ORIGINALRESEARCHARTICLEDrugsRD2011;11(3):259-275
ª2011Websteretal.,publisherandlicenseeAdisDataInformationBV.Thisisanopenaccessarticlepublishedunder
thetermsoftheCreativeCommonsLicense‘‘Attribution-NonCommercial-NoDerivative3.0’’(
andreproduction,providedtheoriginalworkisproperlycitedandnotaltered.
ImpactofIntravenousNaltrexoneonIntravenousMorphine-InducedHigh,
DrugLiking,andEuphoricEffectsinExperienced,NondependentMaleOpioidUsers
LynnR.Webster,1FranklinK.Johnson,2JosephStauffer,2,3BeatriceSetnik2andSabrinaCiric4
1LifetreeClinicalResearch,SaltLakeCity,UT,USA
2AlpharmaPharmaceuticalsLLC,awhollyownedsubsidiaryofKingPharmaceuticalsInc.,Bridgewater,NJ,USA,acquiredby PfizerInc.inMarch2011
3JohnsHopkinsUniversitySchoolofMedicine, Baltimore,MD,USA
4Celerion,Montreal,QC,Canada
AbstractBackground:Opioidanalgesicscanbeabusedbycrushingfollowed by solu-bilizationandintravenousinjectiontoattainrapidabsorption.Morphinesulfateandnaltrexonehydrochlorideextendedreleasecapsules(EMBEDA®,
MS-sNT),indicatedformanagementofchronic,moderatetoseverepain,containpelletsofmorphinesulfatewithasequesterednaltrexonecore.Shouldproducttamperingbycrushingoccur,thesequesterednaltrexoneisintendedforreleasetoreducemorphine-inducedsubjectiveeffects.
Objective:Thisstudycomparedself-reportsofhigh,euphoria, and drug-likingeffectsofintravenousmorphinealoneversusintravenousmorphinecombinedwithnaltrexoneinaclinicalsimulationofintravenousabuseofcrushedMS-sNT.
Methods:Thissingle-center,randomized,double-blind,crossoverstudychar-acterizedsubjectiveeffectsofnaltrexoneadministeredintravenouslyatthesameratiotomorphinepresentinMS-sNT.Subjectsweremaleandhadusedprescriptionopioidsfiveormoretimeswithinthe previous12months toget‘high’butwerenotphysicallydependentonopioids.TheprimaryoutcomewastheresponsetotheDrugEffectsQuestionnaire(DEQ)question#5,‘‘Howhighareyounow?’’(100mmVisualAnalogScale[VAS]).Thesecondary
outcomewastheresponsetoaCole/AddictionResearchCenterInventory
(ARCI)Stimulation-Euphoriamodifiedscale.AdditionaloutcomesincludedresponsetoVASdrugliking,theremainingDEQquestions,andpupillometry.Results: Administration of intravenous naltrexone following intravenous
morphinediminishedmeanhigh(29.8vs85.2mm),Cole/ARCIStimulation-
Euphoria(13.7vs27.8mm),anddrug-liking(38.9vs81.4mm)scores(all
p0.0001)comparedwithintravenousmorphinealone.Noseriousadverse
eventsoccurredasaresultofthetestedratioofnaltrexonetomorphine.
Conclusions:Resultsinthisstudypopulationsuggestthatnaltrexoneaddedtomorphineinthe4%ratiowithinMS-sNTmitigatesthehigh,euphoria,and
druglikingofmorphinealone,potentiallyreducingtheattractivenessforproducttampering.Assessmentofthetrueclinicalsignificanceofthesefindingswill requirefurther study.
Introduction
Opioidanalgesicsareanimportantcomponentofcomprehensivemanagementplansforchronicpaininappropriatelyselectedandmonitoredpatients.Extended-releaseopioidformulationshaveenabledpatientstoattainaround-the-clockpainreliefwithlessfrequentdosingthanwithimmediate-releaseproducts;however,theyarevulnerabletotamperingbyabuserswishingtogainaccesstothelargersupplyofopioidwithineachdoseunit.[1,2]Forexample,someprescriptionopioidscanbeabusedbyinjectionof solubilizedcrushedproducttoachievetherapidabsorptionandhighopioidplasmalevelsassociatedwitha‘rush’or‘high.’[2]
Abuseofprescriptiondrugs,includingopioidanalgesics,hasincreasedsubstantiallysincethemid-1990s,[3-8]creatinganeedforproductsthatarealessinvitingtargetforabuse.[9-13]AmongUSDepartmentofHealthandHumanServices,FDA,CenterforDrugEvaluationandResearchrecommendationsisthecallfordrugmanufac-turersto‘‘modifyopioidpainkillerssothatthey
are moredifficult totamper withand/orcombine
them withagentsthatblock theeffect of theopioidifitisdissolvedandinjected.’’[14-16]Nal-trexonehydrochlorideisanorallyavailableopioidantagonistthatcompetitivelybindstom-opioid
receptors and reduces the euphoric effects of
m-opioidagonists,suchasmorphine.[17]Naltrexone,administeredgenerallyatdosesof50–100mg/dayfororaladministrationor380mg/monthforintra-
muscularadministration,isusedasanadjunctivetreatmentofalcoholismandforblockadeoftheeffectsof opioids.[18,19]Naltrexoneis also presentinamuchsmalleramountasasequesteredcomponentintheindividualpelletsinmorphinesulfateand
naltrexonehydrochlorideextendedreleasecap-sules(EMBEDA®,MS-sNT,formerlyALO-01).
MS-sNTisindicatedforthemanagementofchronic,moderatetoseverepain.[20]Theratioofmorphinesulfatetonaltrexonehydrochloridein
MS-sNTis100:4.[20] Thus,a30mgcapsuleof
MS-sNTcontains30mgofmorphinesulfateand
1.2mgofsequesterednaltrexone,anamountmuchlowerthantheaforementionedclinicaldosesofnaltrexone.
ThesequesteredcoreofnaltrexoneinMS-sNTisintendedforreleaseonlyuponproducttam-pering(crushing)toreducemorphine-inducedsubjectiveeffects.[20]PreviouspharmacokineticstudieshaddemonstratedthatwhenpelletsfromMS-sNTwerecrushedandtakenorally,boththemorphine and the naltrexonewerefully bioavail-ablewhencomparedwiththeequivalentamountofmorphineandnaltrexoneinsolution.[21,22]Resultsofanoralabuseliabilitystudyin32rec-reationaldrugusersindicatedthatMS-sNTcap-sules,takenorallyeitherwholeorwithliquidafterthepellets werecrushed,were significantlyless de-sirablethanmorphinesulfatesolution,aseval-
uatedusingseveralsubjectivemeasuresincludingCole/AddictionResearchCenterInventory(ARCI)
Stimulation-Euphoria,[23]drugliking,andsub-jectivemonetaryvalueofdrug.[21]Overall,87.5%
ofsubjectsintheoralstudyexperiencedsomedegreeofreduceddruglikingafterreceivingthecrushedMS-sNTcomparedwithmorphinesul-fatesolution.[20]
ThepurposeofthestudypresentedherewastoassesstheabuseliabilityofMS-sNTiftheproductwereabusedintravenously.Sincetheexcipientsinthecrushedoralformulationcouldcauseundueharmifinjectedintravenously,aclinicalsimula-tionwasperformed.Therelativehigh,euphoric,
anddrug-likingeffectsof30mgofintravenousmorphine alone versus 30mg of intravenous
morphinecombinedwith1.2mgofintravenousnaltrexone(100:4morphinesulfatetonaltrex-
onehydrochlorideratiocontainedinMS-sNTcapsules)wereassessedin recreationalopioidusers.ResultsmayfurtheraidincharacterizingtheabuseliabilityofMS-sNTandthepotentialtoreducedesirabilityforproducttampering.
Methods
Participants
Subjects were menaged 18–50 years whohadusedprescriptionopioidstoachievea‘high’atleastfivetimesinthelast12months,butwerenotphysicallyopioiddependent.Theywererecrea-tionalopioidabuserswhoonlyusedopioidsoral-lyorsnorted.Themostcommonlyabusedopioids
among thesubjectswereconsistentwith nationaldata[24]andincludedhydrocodone/acetaminophen,
oxycodoneimmediatereleaseandextendedre-lease,andmorphine. Subjectswhousedmultipledrugsexpressedapreferenceforopioids.Thesub-jectswererecruitedfromthedatabaseofLifetreeClinicalResearch(SaltLakeCity,UT,USA)andwerecompensatedfortheirtimeduringpartic-ipationinthestudy.
Subjectswereingenerallygoodhealthasas-sessedbymedicalhistoryandphysicalexamina-tion,laboratorytests,andECG,andhadnegativeurinedrugscreensforamphetamines,barbitu-rates,benzodiazepines,cocaine,andopioidsuponpresentationforadmissiontotheclinic.Subjectswithahistoryofsignificantneurologic,hepatic,renal,endocrine,cardiovascular,gastrointestinal,pulmonary,ormetabolicdiseasewereexcluded,aswerethosecurrentlyintreatmentforsubstanceabuseorwhohadcompletedasubstanceabuseprogramwithintheprevious90days.
Subjectscouldnothaveused,orhaveintendedtouse,anyprescriptionorover-the-counter(OTC)medicationsthatcouldinterferewiththeevaluationofmedicationduringthestudy.Prescriptionmedi-cationscouldnothavebeenusedwithin14daysofdosingandOTCmedicationscouldnothavebeenusedwithin48hoursofdosing.Subjectscouldnot
ingestalcohol,grapefruit,orgrapefruitjuicewithin48hoursofdosingorduringthestudy.
StudyDesign
Thissingle-center,randomized,double-blind,crossoverstudyincludedthefollowingthreephases:
(i)naloxonechallenge;(ii)drugdiscrimination;and
(iii)treatment.Itwasconducted inaccordance withthecurrentFDAregulations,International Con-ferenceonHarmonisationguidelines,GoodClin-icalPracticestandards, theDeclarationofHelsinki,andlocalethicalandlegalrequirements.[25,26]
NaloxoneChallengePhase
Analoxonechallengewasperformedonthedayofadmission(day0)toruleoutsubjectswhowerephysicallydependentonopioids.Subjectswereadministered0.1mgofintravenousnalox-one;iftherewerenosignsofopioidwithdrawalwithin30seconds,anadditional0.3mgofintra-venousnaloxonewasadministeredandsubjectswereobservedforwithdrawalsymptomsfor20min-utes.Subjectswereterminatedfromthestudyattheendofthenaloxonechallengephaseiftheyexhibitedsignsof opioidwithdrawal.
DrugDiscriminationPhase
Subjectswererandomizedtoreceiveonein-travenousinjectionofeither10mgofmorphineorplaceboon inpatientdays1and3 inadouble-blind,crossoverfashion,witha1-daywashoutonday2.Abilitytodistinguishmorphinefromplacebowasassessed bytheinvestigatorbasedon subjectresponsestoaDrugEffectsQuestionnaire(DEQ;
anine-itemquestionnairewitha100mmvisualanalogscale[VAS];0=none,100=extreme)[27]and the Cole/ARCI Stimulation-Euphoria modi-
fiedscale,descriptionfollowingintheStudyEndpointssection,atdesignatedtimepointsfol-lowingeachdose.[23,28]Attheconclusionofthedrugdiscriminationphase,theblindwasbroken.Theinvestigatordeterminedthesubjectswhowereabletodiscriminatebetweenmorphineandplaceboand,further,toreportamorepositiveoverall responsetomorphineversusplacebo, usingtheresponsetotheaforementionedstudyend-point measures,alongwithclinicaljudgment.
TreatmentPhase
Aftera1-daywashout(day4),subjectsenteredthetreatmentphase(days5–19)consisting ofthreetreatmentperiods.Duringeachtreatmentperiod,subjectsreceivedoneofthefollowingdosese-quences:(i)asingle30mgintravenousbolusofmorphineimmediatelyfollowedbyasingleintra-venousbolusofnaltrexoneplacebo;(ii)asingle30mgintravenousbolusofmorphineimmediatelyfollowedbyasingle1.2mgintravenousbolusofnaltrexone;or(iii)asingleintravenousbolusofmorphineplaceboimmediatelyfollowedbyasingleintravenousbolusofnaltrexoneplacebo.
Dosingswerespaced30secondsapart.There
wasa6-dayoutpatientwashoutbetweentreat-ments.Subjects wererequiredtohavea negativescreenfordrugsandalcoholonreadmissionforeachtreatmentperiod.
StudyTreatments
LifetreeClinicalResearchsuppliedstudytreat-mentsascommerciallyavailabledrugproductsforintravenous injection.Subjects,investigators,andthoseassessingtheoutcomeswereblindedtothestudydrug.Subjectswereassignedtotreat-mentinorderofenrollmentaccordingtoaran-domizationschedulegeneratedbythe statisticianandstoredinasecuredlocation.Thepharmacistwasresponsibleforcompletingamasterdrugaccountabilitylogdocumentinglotnumber,date,andtimeofdrugpreparation,anddateandtimeofdeliverytothestudycenter.Treatmentswereprovidedtostudycentersinprefilledsyringespackagedandlabeledwithprotocolnumber,date,andsubjectinitialsforthedrugdiscrimina-tionandtreatmentphases.AbbottLaboratories(NorthChicago,IL,USA)manufacturedthemorphinesulfate,KingPharmaceuticalsInc.(Bridgewater, NJ, USA) provided the naltrex-
onepowder,andBaxter(Deerfield,IL,USA)manufacturedthesodiumchloride0.9%sterile
diluent.
StudyEndpoints
Studyassessmentsincludedpharmacodynamic,pharmacokinetic,andsafetyendpoints.Ondos-
ingdaysduringthetreatmentphase,bloodsamplesforpharmacokineticmeasuresweredrawnatbaseline(beforedosing)andatsched-uledtimepoints(5minutesto24hourspost-dose).Pharmacodynamicoutcomeswereassessedimmediatelyfollowingeachpharmacokineticsampling.
The primary pharmacodynamic endpoint ofthisstudywasassessedbytheresponsetoDEQ
question#5,‘‘Howhighareyounow?’’[27] The
DEQcontainednineitemsorsubscales,eachpresentedasa100mmVAS.TheDEQquestionswereasfollows:(1)‘‘Doyoufeelanydrugef-fects?’’;(2)‘‘Doesthedrughavegoodeffects?’’;
(3)‘‘Doesthedrughavebadeffects?’’;(4)‘‘Doyoulikethedrug?’’;(5)‘‘Howhighareyounow?’’;(6)‘‘Doesthedrugmakeyoufeelsick?’’;
(7)‘‘Doyouhavenausea?’’;(8)‘‘Doesthedrugmakeyousleepy?’’;and(9)‘‘Doesthedrugmakeyoudizzy?’’Subjectswerefamiliarwithusingthe
DEQandtheCole/ARCIfromusing thesescales
duringthedrugdiscriminationphase.Thesecondaryendpointwasresponsetotheques-
tions on the Cole/ARCI Stimulation-Euphoria
subscalewhichconsistsof15statementsthatsub-jectsratedusinga4-pointscale(0–3,amod-
ificationofthe7-pointversion),where0=false,1=morefalsethantrue,2=moretruethanfalse,and 3=true. The total score is calculated by
addingtheindividualscores(maximumpos-sibletotalscore=45).[23,28]Sincethedrug-liking
VAShasbeenusedinotherstudiesasamea-
sureofdrugattractiveness,[21]datafromDEQquestion#4,‘‘Doyoulikethedrug?’’arereport-
edhere.DatafromtheremainingDEQsub-scales(#1–3and#6–9)andpupillometryarealso
summarized.
For pupillometry, lighting was controlledusingalightmetertoensurethatlightwasbetween
3.6luxand4.4lux.Pupildiameterwasmea-suredusingapupildensitometer,[29]withsmallervalues(pupillarymiosisorconstriction)indi-catingagreatermorphineeffect.End-tidalcar-bondioxidelevels,measuredbynoninvasivecapnography,wereassessednotasasafetyend-pointbutasanadditionalexploratorypharma-codynamicendpointandarenotincludedinthisreport.
AnalyticalMethods
Bloodsamples(approximately10mL)forphar-macokineticanalysiswerecollectedinVacutainer®
tubescontainingK2-ethylenediaminetetraaceticacidforassayofplasmamorphine,naltrexone,and6-b-naltrexol(themajornaltrexonemetabo-lite)concentrations.Immediatelyaftercollection,thetubesweregentlyinvertedtoensuremixingoftheanticoagulantwiththeblood;sampleswerepooled,splitintotwoaliquots,andkeptonice.Within45minutesofcollection,sampleswere
centrifugedat4°Cfor10minutesat3000revolu-
tionsperminute.Harvestedplasma(within30min-
utesofcentrifugation)wasstoredinanuprightpositionat-20–10°Cor colderin polypropylene
tubesuntilanalysis.Twocompletesetsoffrozensamples(aduplicatesetforbackup)wereprepared.Onecompletesetofsampleswascarefullypackedinapolystyreneshipperwithdryice,tightlysealed,andshippedviaovernightcourierto MDSPharmaServices(nowCelerion)[Lincoln,NE,USA]foranalysis.Theduplicatesetof sampleswas storedatLifetreeClinicalResearchuntilthesponsorprovideddirectionfordisposal.ConcentrationsoriginallycalculatedinconventionalunitswereconvertedtoSIunitstoallowdirectcomparisonofnumberofmoleculesofmorphineversusnaltrexoneand
6-b-naltrexol.Themolecularweightsusedforthecalculationsweremorphinemonomer285.34,naltrexone341.4,and6-b-naltrexol343.42(e.g.
toconvert50ng/mLmorphinetonmol/L,divide50ng/mL/molecularweightandmultiplyby1000,whichyields175nmol/L).Plasmaconcentrations
oftheanalytesweremeasuredusingvalidatedliquidchromatography-tandemmassspectrome-trywiththefollowinganalyticalranges:0.876–
175nmol/Lformorphine,0.0117–1.465nmol/Lfornaltrexone,and0.0116–4.66nmol/Lfor6-b-naltrexol. Samples with 0.0116nmol/L
6-b-naltrexolwerere-assayedwithamoresensi-tivemethod(range0.00146–0.0728nmol/L).
SafetyOutcomes
Safetywasevaluatedbyvitalsigns,pulseoxim-etry,physicalexaminations,ECGs,clinicallab-oratorytests,andadverseevents(AEs).Allsafety
analyseswerebasedonthedouble-blindsafetypopulationthatincludedallrandomizedsubjectswhoreceivedoneormoredosesofstudymed-ication(intravenousmorphine,intravenousnal-trexone,orintravenousplacebo)inthetreatmentphase.
StatisticalAnalysis
Samplesizewasdeterminedusingexperiencewithstudiesofsimilardesignthatevaluateddif-ferencesbetweenthetwoactivetreatments.Itwasexpectedthatapproximately76subjectswouldbescreened,with40participatinginthenaloxonechallenge,34continuingintothedrugdiscrim-inationphase,and24enteringthetreatmentphase.
Foreachsubjectinthepharmacodynamicpop-ulation(receivedoneormorestudytreatmentsinthedouble-blindtreatmentphaseandprovidedoneormoresubsequentpharmacodynamicassess-mentsduringthatphase),themaximum-effectscorewithinaperiod(Emax)andtimetomaximumeffect(TEmax)wereidentifiedforeachtreatmentperiod.Eachpharmacodynamicassessmentwassummarizedbytreatmentusingdescriptivesta-tisticsateachtimepoint.Inaddition,themeanforeachpharmacodynamicassessmentovertimewasplottedforeachtreatment.
WinNonlin® version 5.1 (Pharsight Corp.,
MountainView,CA,USA)wasusedtocalculateindividualsubjectpharmacodynamicoutcomes.All other analyses and tabulations were per-
formedusingSAS®version9.1.3(SASInstitute
Inc.,Cary,NC,USA)onaPCplatform.Eachpharmacodynamicassessmentwasanalyzedandp-valuesdeterminedusingalinearmixedmodel(PROCMIXED,SAS)withfixedeffectsforse-quence,period,andtreatmentarm,andarandomeffectforsubjectnestedinsequence.AdjustmentsformultiplecomparisonsweremadeusingtheBenjaminiandHochberg[30]methodinSASPROCMULTITEST.Leastsquares(LS)means
alongwith95%confidenceintervalswerepro-
vided foreachtreatmentarmand forall pairwisecomparisonsbetweentreatmentarms.TheEmaxwasusedforpharmacodynamicanalyses. TheEmax valueswereexpectedtobelog-normally
distributedandweretransformedpriortoanalysisbytakingthenaturallogarithm.Zerovalueswerereplacedwith0.0001asanarbitrarysmallvaluebecausealogtransformationisnotpossiblewithzerovalues.Descriptivestatisticsaswellasesti-
mates of geometric LS means and 95%con-
fidenceintervalswerecalculated.
The pharmacokinetic analyses were basedon all available post-dosing pharmacokinetic
data(n=28).Foreachsubject,thepharmaco-
kineticassessmentsweredeterminedusinganon-compartmentalapproachforallparametersinPhASTversion2.3-001software(1999;PhoenixAutomatedStatisticsandTabulation;manufac-turedbyPhoenixInternationalLifeSciences,locatedinMontreal,QC,Canada),exceptcon-centrationattime0[C0];C0wasestimatedwith
mentphase)included27subjects.Onesubjectwhohadcompletedthemorphineandtheplace-boarmswasdiscontinuedfornoncomplianceandhisdatawereexcludedfromtheevaluablepharmacodynamicpopulation.Asecondsubject,whowasincludedintheevaluablepharmacody-namicpopulation,wasdiscontinuedbeforecom-pletingplacebotreatmentduetoanAE(atoothinfectionunrelatedtostudydrug).
Inthesafetypopulation,theagerangewas18–36years(mean–standarddeviation:23.8–
4.5 years). Twenty-five subjects (89.3%) were
White,two wereAfricanAmerican,andonewasAsian.
Morphine
Morphine naltrexone
ADAPTIIRelease4(1997,BiomedicalSimula-
tionsResource,UniversityofSouthernCalifornia,LosAngeles,CA,USA).Summarystatisticsforplasmaconcentrationsofmorphine,naltrexone,and6-b-naltrexolwerecalculatedbytimeandtreatment.Fordataplotting,plasmaconcentra-tionvaluesthatwerebelowthelimitofquantifi-cation(BLQ)embeddedbetweentwomeasurableconcentrationsweresettomissing;however,BLQvaluesoccurringafterthelastmeasurableplasmaconcentrationweresettozero.Forthe
purposeofthecompartmentalpharmacokineticanalysis(C0calculations),allBLQvaluesoccur-ringafterthefirstmeasurableplasmaconcen-trationweresettomissing.
Results
Participants
Thestudywasconductedbetween20September2007and21November2007.Ofthe41subjectswhowerescreened,29wereenrolled.Onesubjectwhofailedthedrugdiscriminationphasewas
a
100
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0
b
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Placebo
0 1 2 3 4 5 6 7 8 9 10 11 12
discontinued.All28subjectsreceivingoneor
04812
162024
moredosesofstudydrugduringthedouble-blind
treatmentphasewereincludedinthepharmaco-dynamicandsafetypopulations.Theevaluablepharmacodynamicpopulation(completedthemorphineplusnaltrexonetreatmentandoneormoreothertreatmentsinthedouble-blindtreat-
Time post-dose (h)
Fig.1.Data(mean–standarddeviation)areshownfortheDrugEffectsQuestionnaire(DEQ)question#5,‘‘Howhighareyounow?’’afterintravenousadministrationofmorphine(n=28),morphineplusnaltrexone(n=27),andplacebo(n=27)asafunctionoftime(ordinate)
sincedrugadministrationinthepharmacodynamicpopulation.Datafor(a)12hoursand(b)24hourspost-dose.VAS=visualanalogscale.
TableI.Pharmacodynamicoutcomes
ParameterPlacebo(n=26)Morphine+naltrexone(n=27)Morphine(n=27)
DEQ#5:‘‘Howhighareyounow?’’(primaryoutcomemeasure)
Emax(mm)
meana–SD0.0–0.029.8–26.4b,c85.2–12.9c
range0–00–93.055.0–100.0
TEmax(h)
median0.00.10.1
range0–00–6.00.1–0.8
AUE2(h mm)
meana–SD0.0–0.022.4–28.2129.3–37.2
range0–00–115.532.3–191.3
AUE8(h mm)
meana–SD0.0–0.041.2–40.4315.0–160.5
range0–00–142.545.8–621.1
Cole/ARCIStimulation-Euphoria(secondaryoutcomemeasure)
Emax(mm)
meana–SD1.3–3.113.7–9.5b,c27.8–11.2c
range0–15.00–39.04.0–45.0
TEmax(h)
median0.00.10.3
range0–24.00–24.00.1–2.5
AUE2(mm unit)
meana–SD-0.2 –1.012.9–15.043.5–23.1
range-4.7to0.6-5.0to61.90.5–85.5
AUE8(mm unit)
meana–SD-0.9 –3.131.3–33.5118.3–73.6
range-14.7to0.1-21.5to113.40.5–250.1
DEQ#4:drugliking(additionaloutcomemeasure)
Emax(mm)
AUE2(mm.unit)
aArithmeticmean.
bp0.0001vsmorphine.c p0.0001vsplacebo.
ARCI=AddictionResearchCenterInventory;AUEx=areaundertheeffectcurvefromtime0toxhours;DEQ=DrugEffectsQuestionnaire;
Emax=maximumeffect;TEmax=timetomaximumeffect.
Morphine
Morphine naltrexone
aPlacebo
45
40
35
30
25
20
15
10
5
0
0 1 2 3 4 5 6 7 8 9 10 11 12
b
45
40
35
30
25
curve(AUE)wasgreaterwhenmorphinewasadministeredalonethanwhencoadministeredwithnaltrexone(seetableI).Themediandiffer-
enceinDEQ#5Emax scorebetweenmorphine
andmorphineplusnaltrexonewas62.0mm(range,7.0–93.0mm).Atmaximumeffect,only2of27
(7.4%)subjectsexperiencedlessthana10-point
difference.
TheresultsfortheCole/ARCIStimulation-
Euphoriasubscaleassessments(seetableIandfigure2)reinforcethefindingsoftheprimarypharmacodynamicassessmentof‘high’.MedianTEmaxformorphineplusnaltrexonewas0.1hourandformorphinewas0.3hours.ArithmeticmeanEmaxscoresweresignificantlygreaterformor-phinethanformorphineplusnaltrexoneorplacebo
Morphine
Morphine naltrexone
20
15
10
5
0
04812
162024
a
100
90
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60
50
40
30
Placebo
Time post-dose (h)
Fig.2.Data(mean–standarddeviation)areshownfortheCole/AddictionResearchCenterInventory(ARCI)Stimulation-Euphoriasubscale scores after intravenous administration of morphine
(n=28),morphineplusnaltrexone(n=27),andplacebo(n=27)as
afunctionoftime(ordinate)sincedrugadministrationinthephar-macodynamicpopulation.Datafor(a)12hoursand(b)24hourspost-dose.
PharmacodynamicOutcomes
MeanDEQ#5(‘‘Howhighareyounow?’’)valuesovertimeareillustratedinfigure1.ThemedianTEmaxwas6minutes(0.1hour)forthemorphineandmorphineplus naltrexonetreat-ments,and0minutesforplacebo(seetableI).
Thearithmeticmean(–standarddeviation)score
20
10
0
b
100
90
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60
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40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12
fortheEmax wassignificantlygreaterformor- / 0 / 4 / 81216 / 20 / 24phinethanmorphineplusnaltrexoneorplacebo / Time post-dose (h)
(85.2–12.9mmvs29.8–26.4mmvs0.0–0.0mm,
respectively;p0.0001).Thisdifferencewassta-
tisticallysignificantacrossallthreetreatmentgroupsaswellasbetweentreatmentgroupsinpairwisecomparisons.Meanareaundertheeffect
Fig.3.Data(mean–standarddeviation)areshownfortheDrugEffectsQuestionnaire(DEQ)question#4,‘‘Doyoulikethedrug?’’afterintravenousadministrationofmorphine(n=28),morphineplusnal-trexone(n=27), andplacebo(n=27)asa function oftime(ordinate)
sincedrugadministrationinthepharmacodynamicpopulation.Datafor(a)12hoursand(b)24hourspost-dose.VAS=visualanalogscale.
TableII.Exploratoryoutcome:pupillometry
AUE2(h mm)
meana–SD0.0–0.9-1.3–1.5-5.0–1.8
range-2.0to1.4-3.4to2.3-8.1to-1.4AUE8(h mm)
meana–SD0.3–4.8-8.5–6.8-18.8–8.0
range-10.6to9.1-19.1to6.4-32.7to-4.7a Arithmeticmean.
b p0.0001vsmorphine.c p0.0001vsplacebo.
AUEx=areaundertheeffectcurvefromtime0toxhours;Emin=minimumpupildiameter(maximumeffect);SD=standarddeviation;
TEmin=timetominimumpupildiameter(maximumeffect).
(27.8mmvs 13.7mm vs 1.3mm, respectively;p0.0001).MeanAUE wasgreaterwhen mor-
phinewasadministeredalonethanwhenad-ministeredwithnaltrexone(seetableI).Overall,
71%ofsubjectsreportedareductionineuphoria
withmorphineplusnaltrexonecomparedwithmorphinealone.[20]
ArithmeticmeanvaluesovertimeforDEQquestion#4, ‘‘Do you likethe drug?’’areshown
infigure3.MedianTEmaxformorphineplusnaltrexonewas0.1hourandformorphinewas
0.3hours.ArithmeticmeanscoreforEmaxfordruglikingwassignificantlygreaterformorphinethanmorphineplusnaltrexoneorplacebo(81.4mm
vs38.9mmvs0.0mm,respectively; p0.0001)
andmeanAUEwasgreaterwhenmorphinewasadministeredalonethanwhenadministeredwithnaltrexone (seetableI).
ForeachoftheremainingsevenDEQques-tions,theEmaxformorphinewasgreaterthanformorphineplusnaltrexoneandplacebo.Statisti-callysignificantgeometricmeandifferencesin
Emaxweredetectedacrossallthreetreatments(p0.0001).Forthe‘desirable’(positivesubjec-tiveeffects)DEQoutcomesof#1(drugeffects),
#2(feelinggoodeffects),and#4(likingthedrug),
themedianTEmaxwassimilarorslightlyshorterformorphinethanmorphineplusnaltrexone.MedianTEmaxvaluesforthe‘undesirable’(neg-
ativesubjectiveeffects)DEQoutcomesof#3(badeffects),#6(feelingsick),#7(havingnausea),#8(feelingsleepy),and#9 (feelingdizzy)wereearlier
for morphine plus naltrexonethanfor morphine.[21]
PupillometryAnalysis
Thepeakmorphinedrugeffectwasobservedwhenthepupildiameterwassmallest(indicativeofmorphine-inducedconstriction).MinimumpupildiameterisnotedasEmin,thebaselineforcom-parisonwhennotingincreaseinpupilsize.Fol-lowingintravenousadministrationofmorphinealone,themeanEmin(2.4mm)wassignificantlyreducedrelativetoplacebo(4.4mm)andmor-
phineplusnaltrexone(3.4mm)[p0.0001for
bothcomparisons].Mediantimetoreachthisminimumpupildiameter(TEmin)aftermorphinealonewasrapid(0.8hours)comparedwithpla-cebo(3.0hours)andmorphineplusnaltrexone(4.0hours).Themioticeffectwastemporallyde-layedrelativetomorphinealonewhenmorphinewasadministeredintravenouslywithnaltrexone.
MeanAUEfromtime0to8hoursformiosiswassmaller(-18.8h mmvs-8.5h mm)formorphine
alonerelativetomorphineplusnaltrexoneandplacebo(seetable IIandfigure4).
Pharmacokinetics
Plasmamorphineconcentration-timeprofilesandpharmacokineticparametersweresimilarforintravenousmorphinealonecomparedwithconcomitantintravenousnaltrexoneadministra-tion,includingextentofexposure(areaunderthe
Morphine
Morphine naltrexone
plasmadrugconcentration-timecurve)atthemeasuredtimepoints(seetableIIIandfigure5).Thissimilaritydemonstratedthatthecoadmin-istrationofnaltrexoneandmorphinehadnoap-parenteffectonthemorphinepharmacokineticswhen compared withmorphineadministered alone.Followingsingle intravenous bolus administrations,
morphine,naltrexone,and6-b-naltrexolreachedpeakconcentrationsimmediatelyafterdosingandthendecreasedinamulti-exponentialmanner(seefigure5).Pharmacokineticassessmentsofmor-phine,naltrexone,and6-b-naltrexolareshownintableIII.
a
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
0
b
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
Placebo
1 2 3 4 5 6 7 8 9 10 11 12
Pharmacokinetic-Pharmacodynamic
Relationship
Basedonadditionalexploratoryanalysis,figure6ashowsahysteresisplotofpercentagechangeineuphoriaabatementversusmeanplasma
naltrexoneconcentration using theCole/ARCI
Stimulation-Euphoriasubscaleovertime.Subjectswhodidnotexperienceeuphoria(18.5%,5of27)
werenotincludedintheanalysis.Theplasmanal-trexonerapidlyreacheditspeaklevel(21.4nmol/L)
by 5minutesandthendecreased.Thisisrelatedtoa median63%abatementofthemorphine-induced
euphoria.Thenaltrexone-inducedeuphoriaabate-mentcontinuedandreachedamaximumof80%by
30minutes.Figure6bshowstheincreaseinpupilsize (relative tothatwithmorphine)plotted againstplasmanaltrexoneconcentrationovertime.Themeannaltrexonepeakplasmalevelat5minutesisrelatedtoa2mmincreaseinpupilsizeshowingtheblockingofthemorphine-inducedpupilconstric-tion.Thiseffectwasmaintaineduntil45minutesandgraduallydecreasedinrelationtothelowerplasmanaltrexone levelsover time.
Safety
Inthisstudy,21of28(75%)subjectsexperi-encedatotalof69AEs.Nineteen(67.9%)sub-
jectsexperienced50oftheseAEswhentreated
0 2 4 6 8 10
12 14 16 18 20 22 24
withmorphinealone.Bycontrast,9of27(33.3%)
Time post-dose (h)
Fig.4.Pupillometrydata(mean–standarddeviation)overtime(phar-macodynamicpopulation).Datafor(a)12hoursand(b)24hourspost-dose.
subjectsexperienced17AEsduringtreatmentwithmorphineplusnaltrexoneandtwo(7.4%)
subjectstakingplaceboreportedtwoevents(seetableIV).ThemostfrequentlyreportedAEswere
TableIII.Summaryofpharmacokineticassessments
ParameterMorphinealone(n=28)Morphine+naltrexone(n=26)
C0(nmol/L)aAUC2(nmol.h/L)AUC8(nmol.h/L)
AUCt(nmol h/L)
a
AUC¥(nmol h/L)
t½(h)bVss(L)bCLt (L/h)b
aGeometricmean(CV%).
bArithmeticmean(SD).
AUCt=areaundertheplasmaconcentrationcurveattimet,wheretiseither12hoursor24hoursdependingonthetimeoflastmeasureableconcentration;AUC¥=areaundertheplasmadrugconcentration-timecurvefromtimezerotoinfinity;AUCx=areaundertheplasmadrugconcentration-timecurvefrom0toxhours;C0=anticipatedinitialplasmadrugconcentration;CLt=totalplasmaclearance;CV=coefficientofvariation;NA=notavailable;t½=terminalhalf-life;Vss=volumeofdistributionatsteadystate.
pruritus,nausea,andvomiting(seetableIV).Onesubject discontinuedbecause ofanAE(toothinfection).TherewerenodeathsorseriousAEs.Noclinicallysignificantabnormallaboratoryvalueswerereported.Onesubjectreportedamoderatelysevereepisodeofvasovagalsyncope,whichwasconsideredbytheinvestigatortobeunrelatedtostudydrugandresolvedsponta-neouslyonthedayofonset.Nostudydrug-relatedchangesinvitalsignsorphysicalfindingswerenoted.
Discussion
Thegoalofthisstudywastoassesstheintra-venousabuseliabilityofMS-sNTbysimulatingtheintravenousabuseoftheproductbyrecrea-tionalopioidabusers.Therelativeeffectsofin-travenous morphine alone or in combination
withintravenousnaltrexoneina100:4ratioon
high, euphoria,anddrug liking were assessed.
For the primary endpoint DEQ #5 (‘‘How
highareyounow?’’)maximumeffectachievedwithmorphinealonewasapproximately3-foldgreaterthanformorphineplusnaltrexone.Themaximum effectforplacebowas0.0mm.Onthe
Cole/ARCIStimulation-Euphoriasubscale,theeu-
phoriceffectofmorphinealonewasapprox-imatelytwicethatofmorphineplusnaltrexone.
Maximumeffectforboth treatments wassig-nificantlydifferentfromplacebo.Themaximumeffectfordruglikingofmorphinealonewasap-proximately2-foldgreaterthanformorphineplusnaltrexone.Resultsconsistentlydemonstrat-edgreatersubjectiveeffectswhenmorphinewastakenintravenouslyalonethanwhenitwasad-ministeredwiththenaltrexone.
The remaining pharmacodynamic analyses(DEQ#1–3and#6–9)demonstratedthat,inmost
instances,themeanmaximumvaluesformor-phinealoneweresignificantlygreaterthanthecorrespondingvaluesformorphineplusnaltrex-one andplacebo groups. ForeachDEQmeasure,morphineplusnaltrexoneprovidedsignificantlygreatereffectcomparedwithplacebo,butwithasufficientdosageofnaltrexonetosignificantlymitigatethemorphinesubjectiveeffects.Com-paredwithmorphinealone,thesubjectivelyap-pealingattributesofthedrug(suchasfeelingdrugeffects,feelinggoodeffects,andlikingthedrug)occurredmoreslowly,whiletheunappeal-ingattributesbecameevidentmorequicklyafterthemorphineplusnaltrexonecombination.Thissuggeststhatthepresenceofnaltrexonecontri-butedappreciablytotheabatementofmorphinehighandeuphoriawithoutdecreasingtheun-pleasanteffects(e.g.nausea,sleepiness)associatedwithmorphineuse.
Ananalysisperformedsubsequenttothisstudysuggestedthatdifferencesof8–10mminVASratingsof‘high’indicateclinicalsignificance.[31]Asshowninfigure1inthecurrentstudy,themeandifferenceinVASscoresforDEQquestion
#5,‘‘Howhighareyounow?’’observedbetween
morphineplusnaltrexoneand morphinealoneremained greater than 10mm from 5 minutes
Morphine and naltrexone
post-dosethrough8hourspost-dose.Atmax-imumeffect,only2of27(7.4%)subjectsexperi-
encedlessthana10-pointdifference.
Inthecontextofthisclinicalsimulation,thestudytreatmentswerewelltolerated.Itislikelythatadverseconsequenceswouldbemuchgreat-er incasesofparenteral abuseof MS-sNTduetothepresence of excipientssuch astalc.However,resultsof thisstudyshouldserve asan indicationthat,inadditiontothepotentialharmcausedbytamperingwithandinjectingMS-sNT,thede-
a
10 000
1000
100
10
1
0.1
Morphine
siredhighwouldnotbeattained.
Asmorphinecausesmiosis,[29,32,33]pupillo-metrymeasurementswereintroducedasanob-jectivemeasureofopioideffect.ThegeometricmeanEminwassignificantlysmallerafterintra-venousmorphinethanafterplacebooraftermorphineplusnaltrexone.Furthermore,theme-dianTEminwassignificantlyquickerwithmor-phinealonethanforplaceboormorphineplusnaltrexone.Inaddition,arelationshipwasobserv-edbetweenplasmanaltrexonelevelsandpupil
100
10
1
0.1
0.01
0.001
10
1
0.1
0.01
0.001
0
04812162024
b
04812162024
c
dilationovertimeinthehysteresisplot,showinganincreaseinpupilsize(relativetomorphinealone)of2mmformaximumnaltrexoneplasmalevelsafter5minutes.Thisfindingsuggeststhatthemorphine-induceddecreaseinpupildiameterwasinhibitedbynaltrexone.Thiseffect wassus-tainedfor45minutesandthengraduallyde-creasedastheplasmanaltrexonelevelsdecreased.Thepersistenceofasmallerpharmacodynamiceffect(continueddifferencebetweenmorphineandmorphineplusnaltrexone)overthere-mainderofthe12-hourperiodislikelycausedbyadoseeffectrelatedtoreceptorbinding.Therelativelysmallerdoseofnaltrexonecombinedwithhighhepaticclearancemayresultinreducedtemporaleffectfromthatofthemuchhigherdoseofmorphine.Thetimingofmorphine-inducedeffectsobservedinthisstudyisinagreementwiththatfromarecentlypublishedstudyin whichintra-
04812
162024
venousmorphinewasadministeredtointravenous-
Time post-dose (h)
Fig.5.Mean (mean–standarderror ofthe mean)plasmaconcen-tration-timeplotsforplasma(a)morphine,(b)naltrexone,and(c)6-X-
naltrexolafterintravenousadministrationofmorphine(n=28)ormorphineplusnaltrexone(n=26)asafunctionoftime(ordinate)
since drug administration in the evaluable pharmacodynamicpopulation.
experiencedrecreationalopioidusers.[34]
Apharmacokinetic-pharmacodynamicrelation-shipwasalsoobservedfortheplasmanaltrexonelevelsinrelationtothemorphine-inducedeupho-
riaasmeasuredbytheCole/ARCIStimulation-
Euphoriasubscale.Theplasmanaltrexoneversus
a
100
90
80
70
60
50
40
30
20
10
Time 0
0
2.50
2.25
2.00
1.75
1.50
1.25
1.00
0.75
0.50
0.25
03691215182124
b
0
Time 0
0.25
0369
1215182124
Plasma naltrexoneconcentration (nmol/L)
Fig.6.Dataareshownforthehysteresisplotof(a) percentagechangeineuphoriaabatementvs naltrexoneconcentrationovertime afteradministrationofintravenous(IV)morphinefollowedbyIVnaltrexone(n=22);and(b)increaseinpupilsizevsnaltrexoneconcentrationovertimeafteradministrationofIVmorphinefollowedbyIVnaltrexone(n=27).
euphoriaabatementandversuschangeinpupildiameterhysteresiscurvesvalidatesthenaltrexoneeffectonthesubjectiveresponses.
Althoughadministeredwithin30seconds,itispossiblethatthesequentialadministrationofmorphineandnaltrexoneallowedatemporary
TableIV.Mostfrequentlyreported(oneormore)adverseevents(AEs)[n(%)]
AE / Placebo(n=27) / Morphine+naltrexone(n=27) / Morphine(n=28)Subjectsreporting‡1AE / 2(7.4) / 9(33.3) / 19(67.9)
Pruritus / 0(0.0) / 1(3.7) / 10(35.7)
Nausea / 1(3.7) / 3(11.1) / 9(32.1)
Vomiting / 0(0.0) / 1(3.7) / 7(25.0)
Headache / 0(0.0) / 4(14.8) / 2(7.1)
Dizziness / 0(0.0) / 2(7.4) / 3(10.7)
Nasaldiscomfort / 0(0.0) / 0(0.0) / 3(10.7)
Hiccups / 0(0.0) / 0(0.0) / 2(7.1)
Irritability / 0(0.0) / 0(0.0) / 2(7.1)
Dysuria / 0(0.0) / 0(0.0) / 3(10.7)
highasthedelayed effectofdisplacementofmorphinefromthem-opioidreceptorsfollowedbytheadministrationofnaltrexonetookplace.
IfpelletsfromMS-sNTcapsuleswerecrushed,dissolved,solubilized,and theninjected,both mor-phineandnaltrexonewouldbesimultaneouslyin-jected.Itwouldhavebeeninappropriatetoconductsuchastudywithcrushedpelletsduetotheconcernoverthepresenceofexcipientssuch astalc,butfu-turestudiesofthisnaturecouldincludesimulta-neousadministration.Additionalstudiesassessingbioavailabilityandsubjectiveresponsestoadmin-istrationoftamperedproductbyroutesotherthanintravenousororal(e.g.nasal)arealsowarranted.Thiscontrolledclinicalstudywasconductedinopioid-experienced, non-opioid-dependent menwho had not previously used the intravenousroutetoabusetheirdrugs.Selectionofthestudypopulationinhumandrug-abuseliabilitystudiesmayimpactoutcomesandpresentchallengesforwhichthereare fewestablished standards.[12,35,36]GuidancefromtheCenterforDrugEvaluationandResearchsuggeststhatsubjectsinastudyshouldhaveexperiencewithdrugswithpsycho-activepropertiessimilartothoseofthestudydrug, but do not specify route of administra-tion.[37]NationalAdvisoryCouncilon DrugAbuseguidelinesstatethatthe‘‘rationaleforexposuretonewdrugs,tohigherdoses,ortonewroutesof administration should be clear and compel-ling.’’[38]Forexample,onemayquestionwhethertheexperienceofintravenousadministrationofanopioidinsubjectswhohadnotpreviouslyused
thisroutetoabuseopioids mightencouragefutureopioidabuseby theintravenous route.Abuseliabilitystudiesinvolvingintravenousadminis-trationofthestudydrughavebeenperformedinnon-drug-abusingsubjects,intravenous-naivesubjects,andintravenous-experiencedabus-ers.[34,36,39,40]Asmallstudyreportedthatcocaineusepatternsdidnotchangeafterintravenous-naivesubjectsparticipatedinastudywithinves-tigationalintravenouscocaineadministration.[40]Kaufman,etal.[40]suggestedthatthisoutcomewasinfluencedbythefactthatthecontrolledclinicalsettinginwhichtheintravenousdrugwasadministeredduringthestudywasverydifferentfromthattypicallyassociatedwithintravenousdrugabuse.Overall,thefindingsfromthisandothersimilarly designed trials provideabasis forestablishingabuseliability.However,thesere-sultsarecenteredonasubsetofthepopulationofabusers(i.e.nondependentrecreationaldrugusers).Abuseliabilitymaydifferinothersubsetsofdruguserssuchasopioid-dependentindividualswho,upontampering,maybesusceptibletonaltrexone-precipitatedwithdrawal(e.g.patientswithchronicpainwhomisuseorabuseopioids,abusersaddictedto opioids,orto new initiatestoopioid abuse).AstudyisunderwaytodeterminetheeffectsofthequantityofnaltrexoneinMS-sNTonopioid-dependentindividuals.FuturestudiesareneededtoaddresstheoverallimpactthatMS-sNTandotherformulationsdesignedtoreduceattractive-nessforabusewillhaveonmisuse,abuse,anddiversioninthecommunity.
Conclusion
Opioidsareeffectiveandimportantinthetreatmentofchronic,moderatetoseverepaininappropriatelyselectedpatients;[41]however,inthecurrentclimateofincreasedillicituseofprescrip-tionopioidanalgesics,thereisaneedtoaddressthe goalofsuccessfully treatingpainwhilemini-mizingtherisksofabuse.[11]MS-sNTcapsulesprovideanalgesiawhentakenorallyasdirectedbutaredesignedtoreleasenaltrexoneiftheyaretamperedwithbycrushing.Resultsofthisintra-venousstudysuggestthattheratioofnaltrexonetomorphinewithinMS-sNTcapsulesissufficienttodecreasethesubjectiveeffectsofmorphineshouldMS-sNTpelletsbetamperedwithbycrushingandsolubilizedandtheninjectedintravenouslyinsubjectssimilartothestudypopulation.Thisfeaturemay reducethe consequentattractivenessofMS-sNTcapsulestotheseabusers.Assessmentofthetrueclinicalsignificanceofthesefindingswillrequirefurtherstudy.
Acknowledgments
LynnWebster,FranklinJohnson,JosephStauffer,andSabrinaCiricwereresponsible forthestudydesignandanal-ysis.Allauthorswereresponsible for analysisandinter-pretationofdata,conception,andwritingofthemanuscript,anddecisiontosubmitthemanuscriptforpublicationandapprovalofthefinalversion.
TheauthorsthankDonaldC.Manning,MD,PhD,andPaulF.CavanaughJr,PhD,formerlyofAlpharmaPharma-ceuticalsLLC(Bridgewater,NJ,USA),awhollyownedsub-sidiaryofKingPharmaceuticalsInc.,whichwasacquiredbyPfizerInc.inMarch2011,forcriticalreviewofthemanuscript;JodyM.Cleveland,MS,ofPfizerInc.(Cary,NC,USA)forstatisticalreviewandsupport;andBradBath,PhD,ofLife-treeClinicalResearch(SaltLakeCity,UT,USA)andTonyaMarmon,DrPH,ofSynteractInc.(Carlsbad,CA,USA)forscientificinput.Writingandeditorialsupportforthismanu-scriptwasprovidedbyCarolBerry,MSc,andJessicaKrauklis,BS,ofQuintilesMedicalCommunications(Parsippany,NJ,USA)incloseconsultationwiththeauthorsandfundedbyPfizerInc.
LynnR.WebsterhasreceivedfundingfromKingPhar-maceuticalsInc.,which wasacquired byPfizer Inc.inMarch2011,forclinicalresearch,consulting,andparticipationinadvisoryboards.Hehasalsoreceivedfundingforclinical
researchand/orconsulting,honoraria,andparticipation in
advisoryboardsfromAdolorCorp.;Alkermes,Inc; Allergen,Inc;AmericanBoardofPainMedicine;Astellas;AstraZeneca;BayerHealthcare;BioDeliverySystemsInternational;BostonScientific;CephalonInc;CollegiumPharmaceuticals;Covidien;
CovidienMallinkrodt;Eisai;ElanPharmaceuticals;GileadSciences;GlaxoSmithKline;JanssenPharmaceuticalK.K.;MeaganMedical;Medtronic;Nektar Therapeutics;NeurogesX,Inc;NevroCorporation;Pharmacofore,Inc.;PurduePharma;ShionogiUSA.Inc.;StRenatus;SuCampoPharmaAmericas,USA;TEVAPharmaceuticals (Sub-1); Theravance;Theravance,Inc;Vertex;andXanodynePharmaceuticals.FranklinK.JohnsonisaformeremployeeofAlpharmaPharmaceuticalsLLC,awhollyownedsubsidiaryofKingPharmaceuticalsInc.,whichwasacquiredbyPfizerInc.inMarch2011,and
ownedstockinAlpharmaPharmaceuticalsLLC.Heisalsoa coinventor of EMBEDA® technology. Joseph Stauffer
isaformeremployeeofAlpharmaPharmaceuticalsLLC,awhollyownedsubsidiaryofKingPharmaceuticalsInc.,whichwasacquiredbyPfizerInc.inMarch2011,andownsstockoptions and patents for Alpharma Pharmaceu-ticalsLLC.BeatriceSetnikisanemployeeofPfizerInc.andownscompanystocksinKingPharmaceuticalsInc.SabrinaCiricisanemployeeofCelerion(formerlyMDSPharmaServices),whichperformedtheanalyticalservicesforthisstudy.
ThisstudywassponsoredbyAlpharmaPharmaceuticalsLLC,awhollyownedsubsidiaryofKingPharmaceuticalsInc.,whichwasacquiredbyPfizerInc.inMarch2011.
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Correspondence:LynnR.Webster,MD,MedicalDirector,LifetreeClinicalResearch,andSeniorConsultanttoOmegaPainClinic,3838South700East,Suite200,SaltLakeCity,UT84106,USA.
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