailable onlyin stand-alonemethadone clinics,which areinconvenient, carrya significantsocialstigma,anduseaninherentlyless safe http://dx.doi.org/10.1016/j.drugalcdep.2014.06.005

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opioid(methadone)withsigniﬁcantadverseside-effects(Peterson etal.,2010;Schwartzetal.,2008;Zalleretal.,2009).However,given theexperienceinEurope,theFDAwascautiousinitsapproach, requiringspecializedtrainingandlimitationsof30buprenorphine patientsatonetimeforphysicians(SubstanceAbuseandMental HealthServicesAdministration(SAMHSA),2014;DrugAddiction TreatmentAct of,2000; Centerfor Substance AbuseTreatment (CSAT),2004).Withtheearlyapparentsuccessoftheseprograms, restrictionswereliftedin2006suchthatupto100patientscould betreatedbyanindividualphysician.Additionally,the introduc-tionoflessexpensivegenericsin2009furthercontributedtolarge increases in buprenorphine prescriptions in thepast ﬁve years (DrugEnforcementAdministration,2009).Asexpectedfrom ear-lierworkshowingadirectlinkbetweentheextentoftherapeutic exposureanddiversionfornon-therapeuticpurposes(Ciceroetal., 2007a,b),therehavebeenreportsofanincreaseinthediversion andmisuseofbuprenorphine(DrugEnforcementAdministration, 2009;SubstanceAbuseandMentalHealthServicesAdministration andDrugAbuseWarningNetwork(DAWN),2011;UnitedStates DepartmentofJusticeandNationalDrugIntelligenceCenter(NDIC), 2011;Wishetal.,2012).

Thepurposeofthepresentstudywastoexaminemultiple fac-torsthatmightaccountfortherapidincreaseinbuprenorphine misuseinrecentyearsandthemotivationsunderlyingtheuseof buprenorphine outsideof therapeutic channels.Toaddress this issue, we used a mixed methods approach utilizing data from structured, self-administered surveys(N=10,568) and reﬂexive, qualitativeinterviews(N=208)amongpatientsenteringsubstance abusetreatmentprogramsacrosstheU.S.withaprimary (DSM-IV)diagnosisofopioiddependence.Toassessdiversion,datawere analyzedfromsemi-structuredinterviewsamongasampleof drug-diversionlawenforcementunitsacrossthecountry(N=30).

2. Methods

ThisreportutilizeddatafromtheResearchedAbuse,Diversionand Addiction-RelatedSurveillance(RADARS®₎_System,_a_{comprehensive}_series_of_programs_that collectandanalyzepost-marketingdataonthemisuseanddiversionofprescription opioidanalgesicsandheroin(Ciceroetal.,2007a,b).

2.1. StudySample1:SKIP

TheSurveyofKeyInformants’Patients(SKIP)Programconsistsofover150 publicandprivatelyfundedtreatmentcenters(KeyInformants),balanced geograph-icallywithcoveragein48states,thatrecruitpatients/clientsenteringtreatmentto completeananonymoussurveycenteredonopioidmisusepatternsandrelated behaviors.Subjectsmustbe18yearsorolderandmeetDSM-IVcriteriafor sub-stanceabusewithaprimarydrugthatisanopioid(prescriptionorheroin).Surveys, receivedonarollingbasisthroughouttheanalyzedperiod,wereidentiﬁedbya uniquecasenumberandsentdirectlytoWashingtonUniversityinSt.Louis(WUSTL) bytherespondent.Participantswerecompensatedwitha$20Wal-Martgiftcard. Surveyswerecategorizedbyhalf-yearandquarter,withSKIPdataforthisstudy analyzedfromJanuary1st,2008toSeptember30th,2013.

2.2. StudySample2:RAPID

TosupplementandaddcontexttothestructuredSKIPsurvey,asub-setof patientsindicated,byamail-inpostcardprovidedwiththeSKIPsurvey,their willingnesstogiveuptheiranonymityandparticipateinanunstructured interview-basedstudy,dubbedResearchersandParticipantsInteractingDirectly(RAPID). Duringthefourthquarterof2013,208treatmentclientsconsentedtoparticipate inaself-administeredinternetquestionnaireviaSurveyMonkey.Thoseparticipants whoindicatedpriorexperiencewithbuprenorphinewerere-contactedtofurther describetheiropinionsandexperienceswithbuprenorphineN=(106).All partic-ipantsintheRAPIDprogramwerecompensatedwitha$20Wal-Martgiftcard. StudyprotocolsfortheSKIPandRAPIDprogramswereapprovedbytheWUSTL institutionalreviewboard.

2.3. StudySample3:Drugdiversion

TheDrugDiversionprogramoftheRADARS® _System_collects_data_from_a nationalsampleoflawenforcementandregulatoryagencieswithagentsassigned toprescriptiondrugdiversioninvestigations.Theprogramincludesapproximately

260investigatorsin49states.Forthisstudy,thirtyinvestigatorsparticipatinginthe DrugDiversionprograminthesecondquarterof2013wererandomlyselectedto participateinaone-time,semi-structuredtelephoneinterview.Theseinvestigators represented23statesandwereaskedgeneralquestionsabouttheirunits,caseload information,primarysourcesofdiversionandprimarydiverteddrugsintheir juris-dictions.ThestudywasdeemedexemptbytheinstitutionalreviewboardatNova SoutheasternUniversity.

2.4. Dataanalysis

BothSKIPandRAPIDprogramsgathersocio-demographicvariables(e.g.,sex, currentageandrace/ethnicity).Inaddition,SKIPandRAPIDparticipantsidentiﬁed theirprimarydrug(e.g.,thedrugusedtogethighmostfrequentlyinthemonth priortotreatment),withSKIPrespondentsaskedtoalsoidentifyallopioid com-poundsusedtogethighinthemonthpriortotreatmentstratiﬁedbyformulation andproduct,includingwhetherornoteachproductwasinjected.“Misuse”isused throughoutthisreporttoreferencebothnon-therapeuticuseanduseoutsideof legaltherapeuticchannels.Exceptwherenoted,SKIPanalysesincludedtheentire sampleofbothheroinandprescriptionopioidusersduetothefactthattherewas highconcurrentuseofbothdrugs;85%ofheroinusersalsoindicatedthepastmonth misuseofprescriptionopioids.

RAPIDinterviewresponsestothequestion“Pleasebrieflyexplaininyourown wordsthereasonsyoutookbuprenorphineorhowbuprenorphineaffectedyou,” weredual-reviewed,andusingtheprinciplesofthematicanalysis,13 motiva-tionsforusingbuprenorphinewereidentified.Inordertogetamoreaccurate accountofthevariabilityinotherbuprenorphine-relatedmotivations,aseriesof true/falsequestionswasdevelopedbasedonelevenidentifiedmotivations,with“to gethigh”and“totreat/preventwithdrawalsickness”excludedbecausetheywere askeddirectlythroughotherSKIPandRAPIDquestions.OtherRAPIDdatareported inthisstudywerebasedondirectquestions,withparticipantsaskedtoexplaintheir responsesinanopen-endedformat.

TheDrugDiversionprogramanalyzedtheresponsesoflawenforcement inves-tigatorsinterviewedaboutthemostcommonlydivertedprescriptiondrugsintheir area.Inadditiontoidentifyingspeciﬁcdrugs,areviewoftheinterviewresponses ledtotheidentiﬁcationofothertopicsofinterest.Topicsnotedbyatleastthree intervieweeswerethendevelopedintothemesandthepresenceofatheme(Y/N) wascodedbacktotheinterviews.QualitativedatafromtheDrugDiversionand RAPIDprogramswerereviewedandcodedusingNVivoversion9.Quantitativedata inbothSKIPandRAPIDdatasetswereanalyzedusingIBMSPSSStatisticsv21.

3. Results

3.1. Demographics

Table 1 summarizes the gross demographic features of those participating in the SKIP (N=10,568; mean N per quar-ter=449.1±36.6SE)andRAPID(N=208)programs.Ascanbeseen, theRAPIDsubset,thoughmuchsmaller,wasquitesimilartothe largerSKIPsample.Themajorityofrespondentswerewhiteandin

Table1

ComparisonofSKIPandRAPIDdemographicdata.

SKIP1_(n₌_10,568) _RAPID2_(n₌₂₀₈₎

Gender

Male 50.4 48.4

Averageage(±SEM) 34.2±0.11 34.9±0.81

Race/ethnicity White 78.4 86.4 AfricanAmerican 9.0 4.3 Latino 4.9 3.7 Other 7.7 5.6 Primarydrug Buprenorphine 1.6 0.7 Fentanyl 1.0 2.0 Heroin 29.8 36.2 Hydrocodone 19.7 20.4 Hydromorphone 3.8 1.3 Methadone 5.6 2.0 Morphine 4.0 3.3 Oxycodone 32.4 29.6 Oxymorphone 1.1 1.3 Tapentadol 0.0 0.0 Tramadol 1.1 3.3

1_Data_collected_from_January_1,_{2008–September}_30,_2013. 2_Data_collected_from_October_1,_{2013–December}_31,_2013.

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Fig.1. Thepercent(95%CI)ofthetotalSKIPsample(A)whousedbuprenorphineinthepastmonthtogethighasafunctionofhalf-yearintervalsfrom2008totheendof 2013.Theyearfollowingthereleaseofgenerics(dashedlines)isexpressedinquarter-yearintervalstoemphasizethesteepnessintherateofincrease;(B)showsthemisuse (95%CI)ofbuprenorphineinthoseSKIPrespondentswhousedotherprescriptionopioidstogethighversusthosewhousedotherprescriptionopioidsandheroin.Dueto thefactthat85%ofheroinusersalsousedprescriptionopioids,theNsforthoseusingonlyheroinweretoosmall(<35)formeaningfulanalysis.

theirearlythirtiesatthetimeofsurveycompletion,withaneven distributionofmalesandfemales.Heroinandoxycodonewerethe mostpopularprimarydrugs(i.e.,thedrugusedmostofteninthe pastmonth)inbothgroups,withbuprenorphineoneoftheleast preferred.

3.2. Buprenorphinemisuse

Althoughbuprenorphinewasendorsedasaprimarydrugby lessthan2percentofeachsample(Table1),asshowninFig.1A thenumber ofSKIPrespondentswho indicatedpastmonthuse of buprenorphine to get high was much higher and the rate almostquadrupled from2008to2013.Mostnotably,therewas a steepincrease in every quarterof 2010(detailed in Fig.1A), theyearfollowingtheintroductionofbuprenorphinegenericsin 2009.Datafromlawenforcementagentschargedwith investigat-ingpharmaceuticaldiversion alsoindicatedthat buprenorphine wasasigniﬁcantproblemin2013.Itwasthefourthmost com-monlydivertedprescriptiondrugasdeterminedbycasereports; oxycodonewasmentionedby96.7%ofrespondents,followedby hydrocodone(80%),alprazolam (57%),buprenorphine(33%) and methadone(30%).

3.3. Heroin

AsshowninFig.1B,thoserespondentswhousedbothheroin andotherprescriptionopioidstogethighinthepastmonthalso misusedbuprenorphineatratestwicethatreportedbythoseonly usingprescriptionopioids.Moreover,asshowninFig.2A,increases in heroin useparalleled theincrease in buprenorphine misuse, mostnotablyintheyearsfollowingtheintroductionofa tamper-resistantformulationofOxyContin® _in_the_second_half_of _2010.

Fortypercentofdrugdiversioninvestigators(N=12)alsonoteda parallelincreaseinheroinandbuprenorphineuse:

We’ve seen an increase in heroin and suboxone, they are oftenpackagedtogether.Suboxoneisbeingprescribedinhuge amounts,thisgirlhad24reﬁllsonherandshewasdealing...we arrestedhershootingupinarestaurant.

3.4. Methadone

AsshowninFig.2B,asthepastmonthmisuseofbuprenorphine increasedovertime,methadonemisusedeclined,suchthat,two yearsaftertheintroductionofbuprenorphinegenerics,methadone waslesscommonlymisusedthanbuprenorphine.Inthiscontext,

Fig.2.Thepercent(95%CI)ofthetotalSKIPsamplethatusedbuprenorphine,OxyContin®_and/or_heroin_to_get_high_in_the_past_month_plotted_as_a_function_of_half-year intervalsfrom2008to2013(A);(B)showsthepercent(95%CI)ofthetotalSKIPsamplethatusedbuprenorphineand/ormethadonetogethighinthepastmonth.The introductionofanabusedeterrentformulationofOxyContin®_is_denoted_by_the_dashed_vertical_line.

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Fig.3.BuprenorphineproductformulationsusedbySKIPrespondentsindicatinganypastmonthuseofbuprenorphinetogethighplottedasafunctionofquarter-year inter-vals(95%CI)(A);(B)showsthetotalpercentageofbuprenorphineproductformulationsinjectedbySKIPrespondentsindicatinganypastmonthinjectionofbuprenorphine togethigh.

40%ofrespondentsintheRAPIDinterviewsindicatedtheyhadused bothbuprenorphineandmethadoneforthepurposeoftreatingor preventingwithdrawalsickness,eitherunderadoctor’scareoron theirowninitiativeasaself-directedpharmacotherapyforopioid dependence.Whenaskedwhichdrugtheypreferred,61.5%chose buprenorphinecomparedtojust25.6%favoringmethadone(9.3% hadnopreference).Reasonsgivenforthepreferenceof buprenor-phineincluded“lastslonger”,“methadoneisworsetocomeoffof,” and“doesnotgetmehigh”.Asonerespondentnoted:

MethadonemademefeelhighjustlikethemedsIwastrying tocomeoffofwherethesuboxonejustmakesmefeelnormal. OnmethadoneIwantedtosleepallthetimeandthesuboxone Idon’t.AlsoIfeltthemethadoneclinicswerelegaldrugdealers whodidn’tcareaboutanythingbutthemoneyIwaspaying them.My suboxonedoctoractuallycaresaboutmeandhow I’mdoinginmyrecoveryandwhat’sgoingoninmylife. Ourdataalsoindicatethatlackofaccesstoabuprenorphine treatment program could be an important factor in the unsu-pervised useof buprenorphineto treat opioid dependence. For example:

BeforeIstartedmytreatmentprogramIhadafriendgetascript, hesoldmeacouple[buprenorphine]totryandseeiftheywould easemywithdraw.Theydid,sothenextdayIcalledhisdoctor andtriedtogetanappointment,thewaitwasoveramonth. Iendedupgoingintoa traditionaltreatmentprogramabout aweeklater where theytried tojust controlthesymptoms anditwashellformorethan2weeksbeforeIﬁnallycalled thesuboxonedocbackandbasicallybeggedmywayintheir ofﬁce.

3.5. Buprenorphineformulations

Fig. 3A shows the misuse of buprenorphine subdivided by formulation type. In the ﬁrst quarter of 2010 (the earliest date for which data were available), Suboxone®

(buprenor-phine+naloxone)tabletsweretheoverwhelmingchoice,withover 90% of buprenorphineusers in the pastmonth selecting them. Coincidentwiththediscontinuationofthecombinationtabletand theintroductionofthecombinationoralﬁlm,misuseofthetablet decreasedandthemisuseoftheoralﬁlmincreasedsharply.Very substantialincreasesinsingleingredient(e.g.,subutex)tablets mis-usealsooccurred.Buprenorphinepatchesandsolutionswererarely endorsedasdrugsofmisuse.

3.6. Intravenousinjectionofbuprenorphine

Overone-third(34.4%,n=461)ofbuprenorphinemisusersin the SKIP sample indicated they had injected it in the month priortotreatment.Thiswasparticularlyprevalentinthose mis-usingboth prescriptionopioidsand heroin:71.1% ofthosewho injectedbuprenorphinehadalsousedheroininthepast30days. AsshowninFig.3B,singleingredienttabletswerethemost com-monlyinjected(61.8%),butasurprisinglyhighnumberinjectedthe buprenorphine+naloxonetablet(43.6%)ororalﬁlm(32.1%).Given thatnaloxoneshouldhaveantagonizedtheeuphorigeniceffects ofbuprenorphine,providingalowqualityhigh,weaskedRAPID participantshowtheycircumventedthebarriersofthis formula-tion.Participantsreportedanumberofsimpleandeasymethods, unethicaltospecifyinthispaper,whichtheybelievedseparated buprenorphinefromnaloxone,resultinginwhattheytermed“pure buprenorphine”forinjection.

3.7. Othermotivationsforbuprenorphineuse

Nearly70%ofRAPIDfollow-upparticipantsindicatedthatthey hadusedbuprenorphine,foranyreason,atsomepointinthepast. AsshownintheresponsetotheTrue–FalsequestionsinTable2, very few individuals indicated that they used buprenorphine

Table2

Motivationsforpriorbuprenorphineuseoutsideofatreatmentprogram. RAPID (n=106) “IhaveusedBuprenorphineatleastonce....”

Becauseitgivesmeabetterhighthanother prescriptionopioiddrugs

2.9 Becauseitwasmydrugofchoicetogethighwith 3.9 Tomaintainmyabstinencefromotherdrugs 62.9 BecauseIwastryingtoweanmyselfoffdrugsonmy

own

54.8 Toholdmeoverduringwork/socialevents 52.9 BecauseIknewIwouldnothaveaccesstoother

drugsforaperiodoftime

59.6 Becauseitwascheaperthanotherdrugs 15.4 Becausemydrugofchoicetogethighwithwasnot

available

60.4 Becauseitwastheonlydrugthatwasavailable 53.9 Totreatmybodilypainwhenotherdrugswere

unavailable

50.0 Becauseithelpedtreatanxiety,depressionorother

psychologicalsymptoms

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becauseitproducedabetterhighthanotheropioids.Thesedata

areconsistentwithourobservationsinthemuchlargerSKIP

sam-plewhereveryfewindividualslistedbuprenorphineastheirdrug

ofchoice(Table1).Theprimaryreasonsgivenforusing

buprenor-phine seem to be divisible into two main categories: (1) use ofbuprenorphinefortheexpresspurposeoftreating/preventing withdrawal sickness;and (2) as a substitute to gethigh when other,more preferreddrugswereunavailable(Table2).Several responsesto ouropen-ended questionasking whyparticipants usedbuprenorphineillustratetheseofteninterrelatedpoints:

WhenIﬁrsttook[buprenorphine]Iwasmainlyshootingheroin ... andthenusedsubutextokeepmefromgettingsickuntilI’d useagain.Surethethoughtofactuallyusingittogetoffheroin crossedmymindbutIbegantouseittogethighaswell. Ihavetakenbuprenorphineinthepasttoweanoffheroin,both underandnotunderthecareofaphysician.Ialsouseditwhen activelyusingtokeepfromgettingsickifIdidnothaveenough heroin,andasasubstitute.

3.8. Co-morbidityandbuprenorphineuse

Asomewhatsurprisingﬁndingwasthat50%ofbuprenorphine users indicated treating pain wasone of themany reasons for usingit(Table2).Athirdofthesamplealsoindicatedtheyused buprenorphinetohelpwithpsychiatricproblems.Thesepointsare underscoredbythefollowingquotes:

Ihadsomeleftoverfrommydoctor(whoIwasnolongerseeing) andhad somehorriﬁcpaininmybackthatmyNorcodidn’t touchsoIdecidedtogobackanduseSuboxone.

Togethigh,togetoffopioid,tocontrolphysicalpain,tonumb emotionalpain,toavoidwithdrawal,toavoidfacinglifewithout thesafetyofafog,tomakeuncomfortablesituationstolerable, tomake unsafesituationsfeelsafe,Iused itjust likeIused opioid–tofacearealityIhadnoideahowtolivein.

4. Discussion

Our results demonstrate that the misuse of buprenorphine hasincreased substantially in the last 5 years, conﬁrming and extendingearlier reports of such increases (Drug Enforcement Administration,2009;SubstanceAbuseandMentalHealthServices AdministrationandDrugAbuseWarningNetwork(DAWN),2011; UnitedStatesDepartmentofJusticeandNationalDrugIntelligence Center(NDIC),2011;Wishetal.,2012;Lavonasetal.,2014). Cer-tainly,muchofthisincreasehasbeenfueledbyanincreaseinthe therapeuticuseofbuprenorphine,whichwasacceleratedbythe releaseofgenericsin2009.Giventhatithasbeenshownthatthere isadirectcorrelationbetweentheextentoftherapeuticuseand diversiontostreetuse(Ciceroetal.,2007a,b;Lavonasetal.,2014), increasesinbuprenorphinemisusearenotunexpected.However, ourquantitativeandqualitativedatasuggestthatanothermajor reasonbuprenorphinemisusehasincreasedinrecentyearsisdue tothefactthatitservesavarietyoffunctionsfortheopioid-abusing population:togethigh,managewithdrawalsickness,asa substi-tuteformorepreferreddrugs,totreatpain,managepsychiatric issues(i.e.,depression andanxiety)andasaself-directed treat-menttoweanoffothermisusedopioids.Thisisespeciallyevident whenviewedinthecontextoftheriseinheroinuseinthesame timeframewhich,atleastinpart,seemstoberelatedtothe intro-ductionofanabuse-deterrentformulationofOxyContin®_._While

thisgreatlyreducedOxyContin’spopularityasadrugofabuse,it appearstohavebeenfollowedbyaconcomitantincreaseinboth heroinandbuprenorphineuse.Thereasonsbuprenorphinemisuse

hasincreasedsosharplyinthepastﬁveyears,particularlyamong heroinusers,arenotfullyunderstood,butmaybereﬂectiveofthree factors.

First,whileitisclearthatbuprenorphinewasveryrarelythe drugofchoice,ourdataindicatethatitwasanacceptable alterna-tiveforgettinghighwhenmorepreferreddrugswereunavailable (e.g.,cost,lackofsupply),particularlyinintravenousinjectiondrug users.

Second,asidefromtheuseofbuprenorphinetogethigh,itslong half-lifemakesitidealtowardoffopioidwithdrawalsicknessuntil preferreddrugsareavailableoraasaself-directedtreatmentto detoxandweanoffopioids.

Self-medication,ratherthan entryintoatreatmentprogram, maybe related to lack of accessor cost of these programs. In this context,ourstudy participantspreferredbuprenorphineto methadonebymore thana 2:1marginwhen askedspecifically about its efficacy in treating withdrawal sickness. Given that methadoneisreadilyavailableonthestreet,accessisunlikelytobe afactor.Ratheritwouldappearthatmethadonehasmore undesir-ablepropertiessuchassideeffects,socialstigmaassociatedwith stand-alongtreatmentclinicsanddifficultyinweaningoffit.

Finally,ourdataalsosuggestthatpainmanagementand self-medicationofseriouspsychiatricproblemsareclearlymotivating factorsintheuseofbuprenorphine.Over50%ofoursample indi-catedthatbuprenorphinewasusefultohelpthemmanagetheir painandoverathirduseditto“numbtheiremotionalpain.”These datareinforcetheconstructthatsubstanceabuseisadisorderthat rarelyexistsasastand-aloneentity,butoftenrepresentsacoping mechanismtotreatphysicalandemotionalissues.

Why heroin users are more inclined to use buprenorphine thanthosewhoexclusivelyuseprescriptionopioidsisnot com-pletelyclear,butmayberelatedtoourﬁndingthatunadulterated buprenorphineis,ofcourse,availableinthesingleingredienttablet andeasilycanbeextractedfromthemorecommonand acces-sible formulation, buprenorphine+naloxone, making it suitable for injection, a route preferred by many heroin users. In con-trast,mostotheropioidsreadilyavailableonthestreetcontain acetaminophen,whichaddictsgenerallytendtoavoidforsafety concerns(i.e.,liverdamage)andthefactthatacetaminophenmakes thesecompoundsunusableforintravenousinjection(Ciceroetal., 2013).Anadditionalfactorwhichmayfavortheuseof buprenor-phine by those who prefer or useheroin regularly is that the immediacyandintensityofwithdrawalismuchgreaterinheroin addictsthanprescriptiondrugusersand,giventhemedical compli-cationsintheseindividuals,effortstoweanthemselvesoffheroin usingbuprenorphinemaybemoreintensethanforprescription opioidusers.Obviously,thesesuggestionsarespeculativeandmore directstudiesshouldbecarriedouttoexaminethis.

In 2011, the company marketing buprenorphine+naloxone tablets,underthebrandnameSuboxone®_,_argued_that_the_tablet

wasinherentlyunsafeduetopediatricexposureandwithdrewit fromdistribution.Asareplacement,theyintroducedanoralfilmas asaferalternative,whichperhapsnotcoincidentallyalsoextended theirpatentexclusivity.AlthoughLavonasetal.(2014)reported thatthefilmhasreducedchildexposureasreflectedinpoison con-trolcentercalls,ourdataindicateitismisusedasreadilyasthe originalbuprenorphine+naloxoneformulationindicatingthat,at leastintermsofusetogethigh,thedeliverydevice–filmortablets –maybeirrelevantforthoseseekingbuprenorphine.Thelarger questioniswhethertheadditionofnaloxonetothebuprenorphine inthecombinationproductactuallydiscouragedusetogethigh. Ontheonehand,thosewhoinjecteditdidextractthe buprenor-phinefromthecombinationproducttoremovethenaloxonewhich apparentlybluntedtheeuphoriceffect.However,oralusersdidnot bothertogothroughthestepsofextraction,andapparentlydidget someeuphoriceffectalbeitonelikelylessinquality.

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Therearelimitationstoourstudywhichneedtobenoted.A treatmentsamplemaynotberepresentativeofthoseusingopioids “recreationally”oroftheracialandgendercompositionofallopioid users.Inaddition,likeallself-administeredsurveys,therearethe usualproblemsinvolvingambiguousresponseandtheinabilityto askfollow-upquestionsforclariﬁcation.Mitigatingthisproblem, tosomeextent,isthequalitativedataprovidedbyourinterviews withstudyparticipantswhichallowedmuchmorein-depth anal-ysisofresponsesandinformationnotcoveredintheSKIPsurvey. Finally,theabsenceofexposuredatadoesnotallowanestimate ofthecorrelationbetweentherapeuticexposureandabuseinthe currentpaper,whichcouldbeuseful,butthistopichasbeen cov-eredin ourearlierwork(Lavonaset al.,2014), which supports theassociationofincreasesinmisuseasafunctionofincreases inexposure.

Roleoffundingsource

The national data were collected as part of the Survey of Key Informants’ Patients (SKIP) Program, a component of the RADARS® _(Researched _Misuse, _Diversion_and _{Addiction-Related}

Surveillance) System, funded through an unrestricted research grantsponsoredbyDenverHealthandHospitalAuthority(DHHA), which collects subscription fees from14 pharmaceuticalﬁrms. Theinterview-driven Research andPatients InteractingDirectly (RAPID)ProgramreceivedsupportfrombothDHHAand private universityfunds.

Contributors

AuthorCicerodesignedthestudyandwrotetheprotocol.Author Ellisperformeddataanalysisandresearchcoordination.Allauthors participatedinreviewingthedataanddraftingthemanuscript.

Conﬂictofintereststatement

AuthorsCiceroandSurrattserveasconsultantsontheScientific AdvisoryBoardofthenon-profitpost-marketingsurveillance sys-tem,RADARS®_._All_other_authors_declare_they_have_no_conflict_of

interest.

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