FightingtheOpioid Epidemic
TheRoleofProvidersandthe ClinicalLaboratoryin UnderstandingWhoisVulnerable
AMITAVADASGUPTA
Professor,PathologyandLaboratoryMedicine, McGovernMedicalSchool, TheUniversityofTexas, Houston,TX, UnitedStates
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Preface
Variousopioiddrugsareusedinpainmanagement,but unfortunatelynonprescriptionabuseofopioidis becomingaseriouspublichealthissue.OnOctober26, 2017,ActingHealthandHumanServices(HHS)secretaryEricD.Hargandeclaresopioidcrisisasapublic healthemergency.Therefore,identifyingpopulation whoarevulnerabletoalcoholanddrugaddictionis importantto fightopioidepidemic.Thereisnosingle geneticpolymorphism,whichisassociatedwithalcohol anddrugabuseincludingopioidabuse,butithasbeen recognizedthatpolymorphismsofmultiplegenes contributecollectivelyinincreasingriskofalcoholand drugaddiction.Ingeneral,geneticscontributeapproximately50%,whereasenvironmentalfactorscontribute 50%inincreasingriskofalcoholanddrugaddictionin anindividual.Thetoxicologylaboratoryalsocanplaya vitalrolein fightingopioidepidemicbyimplementinga robustsystemfordrugsofabusetestingaswellasdrug testinginpainmanagementpatients.Notdetecting intendeddruginurineindicatesnoncomplianceor sellingsuchdruginclandestinemarket.Inaddition,itis alsoimportanttoidentifypatientswhoabuseotherillicit drugsalongwithprescriptionopioid.Moreover,opioid abusemaycausemedicalemergencywhereidentificationofalcoholandanyotherdrugsalongwithopioidis essential.However,commonpitfallsofpainmanagementtestingmustbeavoidedbycommunicatingwith orderingphysician.Acommonmistakeisnegativedrug testingresultinapatienttakingketo-opioidssuchas oxycodoneandoxymorphonebecausetheclinicianorderedopiatedrugscreeninginurinewhereimmunoassayantibodydesignedtodetectmorphinelacks sufficientcross-reactivitywithketo-opioidsfordetecting therapeuticlevelsofsuchdrugsinurineafterproperuse. Similarly,othercommonlyusedopioidssuchasoxymorphone,tramadol,buprenorphine,methadone,and
fentanylcannotbedetectedbyopiateimmunoassay. Therefore,tomonitorpainmanagementpatients,itis importanttoimplementpropertestingandpoliciesin thetoxicologylaboratoryincludingcapabilityofconfirmingdrugsusinggaschromatography/massspectrometryorliquidchromatography/tandemmass spectrometry.Thisbookcoversallimportantaspects essentialto fightopioidepidemic.
Thisbookhassevenchapters.InChapter1,brief historyofopiumabuseandcurrentabuseofheroinare discussed.InChapter2,anoverviewofprescription opioidsispresented,whileinChapter3,opioidabuse andopioidepidemicarediscussedindetail.InChapters 4and5,geneticfactorsandenvironmentalfactorsthat contributetosusceptibilityofopioidsaswellassubstanceabuseareaddressed,respectively.Somepeople usepoppyseeddefensetojustifyheroinabuse.Factors thatcandifferentiatebetweenpoppyseeduseandheroin abusearediscussedindetailinChapter6,and finallyin Chapter7,drugtestinginpainmanagementisaddressed alongwithitspitfalls.
Thisbookiswrittenwithanobjectivetohaveabroad rangeappealtophysicianspracticingpainmanagement, psychiatristsdealingwithdrugandalcoholrehabilitation,pathologists,toxicologists,andclinicalscientists involvedindrugtestinginpainmanagement,resident physicians,seniormedicalstudents,nursepractitioners, andsocialworkers.Iwanttoacknowledgesupportofmy wifeAlicewhileIspendlongeveninghoursandweekendstowritethisbook,whichtookme1year.Ifreaders enjoythisbook,myeffortswillbedulyrewarded.
Respectfullysubmitted AmitavaDasgupta,PhD Houston,TX
CrudeOpium,Morphine,Codeine,and Heroin:PastandPresent
INTRODUCTION
Poppyplants(Papaversomniferum, Papaverpaeoniflorum, and Papavergiganteum)areherbaceousannualplants thatcangrowalmostanywhere.Ofallthedifferent species, P.somniferum isthemostpopularplantdue toitsbeautiful flowersaswellasitsseeds,whichare usedformakingmuffins,bakingbreads,andother purpose.Thisplantisoneoftheoldestmedicinalplants knowntomankind.Theplant’sseedpodcontainsa latexsolutionthatexudesifscoredwithasharp instrument.Thelatexisrawopiumthatcontainsboth alkaloidsandnonalkaloids[1].Crudeopiumwas usedforvariouspurposessinceancienttime.Most likely,opiumwasthe firstnarcoticsubstancediscovered atthedawnofmankind[2].
OPIUMUSE:FROMANCIENTTIMETO MODERNTIME
Opiumusewasknowntoancientculturesasearly as3500BCbySumerianswhocalledit “ HulGil, ” whichmeans “ joyplant.” TheSumerianspassedthe knowledgeofpoppycultivationtotheAssyrians, theBabylonians,andultimately,theEgyptians.The descriptionfoundontheEbersPapyrus(1500BC) fromEgyptindicateduseofpoppyseedsasaremedy forpainreliefaswelltopreventexcessivecryingin children.Interestingly,artifactualremainsrelatedto opiumusagewerealsofoundintheEgyptiantomb from15thcenturyBC.Agoddessfromabout1500 BCshowedherhairadornedprobablywithpoppy capsulesandherclosedeyeswereindicationof sedation,thusspeculatingopiumuseinancienttime. Inaddition,jugletsprobablyimitatingthepoppycapsuleswerefoundinthatperiodinbothCyprusand Egypt.By1300B.C.,theEgyptianswerecultivating opiumandprobablytradedopiumalloverthe MiddleEastandintoEurope[ 3].Around850BCE, thegreatGreekauthorHomerconsideredopiumas anintoxicatingsubstancewithpain-relievingand sleep-inducingproperties[4].
Hippocrates(460 375BC),thefatherofmedicine, recognizedanalgesiceffectsofopiumandprobably prescribedpoppyjuiceasapurgative,anarcotic,and possiblyacureforleucorrhea.Around330B.C., AlexandertheGreatintroducedopiumtothepeople ofPersiaandIndia,wherethepoppieslatercameto begrowninvastquantities.The firstrecordedreference ofutilizingjuicefrompoppyasatherapeuticagentwas madebyTheophrastus,theGreekscholarinthethird centuryBC.Inthesecondcentury,ADRomanphysician Galenintroduceduseofopiumformedicaluse. However,hewasalsoawareofabusepotentialof opium[4].Theantidiarrhealpropertyofopiumwas mentionedbyPersianphysicianAvicenna(980 1037 AD).Healsoreportedthatuseofopiumcommonin Khorasan(northeastofIran)andBokhara(southwest ofUzbekistan).Arabtradersintroducedopiumto IndiaandChinaduringlaterpartofTangdynasty (618 907AD).Probablybetween10thand13th century,opiumwasintroducedintheAsiaMinorand thentoEurope[4].
IngestionofopiumasanoralpreparationhasundergonemanymodificationsovertheCenturies.Thomas Dover(1660 742),anEnglishphysician,developeda powderedformofedibleopiumthatwasalsoknown tocontainsaltpeter(mostlypotassiumnitrate),tartar, licorice,andipecacuanha.Laudanum,analcoholictinctureofopium,wascreatedbythe17thcenturyEnglish physician,ThomasSydenham,andwascommonly pairedwithwhiskeyorrum.Asameansforpreparing patientsforsurgery,Laudanumbecamewidelyused inEuropeandNorthAmericaintoearly20thcentury. Moreover,oneofthe firstbooksdedicatedtotheuses andeffectsofopium, MysteriesofOpiumReveal’d, writtenbytheWelshphysician,JohnJones,was publishedin1701.However,healsolistedmanyside effectsofusingopium[5].
Opiumwasusedforbabysedationfromtheancient time.Asafreeriderofgumlancing,opiatesjoinedthe treatmentofdifficultteethinginthe17thcentury.DuringIndustrialRevolution,opiumwasusedbyworking
class.Withindustrialization,privateusewasrampant amongtheworkingclass.InGerman-speakingcountries,poppyextractswereadministeredinsoupsand pacifiers.InEnglish-speakingcountries,proprietary drugscontainingopiumweremarketedundernames suchassoothers,nostrums,anodynes,cordials,preservatives,andspecificsandsoldatthedoorsteporingrocerystores.Opium’stoxicityforinfantswascommon knowledge;thousandsofcasesoflethalintoxication hadbeenreportedfromantiquity,butphysicians continuedtoprescribeitforbabies.Unregulatedtrade ledtogreatlyincreasedprivateuseofopiatesduring the19thcentury.Intoxicationbecameasignificantfactorininfantmortality.Aslateas1912,theInternational HagueConventionforcedgovernmentstoimplement legislationthateffectivelycurtailedaccesstoopium andtodiscontinuethedangeroushabitofsedating infants[6].
Beforethedevelopmentofgeneralanesthesia, surgerywasperformedonlyinextremenecessity.Itis probablethatananalgesicsuchasopiumwouldhave beengivenduringorfollowingsurgery.The first descriptionofopiumusageforpostoperativeanalgesia isdatedto1784,whentheGlasgow-bornLondon surgeon,JamesMoore,describeduseofopium.The Scottishsurgeon,BenjaminBell,alsonotedthatopium wasusefulincontrollingpostsurgicalpain[5].
Accordingtohistoricalevidence,theabuseofopium hasbeenreportedallovertheglobe specifically throughoutEasternnationssincethe16thcentury. Beforethat,opiumwasmostlyusedasmedicine. ReferencehasbeenmadeintraditionalPersianmedical literaturetothemethodofcultivation,properties,side effects,andtoxicity.In16thcenturyIran,opiumuse beganduringthereignoftheSafavids.Thenfamous scholarImadal-DinMahmudibnMas’udShirazi composedabookconcerningaddiction, Afyunieh,a comprehensivebookonthetopicofopiumandallissuesofopiumabuse.Furthermore,herecommended methodsforreducingopiumdoseaswellassubstitutionwithothermedicationsthathadanarrowerrange ofsideeffects,inordertoeradicatedependencyupon opiumandopium-derivedmaterials.Thisismostlikely the firstbookthatcomprehensivelyaddressedopium anddiscusseddrugrehabilitationmethodology,in traditionalPersianmedicalliterature[7].
Alongwithopiumuse,opiumaddictionsalso becomeasignificanthealthhazard.Opiumaddiction waswidespreadinChina,andfollowinga1799ban onopiuminChina,smugglingofopiumbecameacommonindustrythatleadtotheopiumwarbetweenthe BritishandChinain1839.Duringthe19thcentury,
opiumwasgrownintheUnitedStatesaswellasimported.Besidesindiscriminatemedicaluse,opiates wereavailableintheUnitedStatesinmyriadtonics andpatentedmedicines.Inaddition,smokinginopium denswasunhindered,resultinginanepidemicofopiate addictionbythelate1800s.Thedevelopmentof hypodermicsyringein1853byAlexanderwoodunfortunatelypushedopiateabuseincludingheroinabuse toanewlevel.ThedecadebeforeCivilWar,United Stateswasarmedwithmostpowerfulpainkillerknown tomankindatthattimewhichwasmorphine.Morphine couldbeeasilyinjectedintothebodyusingahypodermicsyringe.Atthattime,opiate-addictedAmerican populationwasmainlyconsistedofCaucasianwomen wholegallypurchasedopium-lacedcoughsyrupatlocal pharmaciesorwhoobtained “laudanum,” atinctureof opiumbymail.Suchaddictionwasvirtuallyinvisible becausemostofthesewomenstayedathome.The generoususeofmorphineintreatingwoundedsoldiers duringtheCivilWarintheUnitedStatesalsoproduced manyaddicts.Surveysbetween1878and1885indicatedthat56% 71%ofopiateaddictsintheUnited Statesweremiddle-toupper-classwhitewomenwho purchasedthedruglegally.Heroinwas firstsynthesized in1874.Heroinwasconsideredasahighlyeffective medicinefortreatingcough,chestpains,anddiscomfort oftuberculosis[8].
Heroinandopioidabuseisnowaglobalpublic healthissue.Accordingtotheworddrugreportof 2014,theestimatedtotalamountofopiumproduced worldwidewas5500tonswiththeoverwhelmingmajorityofproductioncontinuedtotakeplacein Afghanistan(80%oftotalproduction)andMyanmar (10%oftotalproduction)[9].
OPIUMANDPOPPYPLANTS:LEGALISSUES
In1875,theCityofSanFranciscoadoptedan ordinanceinordertoprohibitsmokingofopium.In 1905,theUnitedStatesCongressbannedopium,and in1906,thePureFoodandDrugActrequiredaccurate labelingofallpatentedmedicines.TheHarrison NarcoticsActof1914taxedandregulatedthesaleof narcoticsandprohibitedgivingmaintenancedosesto addictswhomadenoefforttorecover,leadingtothe arrestofsomephysiciansandclosingofmaintenance treatmentclinics[10].Sincethen,numerouslaws attemptingtoregulateimportation,availability,use, andtreatmenthavebeenpassed.Opiumandits constituentchemicalsarelistedasScheduleIIdrugs, whileheroinisaScheduleIdrug.Opiumpoppyfor legalpharmaceuticalpurposesisgrowninvarious
countriesundergovernmentlicense,butverylittleis producedintheUnitedStates.Thecountriesthatcan legallyimportcrudeopiumtotheUnitedStates includeIndia,Turkey,Spain,France,Poland,Hungary, andAustralia.Indiaisthelargestimporterofopiumto legalpharmaceuticalmarketsoftheworld.Unfortunately,largequantitiesofopiumarestillgrown worldwidemostlyforuseintheillegalmanufacture ofheroin.Theopiumgummaybecrudelyrefined andsmoked(e.g., “brownsugar” )orconvertedto morphineandheroin.
Growingopiumpoppies(P.somniferum)are currentlyillegalintheUnitedStates.Thesaleofpoppy seedfrom P.somniferum isbannedinSingaporeand SaudiArabia.
ALKALOIDSFOUNDINOPIUM
Opiumisacomplexmixtureofnonalkaloidsandalkaloids.Thenonalkaloidpartsincludewater(5% 20%), sugar(20%)andseveralorganicacid,mostcommon beingmeconicacid(3% 5%).Morethan40different alkaloidshavebeenisolatedfromopium.However, majoralkaloidsaremorphine(4% 21%),codeine (0.8% 2.5%),thebaine(0.5% 2.0%),papaverine (0.5% 2.5%),noscapine(narcotine:4% 8%),and narceine(0.1% 2%)[4 9].Minoralkaloidspresent inopiumincludeoripavine,boldine,reticuline,codamine,laudanidine,laudanosine,norlaudanosine, andcryptopine.
Identificationofspecificopiumalkaloidsinthe seizedopiumsamplesisusefulnotonlyforjudicial purposebutalsotolocategeographiclocationof cultivationofopiumandtraffickingofopium.The morphinecontentinopiumisakeyvariablein calculationstoestimateglobalillicitsupplyofheroin. Rembergetal.analyzed78opiumsamplescollected fromdifferentregionsinAfghanistanduringtheyears 2000 05toestablishpossiblecorrelationsbetween alkaloidcontentsandselectedexternalfactors,suchas regionoforigin,yearofharvest,useoffertilizer,extent ofirrigation,orintrabatchvariation.Theauthors analyzedmorphine,codeine,papaverine,andthebaine inopiumsamplesusinghigh-performanceliquidchromatography.Theaveragemorphinecontentwas14.4% in78specimens.Meanandrangeofalkaloidscontent inopiumspecimensanalyzedbytheauthorsare listedin Table1.1.Theauthorsobservedhigher alkaloidcontentwhenpoppyplantswerecultivated duringwarmerseasons.Using14.4%,theaverage morphinecontentofall78samplesanalyzed,and assuminganoveralllaboratoryextractionefficiencyof
TABLE1.1
MeanandRangeofAlkaloidsContentof78 OpiumSpecimensAnalyzedbyRembergetal. Opium
Sourceofdata:ReferenceRembergB,SterrantinoAF,ArtnerR, JanitschC,KrennL.Scienceindrugcontrol:thealkaloidcontentof afghanopium.ChemBiodivers.2008;5:1770 1779.
70%,10kgofdryopiumcouldbeconvertedintoabout 1kgofpureheroinbase(i.e.,thetraditionallyused10:1 ruleofthumbforopium-to-heroinconversions)[11].
Narayanaswamietal.analyzed28opiumspecimenscollectedfromdifferentgeographiclocations andanalyzedthemusinggaschromatographyafter convertingthemtosilylethers.Theauthorsconcluded thatJapanesesamplehadthehighestmorphine contentandthelowestnarcotinecontentwhen comparedwiththesamplesfromninedifferent geographicalregions.Ecuadorsampleswerelowin codeineandthebainewhilehighinnarcotine.The Mongoliansamplehadthelowestmorphinecontent. However,highestmorphinecontentwasobservedin onespecimencollectedfromIndianstateofMadhya Pradesh[ 12 ].Alkaloidcontentsofopiumcollected fromdifferentcountriesarelistedin Table1.2 .
MORPHINE
Morphine(fromMorpheus,theGreekgodofdreams)is the firstalkaloidthatwasisolatedfromopiumin1817. Chemicalstructureofmorphineisgivenin Fig.1.1. Morphineisprobablythemostpotentalkaloidpresent inopiumbecauseitisresponsibleforanalgesic, euphoric,sedative,andalsoaddictivebehavior.However,morphineisalsoresponsibleformanyadverse effectsofopium.During1830s,morphinebecame verycommonanalgesic,andafterAmericanCivilWar, manywoundedveteranswereaddictedtomorphine, totheextentthatthename “soldier’sdisease” was coinedtodescribedependenceofsoldiersonmorphine [4].Atpresent,crudeopiumisonlyusedasarawmaterialforsynthesisofvariousopioids.Morphineiswidely usedtodayasanarcoticanalgesic,butitisalsoabused. MedicaluseofmorphineisdiscussedinChapter2.
InnerMongolia6.97%4.88%1.29%0.93%6.62%
Manchuria9.25%4.69%2.75%1.22%5.43%
China10.13%6.47%1.64%1.27%8.79%
Japan17.85%2.32%1.05%2.17%3.47%
Korea11.27%3.92%1.74%0.70%4.65%
Yugoslavia11.28%5.58%0.48%2.73%6.30%
Greece16.9%1.71%0.5%3.31%8.8%
Turkey14.02%2.05%0.84%1.65%5.82%
Equator13.81%1.71%0.25%2.62%10.17%
India(MadhyaPradesh,neemuchII)18.94%2.31%0.64%1.11%4.99%
Sourceofdata:referenceNarayanaswamiK,GolaniHC,DuaRD.Assayofmajorandminorconstituentsofopiumsamplesandstudiesoftheir origin.ForensicSciInt.1979;14:181 190.
FIG.1.1 Chemicalstructureofcodeine,morphine,andheroin.
CODEINEANDTHEBAINE
Codeine(7,8-didehydro-4,5-epoxy-3-methoxy-17methylmorphinan-6-olmonohydrate)isanaturally occurringconstituentoftheopiumpoppy, P.somniferum.Itwasisolatedfromopiumin1833,and itspain-relievingeffectswererecognizedshortlyafter. Codeineconstitutesabout0.5%ofopium,whichcontinuestobeausefulsourceofitsproduction,although thebulkofcodeineusedmedicinallytodayisprepared bythemethylationofmorphine.Codeineislesspotent thanmorphine,withapotencyratioof1:10[13].Chemicalstructureofcodeineisgivenin Fig.1.1.Medicaluse ofcodeineisdiscussedinChapter2.
Thebaine,anotheralkaloidisolatedfromopium,is almostdevoidofanyanalgesiceffect.Itisusedasa startingmaterialforsynthesisofotheropioids.
HEROIN
Heroinisthe firstdesignerdrugthatwassynthesizedby BritishpharmacistAlderWrightfrommorphinein 1874.Chemically,heroinisdiacetylmorphine,which isacetylatedformofmorphine.Themotivationofsynthesisofheroinwastodiscoveranovelcompoundwith analgesicpropertiesofmorphinebutwithoutanyabuse potential.Henamedtheproduct “Heroin” becauseof itsheroicpropertiesasananalgesic[4].Chemicalstructureofheroinisgivenin Fig.1.1.Heroinwas firstmarketedasanantitussiveforpatientwithasthmaand tuberculosisin1898.However,afternearly12yearsof use,clinicalrationaleforusingheroinmedicallywas challengedbecauseofitsabusepotential.Becauseheroinisaboutastwiceaspotentasmorphineasacough suppressant,thesmalldoseofheroinusedfortreating thosepatientsmaynothaveshowedabusepotential initially,butlateritwasevidentthatheroinishighly addictive.Thequestionofaddictionbecameaserious issuein1912whenreportsshowedthataddictsused heroinbecauseitwaseasilyavailableoverthecounter invariousformulations.InDecember1914,US congresspassedtheHarrisonActthatlimitedmaximum amountofheroininproprietarypreparationslessthan 10mgpergramofproduct.Thetotalbanofheroinin theUnitedStateswasachievedin1924[14].
HeroiniscurrentlyclassifiedasaScheduleIdrug withnoknownmedicalusebutveryhighabusepotential.Streetnamesofheroinaregivenin Table1.3. Althoughheroinhasbeenabusedinover100years, during2002 13,heroinoverdosedeathratesnearly quadrupledintheUnitedStates,from0.7deathsto 2.7deathsper100,000population,withanear doublingoftheratesfrom2011to13[15].Datafrom theNationalSurveyonDrugUseandHealthindicate
OpiumChinesemolasses,Ope,blackstuff
HeroinBrownsugar,dope,junk,whitehorse, smack,H,tar,chiba,mud,etc.
OpiumBigO,blackstuff,buddha,chillum, Chinesemolasses,gum,hop,etc.
thatheroinuse,abuse,anddependencehaveincreased inrecentyears.In2013,anestimated517,000persons reportedpast-yearheroinabuseordependence,anearly 150%increasesince2007[16].
Inrecentyears,anumberofmainstreammedia reportsthattheabuseofheroinhasmigratedfrom low-incomeurbanareaswithlargeminoritypopulationstomoreaffluentsuburbanandruralareaswith primarilywhitepopulations.Partofthisincreasein heroinabuseandapparentmigrationtoanewclassof userscoincideswithprescriptionopioidabuseover last20years.Ciceroetal.reported,basedontheir reviewofsurveyresults,thattherearedemographicdifferencesbetweenrecentheroinabusersandpeoplewho startedabusingheroin40 50yearsago.Itisinteresting tonotethatrecentusersofheroinareolder,whitemen, andwomencurrentlylivingprimarilyinnonurban areaswhostartedtakingopioidsthroughvalid prescription.Unfortunately,someofthemsuffered fromopioidaddictionandswitchedtocheaperand moreaccessibleheroinoverprescriptionopioidsuch asoxycodone(OxyContin).Incontrast,earliersurveys indicatedthatin1960and1970s,heroinabusewas aninnercityissueamongminoritypopulation.Therefore,withintroductiontoopioidsforpainmanagement,certainpopulation(whitemiddle-classmen andwomeninlessurbanareas)were firstexposedto opioidthroughprescriptionandlaterdeveloped addiction.Theymayhavechosenheroinbecauseitis cheaperalternativetoprescriptionopioids.Another interestingaspectofthestudyisthattheageat first opioidusehasincreasedoverthepast50yearsfrom 16yearsofageto23yearsofage[17].
Othersurveyshaveindicatedthatduring2002 11, ratesofheroininitiationwerereportedtobehighest amongmales,personsaged18 25years,nonHispanicwhites,thosewithanannualhousehold income <$20,000,andthoseresidinginthenortheast. However,duringthisperiod,heroininitiationrates generallyincreasedacrossmostdemographicsubgroups.Mostheroinusershaveahistoryofnonmedical useofprescriptionopioidpainrelievers,andan
increaseintherateofheroinoverdosedeathshas occurredconcurrentlywithanepidemicofprescription opioidoverdoses.However,whenopioidprescriptions wererestricted,heroinabusewasincreased.Interestingly,analysisof2010 12drugoverdosedeathsin 28statesfoundthatdecreasesinprescriptionopioid deathrateswithinastatewerenotassociatedwithincreasesinheroindeathrates;infact,increasesinheroin overdosedeathrateswereassociatedwithincreasesin prescriptionopioidoverdosedeathrates.Inaddition, astudyexaminingtrendsinopioidpainrelieveroverdosehospitalizationsandheroinoverdosehospitalizationsbetween1993and2009foundthatincreasesin opioidpainrelieverhospitalizationspredictedan increaseinheroinoverdosehospitalizationsinsubsequentyear[18,19].
HeroinSynthesisandCuttingofHeroin
Themajorityofclandestinelaboratories firstisolate morphinefromthecrudeopiumextractsusing “Lime Method.” Inthismethod,apolarimpuritiesare removedbydissolvingtheopiuminhotwaterfollowed by filtration,additionofcalciumhydroxide,andagain filtration.Thensolutionisboiledandammonium chlorideisaddedinordertoprecipitatemorphine.Laboratoriesproducingmorphineasanendproduct performfurtherpurification,butclandestinelaboratoriespreparingillicitheroinmaynotcarryanyextra steptopurifymorphine.Therefore,herointhus producedconsistsofamixtureofmorphineandtraces ofotheropiumalkaloids,likecodeine,noscapine, papaverine,andthebaine.Innearlyallregionsofthe world,the “limemethod” isusedforfurthersynthesis ofheroin.Thetraditional “large-scale” synthesis,however,isasimpleone-stepacetylationreactionandis typicallyperformedbytheadditionofalargeexcess ofaceticanhydridedirectlytothecrudemorphine,followedbyheatingtheresultingsolutionto,ornear, boiling.Althoughaceticanhydrideisbyfarthemost commonacetylatingreagentused,onrareoccasions, acetylchlorideandethylidenediacetatemayalsobe usedasacetylatingagent.Afteracetylation,reaction mixtureiscooledandtheintendedproductisisolated bytreatingthereactionmixturewithsodiumcarbonate andcollectingtheheroinbaseby filtration.Theresultingproductismostlyusedforsmoking.ForIV injection,thebaseheroinisfurthertransformedinto granularheroinhydrochloridebydissolvingitin acetoneandadditionofhydrochloricaciduntilthesolutionchangescolorwithbluelitmus.Thecontentis driedinair,andpowderedheroinisproducedby grinding.Duringacetylation,otheralkaloids,foundas
impuritiesintheoriginalmorphineandhavingfunctionalgroupsthatcanbeacetylated,willproduce severalrearrangementandacetylationby-products suchasacetylcodeine,acetylthebaol,ortheveryunstable3-monoacetylmorphine.Afterheroinisformed,a smallpartwillspontaneouslydeacetylateinto6monoacetylmorphine,amajorimpurityofallheroin samples.Finally,cuttingsubstancesareaddedinorder toincreasethebulkoftheproducttoincreasenetprofit fromsellingillicitheroin.Sugars,suchasglucose, lactose,andmannitol,arethemostcommonlyused diluents.Oftensamplesarecutwithmorethanone diluent.Inaddition,alsopharmacologicallyactive substancesoradulterantsareincorporatedintothecut heroinsamples.Someofthesecomponentsareadded toenhancetheeffectofheroin.Acetaminophen,for example,increasesthevolatilityoftheheroinbase andthusincreasestheeffectby “chasingthedragon.” Others,however,areaddedtofacilitatetheuse.For example,additionofprocaineismostlikelydoneto locallyreliefthepainofanIVinjection.Becauseof thelargenumberofparametersthatcanvaryduring thepreparationofheroin,itwasthoughtthatspecific profiles,characteristicforthedifferentheroinproducingcountriesorregions,couldbeconstituted bycomparativeanalysis[20].
Speci ficcompoundsusedforadulterationofurine mayvarydependingongeographiclocations.For example,inMalaysia,wherethe firstreportofheroin abusewaspublishedin1972,the firstfewclandestine heroinlaboratoriesthatsynthesizedheroinviathe acetylationofimportedmorphinewereuncoveredin 1973and1977.Interestingly,bythemid-1980s,this typeoflaboratorywasreplacedbyheroin-cutting laboratories,wherebyimportedhigh-gradeheroin wascuttostreetheroin.Thiswastomeettherising demandforthedrugowingtotherapidescalationof thenumberofdrugusers.Overtheyears,themost signi ficantchangeinthecompositionofthestreet heroinisthedecreaseinitspurityfrom30% 50%to 3% 5%.Caffeinehasremainedthemajoradulterant, andchloroquineisdetectedinvirtuallyallrecent seizedheroinproducts[21].
ConcerningcuttingofheroininEurope,between 1960and1970s,substancessuchascaffeine,quinine, lactose,andmannitolwereused.Inthe1980s,caffeine, procaine,acetaminophen(paracetamol),andphenobarbitalwerecommonadulterants,whilequininewas lessfrequentlydetectedinseizedheroinspecimens. Atthebeginningofthe1990s,procaine,phenobarbital,andmethaqualonedisappearedasadulterants inheroinproductsabusedinEurope.Currently,
caffeineandacetaminophen(morethan90%specimens)arethemajoradulterantsusedforcutting heroin.Inaddition,glucose,sucrose(saccharose), lactose,mannitol,andeveninositolhavebeenfound asdiluentsinillicitheroinspecimens[22].Schneider andMeysalsoreportedthatparacetamol(acetaminophen)andcaffeinearethemostcommonlyencounteredadulterantsinillicitheroinspecimensinEurope [23].Heroinadulteratedwithscopolaminemaycause severeanticholinergictoxicityinheroinuserswith patientsoftenpresentingtoemergencydepartments ingreatnumbers[ 24].Clenbuterolisa b2-adrenergic agonistwithveterinaryuses,whichhasnotbeen approvedbytheUSFoodandDrugAdministration forhumanuse.Clenbuterolisinfrequentlyreported asheroinadulterant,butifused,itmaycauseserious adversereactionsandmayrequirehospitalization. Hiegeretal.reportedcasesoftenpatientspresented withunexpectedsymptoms(chestpain,dyspnea, palpitation,andnausea/vomiting)shortlyafterheroin use.Allpatientsweremale,withamedianageof 40years(range:38 46years).Theauthorsdetected clenbuterolinallpatients,thusexplainingcause oftoxicity.Fortunately,allpatientssurvivedwith supportivecare[25].
Risseretal.investigatedpotentiallinkbetweenpurityofstreetheroin andheroin-relateddeathsin Viennain1999.Theauthorsanalyzedatotalof415 seizedheroinspecimenswithatotalweightof 128.02g.Themedianpurityofheroinspecimenswas 6.5%(range:0.0% 47%diacetylmorphine).Allthe samplescontainedadiluent,mainlylactose,aswellas adulterants,suchascaffeineand/orparacetamol(acetaminophen).Duringthestudyperiod,theauthors investigated75heroin-relateddeathsand387heroinrelatedemergenciesbutdidnotobserveanycorrelation betweendeathrelatedtoheroinabuseandpurityof streetheroin.Theauthorsconcludedthatthewidely heldbeliefthatthenumberofheroin-relateddeaths couldbeexplainedsimplythrough fluctuationsinthe purityofstreetheroincouldnotbesubstantiated, eventhoughtheresultsofthisstudydonotruleout anassociationbetweenthepurityofheroinand heroin-relateddeaths/emergencies[26].Toprakand Cetinconcludedthattheweightofheroinandthe numberofheroinseizures,butnottheheroinpurity, weresigni ficantlyassociatedwiththenumberof heroin-relateddeaths[27].Incontrast,inanotherstudy, theauthorsobservedthattheoccurrenceofoverdosefatalitieswasmoderatelyassociatedwithboththeaverage heroinpurityandtherangeofheroinpurityoverthe studyperiod[28].
WhiteversusBrownandBlackTarHeroin Pureheroiniswhiteincolorbutdependingonorigin heroinmaybebrownorlooklikeblacktar.Exclusive regionalheroinmarketshavedevelopedworldwide: poppiesgrowninAfghanistanpredominatelyendup asheroininEurope;SoutheastAsianheroinalmost exclusivelygoestoAustraliaandWesternCanada;and ColombianandMexicanheroinenterstheUnited Statesillegally.Priorto1980,heroinintheUnited Stateswassourcedfromthethreepredominateproducingregionsintheworld:Afghanistan,Pakistan,andIran aswellastheGoldenTriangleofSoutheastAsia (Myanmar,Laos,andThailand)andtosomeextent Mexico.OpiumfromtheGoldenTriangleaccounted for55%oftheworld’sillegalopiumandtheheroin derivedfromitaccountedfor19%oftheUSmarket. Themarketshareofthesesourceshaschangeddramaticallyoverthelasttwodecades,especiallysinceanew sourceofheroin,Colombian,beganexportinginthe early1990s.By2000,thedistributionofUSretailheroinchangeddramaticallywith48%comingfrom Colombia,39%fromMexico,3%fromSouthwest Asia,1%fromSoutheastAsia,and9%unclassi fied. Thistrendhasonlycontinued,withthelatestdata showingthatmarketsharehasincreaseto58%for Colombian-sourcedheroin,40%forMexican-sourced heroin,withSoutheastandSouthwestAsiaheroincombinedfallingto2%share.Heroinhasseveralcharacteristicsthataffecthowitisusedandevenhowitis distributed.Thesecharacteristicsincludecolor,physical state,watersolubility,pHbalance,heatstability,and purity.SoutheastAsianheroinistypicallywhite, powdered,highlywatersolubleandacidic,whileheroincomingfromSouthwestAsianistypicallyabrown coarsepowderwithpoorwatersolubility(untilacidifiedfromitsbasicformbytheadditionofanacid) andgoodheatstability;Colombianheroinisoffwhitetolightbrown,powdered,andacidicwithgood watersolubility.However,Mexicanheroinisdark browntoblack,solid,vaporizable,andoflowerpurity, anddespiteitsacidity,itrequiresheattodissolvethis intoaqueoussolution.Theriskofbacterialinfections iswellestablishedwithheroinuse,especiallyuseof blacktarheroin[29].
IntheUnitedStates,whiteandlightbrownpowder heroinfromColumbiapredominateinEastCoastdrug markets,whileMexicanblacktarheroinpredominates WestCoastdrugmarkets.Typicalblacktarheroinpreparationincludesstirringaninjectableportionofblack tarheroinandwateroverheatuntiltheheroindissolves.Powderheroincanbepreparedforinjection bystirringitwithroomtemperaturewater.Heating
heroinsolutionabove65 CinactivatesHIVlivinginthe heatingvessel,whichmaypartiallyexplainwhyratesof HIVinfectionarelowerinsettingswithblacktarheroin, likeCalifornia,comparedtosettingsdominatedby powderheroin,liketheEasternUnitedStates[30].
Inthelastdecade,heroinsourcetypesinSanFranciscohaveexpandedbeyondblacktarheroin,withthe additionofreportedlymorepotentgunpowderheroin thatisastickypowderversionofblacktarheroin.It mayappearinasolidformthatcrumblesandother timesasamixofchunksandpowderorwitha “dried coffee” powderedappearanceandsometimesspeckled whiteandblack.Gunpowderheroinhasgained popularityasahigherpotencyalternativetothelonger establishedproduct.Likeblacktarheroin,gunpowder heroinshouldbeheatedtodissolvequicklybuttended tobemoresolublethanblacktarheroin[31].
HeroinLacedwithFentanyl
IntheUnitedStates,thereisadramaticincreaseinthe adverseconsequencesofheroinuseasnumberof deathsrelatedtoheroinoverdoseisincreasingyearly. Thisisduetotransitioningaportionoftheat-riskpopulationfromonesourceofopioids(prescriptionpills) toafullyillicitdrug(heroin).Inaddition,contaminationoftheheroinsupplywithpowerfulsynthetic opioids,especiallyfentanylanditschemicalanalogues, resultsinapublichealthcrisisassociatedwithopioidrelateddeaths.Fentanylisthecentralchemicalina familyofover20analogues;itisasyntheticopioid withpotent m-receptoractivity,registering30 50times morepotentbyweightcomparedwithheroin.Therefore,whenheroiniscutwithmorepotentfentanyl, theusershavenoideathattheyareabusingfentanyl. Thiscuttingofheroinwithfentanylsigni ficantly increasesheroin-relatedoverdosesaswellasfatalities [32].Useoffentanyltocutheroinistoincreasethe profitmarginbecauseheroincosts$65,000perkilogramwhilefentanylisavailableroughlyat$3500per kilogram.Producingprecisefentanyldosagedemands specialequipmentandknowledge,butstreetsuppliers ofheroinwhocutheroinwithfentanylhaveneitherthe knowledgenortherequiredequipment.Therefore,risk ofheroinoverdoseissubstantiallyhigherinaddicted peoplewhoabuseheroincutwithfentanyl[33].
ApublichealthemergencywasdeclaredinBritish Columbia,Canada,inApril2016duetotheunprecedentednumberofdeathsfromopioidoverdoses,where fentanylabusewasamajorreason.Whilein2012, fentanylwasimplicatedin5%ofdrugoverdosedeaths; theproportionhasincreasedtonearly80%in2017. Amlanietal.reportedthataboutone-thirdofclients testedpositiveforfentanyl.Amongthosewhotested
positive,73%werenotawareoftheirfentanylexposure [34].Basedonastudyof24participants,Memaetal. concludedthatfentanylurinetestingappealedtoillicit opioidusersandmayhavecontributedtoadopting behaviorstowardsaferdruguse.Arelationshipoftrust betweentesterandclientseemedimportantforclients whoexpressedconcernswithprivacyoftheurinetest results[35].
Baldwinetal.reportedthatthenumbersofseized fentanylandheroinsamples,aswellasbothtotalillicit drugoverdosedeathsandfentanyl-detectedoverdose deaths,areincreasingrapidlyinBritishColumbiasince 2009.Theauthorsidentifiedapositiveassociationbetweenseizedfentanylandtotalunintentionaloverdose deathsthatisstrongerthantherelationshipbetween seizedheroinandtotalunintentionaloverdosedeaths [36].Numberofseizedheroinandseizedheroincut withfentanylbetween2008and2016inBritish Columbia,Canada,aregivenin Table1.4
HeroinPharmacokinetics
Duringheroinsynthesisfrommorphine,initialacetylationoccursatposition3ofthephenolichydroxylgroup ofmorphine.Thenthephenolichydroxylgroupat position6isalsoacetylated,producingdiacetylmorphine(heroin).Thechemicaladditionoftheester groupstomorphinerendersheroinmorelipophilic thanmorphine.Therefore,heroincancrossthebloodbrainbarriermuchfasterthanmorphineexplaining earlyonsetofpharmacologicaleffectscomparedto
TABLE1.4
NumberofSeizedDrugsContainingHeroinor HeroinLacedWithFentanylBetween2008 16in BritishColumbia,Canada.
Sourceofdata:ReferenceAmlaniA,McKeeG,KhamisN,Raghukumar Getal.WhytheFUSS(FentanylUrineScreenStudy)?Acrosssectionalsurveytocharacterizeanemergingthreattopeoplewho usedrugsinBritishColumbia,Canada.HarmReductJ.2015;12:54.
morphine.However,opiatereceptorsinthebrainare stereospecific.Asaresult,heroinhasloweraffinities foropiatereceptorsthanmorphine.However,heroin metabolitesuchas6-monoacetylmorphine(also knownas6-acetylmorphine[6-AM])hasmuch higheraffinityforopiatereceptors.Inaddition,6monoacetylmorphineisalsometabolizedinto morphine.Therefore,heroincanbeconsideredasa “prodrug,” wherepharmacologicaleffectsaremostly duetoitsactivemetabolites,6-monoacetylmorphine andmorphine[37].
Theionizationconstantofheroin(pKa)is7.6. Therefore,atphysiologicalpH,average40%heroin willbeinnonionizablestateandaccessibleformembranetransport.Incontrast,pKaofmorphineis9.4. Theproteinbindingis20% 40%.Afterenteringinto circulation,heroinisrapidlyhydrolyzedinto6monoacetylmorphineand finallyintomorphine.Thehydrolysisofheroinandalso6-monoacetylmorphineis catalyzedbydifferenttypesofesteraseenzymes:acetylcholinesteraseinerythrocytesandpseudocholinesterase inplasma.Thenmorphineisconjugatedtoproduce morphine-3-glucuronide(majormetabolite)andalso morphine-6-glucuronide(minoractivemetabolite). Glucuronidationiscatalyzedbytheliverenzymeuridine-50 -diphosphateglucuronosyltransferase.Morphine glucuronidesarehydrophiliccompoundsandaremostly excretedinurine,butaminorfractionisalsoexcretedin bile.Afterintravenousadministrationofheroin,approximately70%ofdosageisrecoveredinurinemainlyas morphineglucuronide[38].
Becauseofrapidhydrolysisbyserumesterases, heroinbloodlevelsdeclinerapidlyafterintravenous administrationandbecomeundetectableafter 10 40min.Thehalf-lifeis1.3 7.8min.Unchanged heroinisnotusuallydetectedinurine.Themaximum concentrationof6-monoacetylmorphine,the firsthydrolysisproductofheroininblood,isachievedrapidly (0.7 2.7min)afterintravenousadministrationof heroin.However,half-life(5.2 52min)ismuchlonger thanhalf-lifeofheroin.Afterheroininjection,6monoacetylmorphinecouldbedetectedinserum 1 3hpostadministration.Thismetaboliteisalso detectedinurine.However,6-monoacetylmorphineis furtherhydrolyzedintomorphine,andmaximum concentrationcouldbeachieved3.6 8.0minafter administrationofheroin.Thehalf-lifeofmorphineas aheroinmetaboliteis100 280mininblood[38].
Thepharmacodynamiceffectofheroindependson thepharmacokineticprofileofheroinandisdependent onrouteofadministration.Theimmediateeffectof intravenouslyinjectedherointhatisoftendescribedby
heroinaddictsasa “flash” (warmandpleasantsensation).Theintensityof flashisrelatedtomaximum serumlevelsofheroinand6-monoacetylmorphine. The flashisfollowedbyeuphoria,whichisrelatedto morphineandmorphine-6-glucuronideplasmalevels. Becauseheroinislipophilicinnature,itisalsorapidly absorbedafterintranasalapplicationasheroinisrapidly absorbedthroughthemucusmembrane.Maximal heroinconcentrationinserumcouldbeachievedin 2 5minafterintranasalapplication.However,peak heroinconcentrationsaresignificantlylowerafter intranasalapplicationthanintravenousinjection,hence lesspharmacologicaleffect.Heroin,likeotheropioids, causesrespiratorydistressandconcomitantuseof alcoholandincreasestheriskofheroinoverdose[38].
Forworkplacedrugtestingaswellasmedicaldrug testing,thepresenceof6-monoactetylmorphinein urineataconcentrationof10ng/mLisconsideredas theconfirmationofheroinabuse.Immunoassaysare commerciallyavailablewithacutoffconcentrationof 10ng/mLfordetecting6-monoacetylmorphineinurine [39].Ingeneral,6-monoacetylmorphinecanbe detectedinserumupto2handinurineupto8hafter heroinabuse.Thisisthemajorlimitationofusing6monoacetylmorphineasthemarkerforheroinabuse. However,detectionof6-monoacetylmorphineinblood confirmsrecentexposuretoheroin.Inaddition,6monoacetylmorphineinvitreoushumorismorestable becauseesterasesarenotpresentinvitreous.Therefore, measuring6-monoacetylmorphineinvitreoushumor isusefulindeathinvestigationswhereheroinoverdose issuspected[40].
AdverseEffectsofHeroin
Heroinaddictionmaychangenormalbrainstructure andfunction.Chronicheroinabuseresultsinalonglastingimpairmentincognitivefunctionandalteration inthenormalfunctionsofcentralnervoussystem. Studiedhaveshownthatchronicheroinabusehas adverseeffectsonprefrontalcortex,temporalinsula, thalamus,nucleusaccumbens,amygdala,andsensomotorstructureofthebrain.Investigationusingmagneticresonanceimagingofthebrainofheroinaddicts indicatedthatheroinabuseisassociatedwithdecreased graymatterdensityintheprefrontalandtemporal corticalregionsofthebrain.Becausegraymatteris associatedwithmusclecontrol,sensoryperception, memory,emotion,speech,anddecision-making abilitiesofthebrain,reducedgraymatterinthe brainofachronicheroinaddictsisassociatedwith impairedbrainfunctions.Electrophysiological studiesofthebrainfunctionsofheroinaddictsusing
electroencephalographyhaveshownmajordeviations comparedtonormalsubjects.Thecognitivedysfunctionofheroinabusersiscorrelatedwith a2mean frequencyshiftatthecentralregion.Thedurationof heroinaddictioniscorrelatedwithfrequencyshiftof a2region,andheroindosageisassociatedwithlower a1meanfrequencyatcentral,temporal,andoccipital sites[41].Shenetal.reporteddiminishedcorticalplasticityinheroin-addictedsubjectsthatindicatesthe involvementofthemotorsysteminadvancedstages ofaddiction.Onepotentialmechanismunderlying thediminishedcorticalplasticityisthelossofdopaminergicsignalingatthesynapticsite,whichreduces inductionofplasticity[42].
Heroinuseisassociatedwithblooddisseminated bacterialinfections,e.g.,endocarditisandosteomyelitis. Morerecently,associationbetweenabuseofblacktar heroinandbacterialskininfectionaswellassofttissue infectionshasbeenreported.Blacktarheroinhasbeen associatedwithwoundbotulism,necrotizingfasciitis, tetanus,andsofttissueinfections.Theseinfectionsmay beduetocontaminationoftheheroinorbyfunction ofsubcutaneousinjectioninuserswithheroin-scarred veins.Clostridiumspecies,e.g.,thosebacteriathatcause botulismandtetanus,maybeabletosurvivetheharsh chemicalenvironmentofblacktarheroinbyforming spores;indeed,thesesporesmaybemademoreviable bytheheatingrequiredtosolubilizetarheroin.
Infectiveendocarditisisalife-threateningcondition withahighmortalityrate.Intravenousdrugabusers areathighriskofdevelopinginfectiveendocarditis. Althoughmostofthecasesofinfectiveendocarditis arecausedbyasinglepathogen,casesofpolymicrobial endocarditisarerareandtheyareassociatedwithareportedmortalityrateofmorethan30%.Mehrzad etal.reportedacaseofa49-year-oldmalewithintravenousheroinandfentanylabuse,whopresentedwith infectiveendocarditiscausedby Neisseriasicca/subflava, Actinomyces, Streptococcusmitis,and Haemophilus parainfluenzae,complicatedbysepticembolitothe lungsandskin,splenicinfarct,andimmunocomplexmediatedproliferativeglomerulonephritis.Thepatient survivedtheinfection[43].
Followingtheintroductionofblacktarheroin mainlyfromMexicointhe1980s,casesofwound botulismdramaticallyincreasedintheWesternUnited States.Contaminationwithsporesof Clostridiumbotulinum ofblacktarheroinoccursalongthedistribution line.Theheatingofheroinpowdertosolubilizeitfor subcutaneousinjection(“skinpopping”)doesnotkill thespores.Thesporesgerminateinananaerobictissue environmentandreleasebotulinumtoxintypeAorB. Skinabscessesontheskininasuspecteddrugabuser mayhelpindiagnosis.However,definitediagnosisis madebydetectionofbotulinumtoxininserumor isolationof C.botulinum fromtheabscess.EarlytreatmentwithequineABEbotulinumantitoxinobtained fromtheCentersforDiseaseControlandPrevention isusefulforgoodtreatmentoutcome[46].Qureshi etal.reportedcasesof15patientswithmeanageof 47years(12menand3women)whosufferedfrom woundbotulismduetoabuseofblacktarheroin.All patientshadabscessesintheadministrationareas.By history,themostcommonsymptomsweredysphagia (66%),proximalmuscleweaknessofupperandlower extremity(60%),neck flexormuscleweakness(33%), ophthalmoplegia(53%),bilateralptosis(46%),dysarthria(53%),doublevision(40%),blurredvision (33%),anddrymouth(20%).Inpatientswithdocumentedwoundbotulism,thepupilswerereactivein 46%.Allpatientsrequiredmechanicalventilationand weretreatedwiththetrivalentantitoxin.Elevenpatients (73.3%)weredischargedhome,twoweretransferredto askillnursingfacility,andtwoweretransferredtolongtermacutecarefacility[47].Woundbotulismdueto abuseofIVdrugsincludingblacktarheroinmayalso beassociatedwithfatality[48].
Heroinaddictionisassociatedwithpoororalhealth. Oralanddentalcareinheroinaddictionmightbe complicatedbyalteredmentalstatus,negativeattitude towardoralhealth,dentalanxietyandfear,druginteraction,andassociatedmedicalcomorbidity[49].
BLOODANDURINELEVELSOFHEROINAND ITSMETABOLITES
Heroincanbeanalyzedbygaschromatography/mass spectrometry(GC/MS)withoutderivatization,but morphinerequiresderivatizationpriortoGC/MSanalysis.Trimethylsilylderivativeisacommonlyusedderivative,butmanyotherderivatizationmethodshavebeen reported.Guillotetal.reportedananalyticalmethodfor
Botulismisarare,treatableyetpotentiallyfataldisordercausedbytoxinsproducedbysomebacteriathat affectsthepresynapticsynapticmembraneresultingina characteristicneuromusculardysfunction.Mostcommoncauseofbotulismisfromeatingimproperly cannedfoodandhoneybyinfants.Morerecently,there hasbeenanincreasedincidenceofwoundbotulism associatedwithintramuscularandsubcutaneous injectionofstreetdrugs,especiallyheroininparticular [44].Woundbotulismcanbedeadly,anditcarriesa casefatalityrateof15%,mostlysecondarytoventilatoryfailure[45].
thedeterminationofheroin,free6-AM,andfree morphineinblood,urine,andvitreoushumorforanalysisofpostmortemcaseswhereheroinwassuspectedto bethecauseofoverdosedeath.Theauthorssynthesized diethylnalorphinefromnalorphinetouseasthe internalstandard.Afterliquid-liquidextractionatpH to9.5,theauthorsconverted6-monoacetylmorphine into6-acetyl-3-propanoylmorphineandmorphineinto dipropanoylmorphinepriortoGC/MSanalysis.Thepropionylationstepwasconductedatroomusingpropionic anhydride,while4-dimethylaminopyridinewasalso usedasacatalyst.Neitherheroinnordiethylnalorphine (internalstandard)istransformedduringthisderivatization.Thereactionproductsareanalyzedusingfull-scan (250 405amu)iontrapGC/MS.Thismethodprovides abaselineseparationanddistinctivemassspectrumof eachcompoundofinterest[50].Heroinanditsmetabolitescanalsobeanalyzedusinghigh-performanceliquid chromatographyorliquidchromatographycombined withmassspectrometry(LC-MS).
Deathduetoheroinabusediswidelyreportedinthe literature.Analysisofheroin,6-monoacetylmorphine, andmorphineinbiological fluidsisveryusefulinboth medicalandforensicinvestigations.Themetabolism ofheroinoffersapotentialapproachwhetherdeathdue toheroinoverdoseisrapidordelayed.Afteradministration,heroinisdeacetylatedinto6-monoacetylmorphine withinanaveragetimeof3min.Theaverageconversion timeof6-monoacetylmorphineintomorphineis 22min.Therefore,thepresenceof6-monoacetylmorphineinthebloodissuggestiveofsurvivaltimesofless than20 30minfollowingheroinadministration.Darke andDuflouinvestigated145casesofdeath(meanage: 40.5years,81%weremale)relatedtoheroinabuseby measuringconcentrationsof6-monoacetylmorphine, freemorphine,morphine-3-glucuronide,andmorphine6-glucuronideinblood.Theauthorsdetectedthe presenceof6-monoacetylmorphinein43%ofcases. Themedian-freemorphineconcentrationin6monoacetylmorphine positivecaseswasmorethan twicethatofcaseswithoutthepresenceof6monoacetylmorphine(0.26vs.0.12 mg/mL).Theauthors concludedthatinheroin-relateddeathsinSydney, Australia,during2013and2014,6-monoacetylmorphine waspresentinthebloodinlessthanhalfofcases, suggestingthataminorityofcaseshadsurvivaltimesafter overdoseoflessthan20 30min.Therefore,detectionof 6-monoacetylmorphineinbloodindicatesrapiddeath afterheroinoverdose[51].
Ropetal.reportedacaseofa40-year-oldmanwho hadalonghistoryofheroinabuse.Hewasplacedina detentioncenterandwasundermedicalsupervision.
Everyeveningbeforebeinglockedup,hewassearched andinoneeveningduringsearchattemptedtohide somedrugbyswallowing.Hetoldtheguardthatit wasacapsuleofbromazepam.Hewasfounddeadin hiscellonthenextmorning.Toxicologyanalysis showedthepresenceofheroin(109ng/mL),6monocaetylmorphine(168ng/mL),andmorphine (1140ng/mL)inhisblood,butinurine,onlymorphine wasdetectedataveryhighconcentration(3650ng/mL). Theauthorsalsoshowedthepresenceofheroin(17ng/ gm),6-monoacetylmorphine(12ng/gm),and morphine(425ng/gm)inthegastrointestinalcontent. However,nobromazepamwasdetectedduringtoxicologicalanalysis.Theauthorsconcludedthattheperson diedduetoheroinoverdosebecauseunderclinicalconditionandafterconstantinfusionofheroinhydrochloride(20mgper180min),bloodconcentrationsof steadystateofheroin,6-monoacetylmorphine,and morphinewerereportedat57,15,and30ng/mL.Heroinand6-monoacetylmorphinecouldonlybedetected inbloodafter5min,butmorphineinbloodcouldbe detectedupto45minaftercontrolledadministration ofheroin.However,inthedeceased,heroin,6monocaetylmorphine,andmorphinecouldbedetected inbloodforalongertime,indicatingmassiveoverdose. Inaddition,heroin,6-monoacetylmorphine,and morphineconcentrationsinthebloodofdeceased were2-,11-,and38-foldshigherthanthosereported inthesteadystate.Themomentofdeathwasprobably atthetimewhenpeakmorphineconcentrationwas achieved,whichwasduringthenight[52].
Hairanalysisofheroin,6-monoacetylmorohine, andmorphineisveryusefulindemonstratinglongtermheroinabuse.A5-year-oldchildinacomatose statewasadmittedtothehospitalwithrespiratoryarrest,scarcecardiacactivity,hypothermia,cyanosis, miosis,andtotalunconsciousness.Herespondedto therapywithnaloxone.Urinedrugscreenusingimmunoassaywaspositiveforopiatesandbarbiturates.When thechildregainedconsciousness,hereportedthatone ofhisrelativesoftenforcedhimtoconsumebitter andunpleasantbrownandwhitepowder.Thejudge putthechildincustodyofasocialassistantafterhe wasreleasedfromthehospitalandalsoorderedtoxicologicalanalysisofchild’shair.Scalphairgrowsatarate of1.5cm/month,andwhendrugsareconsumedona regularbasis,theyaccumulateinthehairmatrixin thezoneoftheshaftrelativetothatperiodofgrowth. Segmentalhairanalysiswasperformedinorderto determineifdrugconsumptionhadcontinued.Quantitativeresultsshowedthepresenceofmorphineand6monoacetylmorphineinincreasingamountsfromthe
secondtothedistalsegmentofhair,eachapproximatelycorrespondingtoaperiodoftimeof1month. The6-monoacetylmorphineconcentrationsranged from0.2ng/mgofhairinthesecondsegmentofhair to0.6ng/mgofhairinthedistalsegment.The morphineconcentrationsrangedfrom0.1to0.3ng/ mgofhair.Theproximalsegmentofhair,which correspondedtotheperiodthatthechildwashoused inasocialcenter,wasnegativeforopiates.Thejudge acceptedresultsoftoxicologyanalysis.Therelativeof thechildwasfoundguilty[53].
Tassonietal.reportedacaseofa39-year-oldman whowasaknownheroinaddictforlast2years.He arrivedinhospitalinacomacausedbyacardiocirculatoryfailureduetoheroinoverdose,assupportedbya witnessstatementandconfirmedbythehospitaltoxicologicalanalysis.After5days,themandiedanddeath wasattributedtocardiacarrest.Thequantitativeresults oftheGC/MSanalysisperformed144hafteradmission tothehospitalshowedahighmorphinelevelof 21.3 mg⁄mLinthebile,butnomorphinewasdetected intheblood.However,morphinewasalsodetectedin hishairataconcentrationof4.8ng/mgofhair.Usually morphinecanbedetectedinbloodandurineupto 2daysafterheroinabuse.Theauthorsconcludedthat bileanalysisisaviableoptiontodemonstrateheroin overdosewhenmorphine,themetaboliteofheroin, cannotbedetectedinbloodorurine[54].
Codeineisoftenpresentinheroinpreparationsasan impurityandisnotametaboliteofheroin.Studies reportthataratioofmorphinetocodeinegreater thanoneindicatesheroinuse.Ellisetal.investigated atotalof166caseswithquantifiablemorphineandcodeineinpostmortembloodspecimens.Fromthese cases,163deathshadmorphine/codeineratioofgreater than1and108caseshad6-monoacetylmorphine detectedinapostmortemsample.Theauthorsfound nostatisticallysignificantdifferencebetweenindividualswithahistoryofintravenousdrugabuseandindividualswithnoknownhistoryofintravenousdrug abusewithrespecttoeithermorphine/codeineratio >1orthepresenceof6-monoacetylmorphine.Theauthorsconcludedthatmorphine/codeineratio >1in anIVdruguserissufficientevidencetoconcludeheroin usebyadecedentevenif6-monoacetylmorphineisnot detectedinapostmortemsample[55].
Alunni-Perretetal.reportedacaseofdeathby heroinoverdoseinanembalmedbody.Thedeceased, a30-year-oldFrenchwhitemale,wasfounddeadin Thailandseveraldaysafterascuffle;theprecisecircumstancesofhisdeathwereunknown.However,the deceasedwasaknowndrugaddict.Beforerepatriation
toFrance,thebodywasembalmed.Externalexaminationoftheembalmedbodydidnotshowanysignsof violence.Alsotherewasnoevidenceindicatingdrug injection.Inaddition,therewasnoevidenceofnatural diseaseandnoanatomicalcauseofdeathwasfound. Alltheinternalorganswereheavy,saturatedwithformaldehyde.Thetoxicologicalstudywasperformedinthe bileandintheliver,usingGC/MSanalysis.Noalcohol wasfoundinthebile,buthighlevelsofmorphine (2476ng/mL)andcodeine(305ng/mL)werefound inthebile.Inaddition,analysisoflivertissueshowed amorphinelevelof4.3mg/kgandhairanalysisshowed thepresenceof6-monoacetylmorphine(6.99ng/mgof hair),morphine(4.21ng/mgofhair),andcodeine (0.23ng/mgofhair).Nootherdrugwasdetected.The authorsconcludedthatthecauseofdeathwasheroin overdoseandcommentedthatasusualincasesof embalmment, fluidssuchasbloodandurinewere unavailable,andtoxicologicalanalysiscouldstillbe performedusingbileandtheliverbecauseseveral drugcanstillbedetectedin fluidsandtissuesthat containformaldehydeduetoembalmmentofcorpse. Thiscasedemonstratesthatinembalmedcorpses,toxicologicalassessmentisstillpossible,e.g.,afterheroin fatalities[56].
TreatmentofHeroinOverdoseandHeroin Withdrawal
Naloxoneistheantidoteforpatientssufferingfrom opioid-inducedrespiratorydepressionorarrest includingheroinoverdose.Becausenaloxonehasa shorthalf-life,usuallypatientsareobservedfor4 6h becauseofconcernforreboundtoxicity.Giventhis concern,paramedicsoftentransportpatientswho receivenaloxoneformedicalobservationforseveral hours.Inadditionafterawakening,someheroinusers attempttorefusefurthertreatmentortransporttothe hospital.ThiscausesconsiderableproblemforparamedicsandEDstaffcaringforthepatientasthey weighattemptstoactinthepatient’sbestinterest againstholdingsomeonewithoutconsent.Concern andcontroversyexistaboutwhetherheroinusers requireobservationafternaloxone,howlongafterthe lastdoseofnaloxoneonemustbeobserved,andthe risks includingrecurrenceofrespiratorydepression oroccurrenceofpulmonaryedema incurredbythese patients.Willmanetal.basedontheirstudy commentedthattheriskofdeathinoverdosedpatients successfullytreatedwithnaloxoneisverysmall. Therefore,heroinabuserswhorespondedtonaloxone therapyandhavenormalvitalsignsmaybereleased, providedtheyaremonitoredbyfriends[57].Theinitial
doseofnaloxoneis0.4 2mgIVoralternativelymaybe administeredbyintramuscularinjectionorsubcutaneously.Ifresponseisnotobserved,dosesmaybe repeated2 3mininterval.Incasesofheroinoverdose, ifrespiratorydepressionisnotreversedfollowing repeatedintravenousbolusdosesofnaloxone atotal of10 12mgofnaloxonecanbegivenasintravenous boluses thenitisnotrecommendedtosetupan intravenousinfusion[58].
Severaltypesofmedicationshavebeenusedfor stabilizingheroinusers:methadone,buprenorphine, natrexone,andlevo-a-acetylmethadol.Thepharmacotherapiesusedtotreatopioiddependencehavealso beenlinkedtoopioidpoisoning.Thelong-acting opioidagonist,methadone,hasbeenassociatedwith highratesofopioidpoisoninginthe first2to4weeks followinginitiationoftreatmentandalso first2weeks afterdiscontinuationoftreatment.Similarly,theopioid antagonistnaltrexonehasbeenassociatedwithhigh ratesofopioidpoisoningmortality,followingthe cessationoftreatment,duetoareductionofopioid toleranceandarapidunblockingofmuopioidreceptorsafterdiscontinuationofnaltrexone.Keltyand Hulsestudiedopioid-dependentpatientstreatedwith methadone(n ¼ 3515),buprenorphine(n ¼ 3250), orimplantnaltrexone(n ¼ 1461)inWesternAustralia between2001and2010andconcludedthatratesof fatalandnonfatalopioidoverdosewerenotsigni ficantlydifferentinpatientstreatedwithmethadone, buprenorphine,orimplantnaltrexone[59].
Theprescriptionofheroinforthemanagementof heroindependenceisacontroversialtreatmentapproach thatwaslimitedtoBritainuntilthe1990s.Sincethen,a numberofcountriessuchasSwitzerland,Holland,and Germanyhaveembarkeduponclinicaltrialsofthis approach,anditiscurrentlylicensedandavailablein severalEuropeancountries.Heroinisusuallyprescribed inintravenousdosagesof300 500mg/day,dividedin twoorthreedoses.Uncommonbutserioussideeffects includeseizuresandrespiratorydepressionimmediately followinginjection.Herointreatmentresultsinacomparableretention,improvedgeneralhealthandpsychosocialfunctioning,andlessself-reportedillicitheroinuse thanoralmethadonetreatment.Cost-effectiveness studiesindicateherointreatmenttobemoreexpensive todeliverbutmayoffersavingsinthecriminaljustice sector.Therehasbeendebateregardinghowheroin treatmentshouldbepositionedwithintherangeoftreatmentapproachesforthiscondition.Thereisincreasing consensusthat,incountriesthathaverobustand accessibletreatmentsystemsforheroinusers,heroin treatmentissuitedtoaminorityofheroinusersasa
second-linetreatmentforthoseindividualswhodonot respondtomethadoneorbuprenorphinetreatment deliveredunderoptimalconditions[60].Therefore, prescriptionheroinadministrationshouldbethelast resortfortreatingheroinaddictswhenothertherapies areineffective.Moreover,herointherapyshouldonly beusedinclinicalsettingswhereproperfollow-upis ensured[61].
CONCLUSIONS
Opiumuseisknownfromancienttimeandmorphine isthe firstnarcoticanalgesicknowntomankind. However,abuseofopiumwaswidespreadinancient time,andnowabuseofmorphineandespeciallyheroin isapublichealthandsafetyissue.Althougheffective treatmentusingnaloxoneisavailableforreversing life-threateningopiateoverdoseincludingheroinoverdose,deathfromheroinabuseiswidespread.Effective interventionandtreatmentisessentialto fightopioid abusecrisisincludingheroinabusecrisis.
ACKNOWLEDGMENTS
Allstructurespresentedinthischapteraredrawnby MathewD.Krasowski,MD,PhD,ViceChairofClinical Pathology,UniversityofIowa,RoyJ.,andLucilleA., CaverCollegeofMedicine,IowaCity,IA.Figuresare courtesyofDr.Krasowski.
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PrescriptionOpioids:AnOverview
INTRODUCTION
Painisthemostcommonreasonapersonseeksmedical attention.Ithasbeenestimatedthatover100million Americansarelivingwithchronicpain[1].Acutepain isdifferentthanchronicpainbecauseperipheralneurons(nociceptors)arecapableofdetectingpainfulstimulussuchasextremechangeoftemperature,pressure, tissuedamage,orbychemicalsmostoftenrelatedto inflammation.Acutepainresolveswhenexternalstimulusnolongerexistsorwheninflammationortissue damageisresolved.However,managementofchronic painismedicallychallenging.
Thereareknowndemographicfactorsthatpredispose apersontodevelopchronicpain.Johannesetal.based onasurveyof27,035individualsintheUnitedStatesreportedthatweightedprevalenceofchronicpain(defined aschronic,recurrent,orlong-lastingpainlastingforat least6months)was30.7%amongthepopulationsurveyed.Interestingly,prevalenceofchronicpainwas higherforfemales(34.3%)thanmales(26.7%)and increasedwithage.Theweightedprevalenceofprimary chroniclowerbackpainwas8.1%andprimaryosteoarthritispainwas3.9%.Halfofrespondentswithchronic painexperienceddailypain,andaverage(past3months) painintensitywassevere( 7onascalerangingfrom0to 10)for32%ofindividualssurveyedbytheauthors.Multiplelogisticregressionanalysisshowedlowhousehold incomeandunemploymentassignificantsocioeconomic indicatorsofchronicpain[2].Shmageletal.alsoreportedthatindividualswithlowerannualhouseholdincomehavegreateroddsofreportingchronicpain comparedwithpersonswithhigherannualincome[3]. Moreover,chronicpainandpsychiatricdisorders frequentlycooccur.McWilliamsetal.basedonasurvey of5877individualsrepresentingUnitedStatespopulationobservedsignificantpositiveassociationsbetween chronicpainandindividual12-monthmoodandanxiety disorders.Thestrongestassociationswereobservedwith panicdisorderandposttraumaticstressdisorder[4]. Thetotalhealthcarecostsforchronicpaintreatmentare estimatedtorangebetween$560to635billionper yearintheUnitedStates,whicharemorethantheannual costsofheartdisease,diabetes,andcancer[5].
HISTORYOFPAINMANAGEMENT
Painistheoldestmedicalproblem.Europeanphysiciansusedopiumforpainreliefforalongtime,andafter1680,laudanum,themixtureofopiuminsherry introducedbyThomasSydenham,waswidelyprescribedforpainmanagement.WilliamT.G.Mortonperformedhisfamousdemonstrationofanesthesiawith etherin1846.TheBritishobstetricianJamesYoungproposedtheuseofchloroforminchildbirthandsurgery in1848.However,throughoutthe19thcentury,opiates werethestandardtherapyforbothacuteandchronic pain.MorphinewasindustriallyproducedinGermany inthe1820sandwasproducedintheUnitedStatesa decadelater.Thenwiththediscoveryofhypodermicsyringein1855byAlexanderWood,painmanagement usingmorphinewasimprovedbecausesuchsyringe madeadministrationofmorphinesoconvenientthat itprobablyalsocontributedtomorphineabuse.During thattime,opiumandalcohol-basedcompoundsinthe formofliquid,pill,orheadachepowderwerefreely availableoverthecounterfrompharmaciesandmany peopleself-medicatedthemwiththeseopiumcontainingproducts.Bythe1870s,physicianswere concernedaboutmorphineabuse.In1898,Bayerintroduceddiacetylmorphineunderthetradename “heroin” asacoughsuppressant.However,by1910,young Americanworkingclasspeoplestartedabusingheroin, and finally,heroinbecamebannedandnowisa ScheduleIdrugwithnoknownmedicalbenefitbut havingaveryhighabusepotential(seealsoChapter1). Bayer’schemistnotonlysynthesizedheroinbutalso synthesizedacetylsalicylate(aspirin),whichturned outtoberemarkablysafeandeffectiveanalgesic.Bayer aspirinbecameanover-the-counterdrugin1917.In 1965,theCanadianpsychologistRonaldMelzackand BritishphysiologistPatrickWall,buildingonthehypothesisofDutchsurgeonWillemNoordenbos,publishedtheirclassic “gatecontrol” paperproposinga spinalcordmechanismthatregulatesthetransmission ofpainsensationbetweentheperipheryandthebrain. Then,JohnBonicain1973formedaninterdisciplinary organizationknownas “TheInternationalAssociation fortheStudyofPain.” Researchinpast30yearsresulted
indevelopmentofavarietyofalternativestoopiate painmanagement[6].Nevertheless,opioidsarewidely usedforpainmanagementtoday.Thischapterfocuses onopioidsusedforpainmanagement,aswellasopioidsusedforreversalofopioidoverdoses.
OPIOIDRECEPTORS
Allopioidsinteractwithopioidreceptorspresentinthe brainfortheirpharmacologicalactivities.Wideinterindividualvariationsinresponsetoopioidsareduetogeneticpolymorphismsofgenesencodingopioid receptors,aswellasliverenzymesmetabolizingopioids,forexample,CYP2D6isoenzyme.ThistopicisdiscussedindetailinChapter4.Inthissection,abrief overviewofopioidreceptorsispresented.
Opioidreceptorsareexpressedbybothcentraland peripheralneurons,aswellasbyneuroendocrine,immune,andectodermalcells.Therearethreemaintypes ofopioidreceptors(m, d,and k receptors).Additional opioidreceptortypessuchassigma,epsilon,andorphaninhavebeenproposed,butcurrently,theyareno longerconsideredas “classicalopioidreceptors.” The opioidreceptorsbelongtotheclassAgammasubgroup ofseventransmembraneGprotein coupledreceptors anddemonstrate50% 70%homologybetweentheir genes[7].
TABLE2.1
VariousFeaturesofOpioidReceptors.
Opioid
m receptor m receptorwasthe first receptorcharacterized,and itisthemajoropioid receptorresponsibleforpain controlbecausemorphine, codeine,andsynthetic opioidsbindwiththis receptor.Bindingofdrugs with m receptorsisalso responsibleforadverse effects.
The m-opioidreceptorismostimportantforpain managementbecauseitplayscentralroleinanalgesicactivityofmorphineandmostopioids.Morphine,hydrocodone,oxycodone,hydromorphone,fentanyl,etc.,are strongagonistof m-opioidreceptor,whilecodeine,tramadol,etc.,areweakagonist.Morphineisalsoaweak agonistofboth d-and k-opioidreceptors.Buprenorphineisapartialagonistof m-opioidreceptor,whileit isantagonistof k receptor.Naloxoneandnaltrexone areantagonistsofallthreeopioidreceptorsandcan reverseeffectsofopioid.Inaddition,someendogenous opioidpeptidesarealsoagonistofopioidreceptors. Therearethreedistinctfamiliesofopioidpeptides:endorphins,encephalin,anddynorphins.Endorphins mostlybindto m-opioidreceptors.Variousfeaturesof opioidreceptorsaresummarizedin Table2.1.
PRESCRIPTIONOPIOIDS
Morphinewasthe firstprescriptionopiateusedfor treatingpain.Sincethen,manymoreopioidshave beenmarketedandapprovedbytheFDAforpainmanagement.Mostrecently,inOctober2018,theFoodand DrugAdministration(FDA)approvedtheopioidanalgesicDsuvia,whichisasublingualformulationof Sufentanil,forusein “medicallysupervisedhealth caresettings.” Dsuviaisupto10timesmorepotent thanfentanyl[8].
Morphine,codeine syntheticopioids Endorphinsa
d receptorResponsibleforanalgesia, respiratorydepression,and physicaldependance. Enkephalinsa
k receptorResponsibleforanalgesia andsedationbutcontribute littletoaddiction.
a Endogenousopioidpeptides.
Pentazocine Dynorphinsa
Naloxone
Naltrexone(strongest interaction)
Brain Spinalcord Submucosal plexus
Mesenteric plexus
Brain Mesenteric plexus
Brain Spinalcord Mesenteric plexus
Bothopiatesandopioidsareusedinpainmanagement.Opiateisreferredtonaturallyoccurringalkaloids foundinopiumsuchasmorphineandcodeineand semisyntheticalkaloidswithsimilarstructuressuchas buprenorphine,dihydrocodeine,heroin,hydrocodone, hydromorphone,oxycodoneandoxymorphone.The termopioidsrefertocompoundsthatarestructurally differentfromnaturalopiatesbutarenarcoticanalgesic becausetheyinteractwithopioidreceptorssimilarto naturalopiates.Opioidscanbesubclassifiedunder threebroadcategories:naturalalkaloidsfromopium, semisyntheticopioids,andsyntheticopioids (Table2.2).Opioidscanalsobeclassifiedbychemical structure(Table2.3).Basedoninteractionswithopioid receptors,opioidsusedinpainmanagementcanbe classifiedasstrongagonist,moderateagonist,weak agonist,mixedagonists(interactingwithmultiple opioidreceptors),andmixedopioidagonists/antagonists.Drugssuchasnaloxoneandnaltrexone,which areusedforreversingopioidoverdose,areantagonists foropioidreceptors(Table2.4).Commonlyusedopioidsinpainmanagementarelistedin Table2.5.Several opioidshaveactivemetabolites,andsomeofthese activemetabolitesarealsousedasindividualdrugs. Opioidsthathaveactivemetabolitesarelisted Table2.6. Allopioidsaresmallmolecules.Theirmolecular weightsarelistedin Table2.7.
TABLE2.3
ClassificationofOpioidsBasedonChemical Structure.
Chemical StructureIndividualDrugs
PhenanthreneMorphine,codeine, buprenorphine,hydrocodone, hydromorphone,levorphanol, oxycodone,oxymorphone, naloxone,nalbuphine
BenzomorphanPentazocine,loperamide
PhenylpiperidinesFentanyl,alfentanil,sufentanil, remifentanil,meperidine
DiphenylheptaneMethadone,propoxyphene
PhenylpropylamineTramadol,tapentadol
Startinginthemid-1990s,allegationsarosethatthe medical fieldsystematicallyundertreatedpain,andthe AmericanPainSocietylobbiedtohavepainrecognized asa fifthvitalsignthat,ifadopted,wouldrequireall physicianstoacceptandtreatpatientcomplaining aboutpain.Asaresult,therewasanincreaseinopioid prescriptionsandincreasingprofitsfordrug manufacturers[9].Atthesametime,publishedpapers inmedicaljournalssuggestedthatcancerpatientsusing prescriptionopioidsdidnotbecomeaddicted.Infact, Schugetal.reportedthatonly1patientoutof550 developedanaddictiontotheirprescriptionpainkillers [10].Anotherstudyreportednocasesofaddiction among10,000burnvictimsusingprescriptionopioid drugs[11].Suchstudiesconvincedcliniciansthatopioidscouldbeusedsafelyforpainmanagement[12]. By2000,theJointCommissionbeganrequiringthat healthcareorganizationsassessandtreatpaininallpatients.OxyContinprescriptionsfornon cancer-related painincreasedfrom670,000in1997tonearly6.2 millionin2002[13].Ithasbeenestimatedthatin 2012,approximately259millionopioidprescriptions hadbeenwritten enoughforeveryadultinAmerica tohaveatleastonebottleofpills[9].
OpioidPrescriptionPattern
Whileopioidprescribinghasbeendecreasinginthe UnitedStatessince2013,theamountofopioidsprescribedisstillthreetimeshigherthanin1999.In 2017,over35%ofopioidoverdosedeathsinvolved aprescriptionopioid[ 14 ].Currently,opioidsareone ofthemostcommonlyprescribeddrugsintheUnited States.Althoughtherateofopioidprescribingishigh, alargeportionofallopioidprescriptionscomesfrom asmallgroupofprescribersandvariesconsiderablyby prescriberspecialty.Inonestudy,theauthorsreported thatbetweenJuly1,2016,andJune30,2017,atotalof 209.5millionopioidprescriptionsweredispensedin theUnitedStates.Primarycarephysicians
TABLE2.4
ClassificationofOpioidDrugsBasedonInteractionsWithOpioidReceptors.
TypeofInteractionExamplesofIndividualDrugsComments
Strong m-opioidreceptor agonists
Heroin,morphine,fentanyl, fentanylderivatives,methadone
Moderate m-opioidreceptor agonists
Codeine,hydrocodone,and oxycodone
Heroinhasnoknowmedicalusewhilemorphine, fentanyl,andfentanylderivativesareusedinpain management,butthesedrugsarealsoaddictive. Methadoneusedfordrugrehabilitationisalso addictive
Oxycodoneandhydrocodonearealsoaddictive
Weak m-opioidreceptoragonistTramadolUseformanagingmoderatepain
MixedopioidreceptoragonistsPentazocinePartialagonistof m receptorandagonistof k receptor
Mixedopioidreceptoragonists/ antagonists BuprenorphinePartialagonistfor m receptorbutantagonistfor k receptorandweakantagonistfor d receptor
AntagonistsforopioidreceptorsNaloxone,naltrexoneAntagonistsofallthreeopioidreceptorsbutmajor actionsarethroughinteractionswith m receptors. Naloxoneisbetterfortreatingopioidoverdose becauseitisshortacting.
TABLE2.5
CommonlyPrescribedOpioids.
OpioidPharmacokineticParameters
MorphineOralbioavailability:23.8%
Volumeofdistribution:2.1 4L/kg.
Plasmaproteinbinding:approximately35%.
Metabolites:morphine-3-glucuronideandmorphine-6-glucuronidethatareexcretedinurine.
Minormetabolite:normorphine
CodeineOralbioavailability:approximately90%
Volumeofdistribution:3 6L/kg
Plasmaproteinbinding:22% 29%
Majormetaboliteiscodeine-6-glucuronide,butmorphine,ametaboliteofcodeine,mayaccountfor someanalgesicactivities.
Minormetabolitesincludefreeandconjugatedhydrocodone,hydromorphone,norhydrocodone, norhydromorphone,normorphine.
OxycodoneOralbioavailabilityis60% 80%,volumeofdistributionis2 4L/kg,andserumproteinbindingis approximately45%.
Peakserumconcentrationisobserved1 2hafteringestingcapsulebut0.5 1.5hafteradministration oforalsolution.
OxycodoneismetabolizedbybothCYP3AandCYP2D6. Only9%ofdoseisrecoveredinurineasunchangedoxycodone,whilemajormetabolitesare noroxycodoneandnoroxymorphone.
HydrocodoneMaximumserumlevelobservedwithin1hororaladministrationwitheliminatinghalf-lifeof4 6. However,forextendedrelease(onceadayformulation),maximumserumconcentrationmaybe observedafter6 30h.
Theaveragevolumeofdistributionis5.7L/kg.
Majormetabolitesarenorhydrocodoneandhydromorphone. Hydromorphoneisanactivemetaboliteresponsibleforpaincontrol.
TABLE2.5
CommonlyPrescribedOpioids. cont'd
OpioidPharmacokineticParameters
HydromorphoneHydromorphonehasadvantageovermorphineinpainmanagement.
Oralbioavailability:50%
Volumeofdistribution:1.22L/kg
Half-lifeis2 3hbutextendedreleaseformulationhasmuchlongerhalf-lifeandcanbeadministered oncedaily.
Majorurinarymetaboliteishydromorphone-3-glucuronide.
OxymorphoneOxymorphoneisa m-opioidagonistwhichismoreactivethanmorphine.
Oralbioavailabilityisapproximately10%.
Proteinbinding:10% 12%
Eliminationhalf-lifeis7 10hforimmediatereleaseformulationbut9 12hforextendedrelease formulation.
Majorurinarymetaboliteisoxymorphone-3-glucuronide,while <2%drugisexcretedunchangedin urine.
FentanylFentanylis80 100timesmorepotentthanmorphine.
Afterintravenousadministration,effectsareobservedwithinminutes.
Oralbioavailability:approximately50%.
Fentanylis80% 86%boundtoserumproteins.
Volumeofdistribution:3 8L/kg
Overlapbetweentherapeuticandtoxicconcentrations.
Majormetabolite:norfentanyl
MethadoneMethadoneisasyntheticopioidthatisusedfortreatingpatientswithopioidaddiction(methadone maintenanceprogram)andalsoforpainmanagement.
Oralbioavailability:approximately75%(upperendupto100%)
Serumproteinbinding:71% 88%,mostlyto a-1-acidglycoprotein,proteinbindingtoserumalbumin minimal.
Meaneliminationhalf-lifeofR-methadoneis37.5h,whichislongerthanmeaneliminationhalf-lifeof S-methadone(28.6h).
VolumeofdistributionishigherforR-methadonethanS-methadone.
Majorinactivemetabolitesofmethadoneare2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine(EDDP)and 2-ethyl-5-methyl-3,3-diphenylpyrroline(EMDP).
MeperidineMeperidineisnolongerconsideredasthe firstchoiceopioiddrugbecauseotheropioidswithbetter safetyprofilesareavailable.
Afteroraladministrationonly50% 60%ofdosereachesthesystematiccirculation.
Thevolumeofdistributionisapproximately3.5L/kg.Meperidineisapproximately65% 75%boundto serumproteins.
Meperidineismetabolizedbytheliverwherehydrolysisofmeperidineproducesmeperidinicacid,and N-demethylationresultsintheformationofnormeperidine.
Neurotoxicityofmeperidineismostlyduetoitsmetabolitenormeperidine.
TramadolTramadolisaracemicmixtureofR(þ)andS( )tramadol.
Tramadolisanatypicalopioidbecauseinadditiontobeingaweakagonistof m-opioidreceptor,italso modulatesthemonoaminergicsystembyinhibitingnoradrenergicandserotoninergicreuptake.
Tramadolisavailablefororalandparenteraladministration.Oralformulationmaybeimmediaterelease orextendedrelease.
Oralbioavailabilityishighandserumproteinbindingisapproximately20%.
TramadolismainlymetabolizedbyO-andN-demethylationandbyconjugationreactionsforming glucuronidesandsulfates.
Tramadolanditsmetabolitesaremainlyexcretedviathekidneys. Themeaneliminationhalf-lifeisabout6h.
TapentadolTapentadolisadualactiondrugwhichactsas m-opioidreceptoragonistandalsoasnorepinephrine reuptakeinhibitors (continued)
TABLE2.5 CommonlyPrescribedOpioids. cont'd
OpioidPharmacokineticParameters
Oralabsorptionisapproximately32%.
Half-lifeis4handduringactionis6h.
VeryfewdruginteractionbecausePhase1metabolismisaminorpathway,whileconjugationwith glucuronicacidandsulfaterepresentmajormetabolicpathway.
BuprenorphineBuprenorphineisusedfortreatingpatientsaddictedtoopioids,aswellasinpainmanagement.
Buprenorphineisapreferredopioidfortreatmentofpaininpatientswithrenalorliverdysfunction. Buprenorphinebioavailabilityis49%afteradministrationofsublingualsolutionand29%withsublingual tablets.
Buprenorphineisapproximately96%proteinboundto a-and b-globulins.
Buprenorphineisextensivelymetabolizedintheliver,andthemajormetaboliteisnorbuprenorphine. BothbuprenorphineandnorbuprenorphinearefurtherconjugatedwithglucuronicacidduringPhaseII metabolism.
Buprenorphineiseliminatedprimarilyviaastool,while10% 30%ofthedoseisexcretedinurineas conjugatedformsofbuprenorphineandnorbuprenorphine.
LevorphanolLevorphanolisauniquesyntheticopioidduetoitswiderangeofactivities,includingagonistfor m-opioid receptor,aswellasboth d-and k-opioidreceptors.Inaddition,levorphanolisanantagonistofN-methylD-aspartatereceptor,aswellasreuptakeinhibitorofbothnorepinephrineandserotonin.
Theterminalhalf-lifeis11 16h,anddurationofanalgesiceffectis6 15h.
Majormetaboliteislevorphanol-3-glucuronide. PropoxypheneWithdrawnfromUSmarketin2010.
(familymedicine,internalmedicine,generalpractice) accountedfor37.1%ofallprescriptions;nonphysician prescribers(physicianassis tant,nursepractitioner) accountedfor19.2%;andpainmedicinespecialists accountedfor8.9%.Comparedwithpreviousresearch, theresultssuggestdecreasesintheshareamongprimarycarephysiciansandincreasesamongnonphysicianprescribersandpainmedicinespecialists[ 15 ]. Natarajetal.reportedthatamongallopioidprescribers,the fi vemostcommonspecialtieswereinternalmedicine(23.8%),familymedicine(15%), surgery(10.5%),emergencymedicine(6.7%),andobstetrics/gynecology(5.7%).Themostcommon
specialtiesamongthesampledhigh-volumeprescriberswerefamilymedicine(32.2%),internalmedicine(22.9%),orthopedics(11.4%),emergency medicine(6.8%),andpainmedicine(5.8%).Themedianageforhigh-volumeprescribersinthesamplewas 53years(comparedwith50yearsforallprescribers). Overall,aswellasacrossallspecialties,hydrocodone hadthehighestmeannumberofprescriptions,followedbyoxycodone,andtramadolwasthethird mostfrequentlyprescribedopioidtypeacrossmost categoriesofspecialists,withafewexceptions.These exceptionsincludeprescriptionofmorphinebyspecialistsofpainmedicine,radiology,oncology,and
