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Thebiologyofaddic/onanditsmedicaltreatment:anoverview
JoshuaSonkiss,MD
ChiefMedicalOfficer
AnchorageCommunityMentalHealthServices
October16,2017
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Disclosurestatement
Ihavenorelevantfinancialintereststodisclose.
Iwilldiscussoff-labeluseofsomemedica/ons.
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LearningObjec/vesAQerpar/cipa/nginthisac/vity,prac//onersshouldbeableto:
• Explaintwobiomedicalmodelsforaddic/on.
• Namethreesubstanceusedisordersforwhichthereareevidence-basedpharmacologicinterven/ons.
• Befamiliarwithmedica/onsmostoQenusedtotreatsubstanceusedisorders.
• Knowwhentoreferpa/entsforpharmacologictreatmentofaddic/on.
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Outline
• Ingredientsofaddic/on• Neuroanatomyoftherewardcircuit• Modelsofcogni/veimpairment• Researchonexecu/vefunc/oninginaddic/on• Pharmacologictreatmentforaddic/on• Whentorefer
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Whybiology?
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Theingredientsofaddic/on
• Tolerance• Withdrawal• Dependence
• Andali_lesomethingmore
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Tolerance
• Toleranceistheneedtotakemoreofadrugtogetthesameeffect.
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WhatCausesTolerance?• Thebrainmakesadjustmentssoitfunc/onsnormallywhenthedrugispresent,andabnormallywhenit’snot.
• Thinkoftolerancelikedrivingwiththebrakeson—youhavetopushharderonthegastogetuptohighwayspeed.
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Imagingstudies
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Changesindopaminereceptordensityinventralstriatumandeffectonrela/veresponsenaturalversusdrugreinforcersincocaineaddic/on.
Volkow et al. The addicted human brain viewed in the light of imaging studies: brain circuits and treatment strategies. Neuropharmacology. 2004;47 Suppl 1:3-13.
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Withdrawal
iswhathappenswhenthegaspedalisallthewaytothefloor–andyousuddenlytakeyourotherfootoffthebrake.
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Dependence
Tolerance+Withdrawal
----------------------Dependence
KostenTR.Theneurobiologyofopioiddependence:implica/onsfortreatment.SciPractPerspect.2002Jul;1(1):13-20
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Isdependencethesameasaddic/on?
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No.
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Isdependencethesameasaddic/on?
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Youneedsomethingmore.Addic&on:achronic,relapsingbraindiseasethatischaracterizedbycompulsivedrugseekinganduse,despiteharmfulconsequences.
15
Na&onalIns&tuteonDrugAbuse:www.drugabuse.gov
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Howdoesaddic/ongetstarted?
16
Dopamineincreasesinresponsetonaturalrewardssuchasfood.JoshuaSonkissMD|AnchorageCommunityMentalHealthServices
DiChiaraetal.Neuroscience.1999Mar;89(3):637-41.DifiorinoandPhillips.JNeurosci.1997Jun15;17(12):4849-55
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Intoxica/ngdrugscauseanexaggerateddopaminergicresponse.JoshuaSonkissMD|AnchorageCommunityMentalHealthServices
DiChiaraetal.Neuroscience.1999Mar;89(3):637-41.DifiorinoandPhillips.JNeurosci.1997Jun15;17(12):4849-55
DichiaraandImperato.ProcNatlAcadSciUSA.1988Jul;85(14):5274-8
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Whatsustainsaddic/on?
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Whatsustainsaddic/on?
• Salienceofdrugseclipsesothers/muli,includingnaturalconsequences
KostenTR.Theneurobiologyofopioiddependence:implica/onsfortreatment.SciPractPerspect.2002Jul;1(1):13-20
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PhotocopyrightSureshEswaren.Nochangesmade.h_ps://crea/vecommons.org/licenses/by-nc-nd/4.0/legalcode
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Salienceinthehealthybrain
21
>>>
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Salienceintheaddictedbrain
22
<<<
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BenowitzNL.MedClinNorthAm.1992Mar;76(2):415-37
Thenico/necycle:runningawayfromwithdrawal
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Therewardcircuit• Prefrontalcortex:theseatofwill
§ Glutamate:inhibi/on(thoughexcitatoryNT)• Nucleusaccumbens:theseatofpleasure
§ Dopamine:desire§ Serotonin:sa/etyandinhibi/on
• Ventraltegmentalarea:theseatofreward§ Dopamine:pleasure
• Locuscoeruleus:theseatofarousal§ Norepinephrine:sympathe/cresponse
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Therewardcircuit
KostenTR.Theneurobiologyofopioiddependence:implica/onsfortreatment.SciPractPerspect.2002Jul;1(1):13-20
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Biomedicalmodelsofaddic/on
• ChangedsetpointOpioidusecausespermanentstructuralandchemicalchangesthatcreateanewbiologicalandbehavioralbaselinefortheaddict.
KostenTR.Theneurobiologyofopioiddependence:implica/onsfortreatment.SciPractPerspect.2002Jul;1(1):13-20
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Biomedicalmodelsofaddic/on
• Cogni.vedeficitsOpioidusedegradesprefrontalcor/calinhibi/onofthedrivetouse,underminingtheaddictedperson’swillataneurologicallevel.
KostenTR.Theneurobiologyofopioiddependence:implica/onsfortreatment.SciPractPerspect.2002Jul;1(1):13-20
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Cogni/vedeficitmodel
KostenTR.Theneurobiologyofopioiddependence:implica/onsfortreatment.SciPractPerspect.2002Jul;1(1):13-20
x
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Domainsofcogni/veimpairment• Impulsiveness
I’mnotgoingtothinktoomuchdecidingtogethigh.
• Rewardhypersensi/vityIwanttogethighmorethananythingelse.
• Harmhyposensi/vityIforgothowbaditfeltthelast&meIwenttojail.
• Increasedrisk-takingMyproba&onofficerprobablywon’tfindout.
• Outcomemyopia(i.e.temporaldiscoun/ng)Mykidsmightgettakenaway,butnotrightnow.
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IGTandabs/nenceinmethamphetamineusers
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Wangetal.Effectsoflengthofabs/nenceondecision-makingandcravinginmethamphetamineabusers.PLoSOne.2013Jul24;8(7):e68791.
Decision-makingabilityontheIowaGamblingTask(IGT)inMETHabusersatdifferentabs/nence/mesandhealthycontrolsover100cardchoices.
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Decision-makinginopioidusers
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Biernackietal.Decision-makingabilityincurrentandpastusersofopiates:Ameta-analysis.NeurosciBiobehavRev.2016Sep17;71:342-351.
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Awordaboutdetoxifica/on• Notatreatment—medically-assistedwithdrawal
• Usefulasabridgetopsychosocialorpharmacologictreatment
• Veryhighrelapserateswhenusedalone• Withopioids,elevatedriskofoverdosedeathwithinonemonthofanydetoxprotocol
NosykBetal.Acallforevidence-basedmedicaltreatmentofopioiddependence.HealthAff(Millwood).2013Aug;32(8):1462-9.
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Tobacco
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*
*OnewaytodothisistorecommendcallingtheQuitLine.
Aroadmapforquiung
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TheQuitLine
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Medica/onsforTUD
• Nico/neReplacementTherapy(NRT)§ Increasesquitratesby50-70%regardlessofse?ng
§ FDA-approved,safe§ Patch,gum,lozenge,spray§ QuitLine
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Medica/onsforTUD• Bupropion(Zyban)
§ Increasesdopamine,norepinephrineandserotonin§ Doubles6-monthquitratecomparedtoplacebo§ An/depressant§ FDA-approved
• Varenicline(Chan/x)§ Partlyblocksnico/nereceptor§ Morethandoublesquitratecomparedtoplacebo§ FDA-approved§ Suicide?Psychosis?
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Gonazlesital.ClinPharmacolTher.2001;69:438-444.Jorenbyetal.JAMA.2006Jul5;296(1):56-63
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Medica/onsforTUD
• Nortriptyline(Pamelor)§ Tricyclic(oldschool)an/depressant§ NotFDA-approved
• Clonidine(Minipress)§ Bloodpressuremedicine§ NotFDA-approved
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Medica/onsforAUD
• Disulfiram(Antabuse)§ “Theonethatmakesyousickwhenyoudrink”§ Blocksaldehydedehydrogenase§ Ethicalconcerns§ Maybeeffec/vewhenobserved§ Rarelyused§ FDA-approved
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Medica/onsforAUD
• Acamprosate(Campral)§ RestoresbalancebetweenGABAandNMDAneurotransmission
§ Reducesrelapsebyhalfcomparedwithplacebo§ 666mgthree/mesdaily§ Reducescravings§ FDA-approved
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Medica/onsforAUD
• Naltrexone(Revia)§ Blocksopioidreceptors§ 30-40%reduc/oninrelapsetoheavydrinking§ Reducesthepleasureassociatedwithdrinking§ Reducescravings§ Four-weekinjec/onavailable(Vivitrol)§ FDA-approved
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SrisurapanontM,JarusuraisinN.CochraneDatabaseSystRev2005;(1):CD001867
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EmergingAUDtreatments(notFDA-approved)
• Gabapen/n(Neuron/n)§ Effec/veforanxiety§ Abusable§ MaybeFDA-approvedsoon
• Topiramate(Topamax)§ “Stupamax,”“Dopamax”§ Weightloss
• Baclofen(Gablofen,Lioresal)
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BenzodiazepinesandAUD
• Benzosincludeclonazepam(Klonepin),lorazepam(A/van),alprazolam(Xanax)andmanyothers
• Importantfordetox• Cross-tolerant• Cancauserelapse• Cancauserespiratorydepression/arrest
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Opioids
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ORTORTNotORT
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FullAgonistTreatment(ORT)
• Methadone§ Spectacularresultssince1965§ Fullagonistbutlonghalf-life§ Administeredonlyinspeciallylicensedmethadoneclinicswhenusedforaddic/ontreatment
§ Canbeusedforpaintreatment§ FDA-approved
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Par/alAgonistTreatment(ORT)
• Buprenorphine(Suboxone,Subutex,etc.)§ Par/alagonist—hardertooverdose§ PrescribersneedspecialtrainingandDEAcer/ficate,butintheorycanbeadministeredinanyprescriber’soffice.
§ Canbeusedforpaintreatment,nospecialtrainingrequired
§ FDA-approved
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AdvantagesofORT
• Consistentevidencetosupportefficacy• Be_ertreatmentreten/on• Feweroverdosedeaths• Lesshospitaliza/on• Costeffec/venessDugoshK.ASystema/cReviewontheUseofPsychosocialInterven/onsinConjunc/onWithMedica/onsfortheTreatmentofOpioidAddic/on.JAddictMed.2016Mar-Apr;10(2):91-101.MauckR.Buprenorphinemaintenanceversusplaceboormethadonemaintenanceforopioiddependence.CochraneDatabaseSystRev.2008Apr16;(2).NosykBetal.Acallforevidence-basedmedicaltreatmentofopioiddependence.HealthAff(Millwood).2013Aug;32(8):1462-9.
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DisadvantagesofORT
• Poten/alforabuseanddiversionofmedica/on
• Lifelongtreatmentformany—upto95percentrelapsewhentapera_empted
• SomepeopleseeORTas“subs/tu/ngoneaddic/onforanother.”
NosykBetal.Acallforevidence-basedmedicaltreatmentofopioiddependence.HealthAff(Millwood).2013Aug;32(8):1462-9.
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WhyuseORT?
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Maucketal.Methadonemaintenancetherapyversusnoopioidreplacementtherapyforopioiddependence.CochraneDatabaseSystRev.2009Jul8;(3):CD002209.
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AntagonistTreatment(notORT)
• Oralorlong-ac/nginjectablenaltrexone(Vivitrol)
• Advantages:• Blockshighfromopioids• Avoidss/gmaofORT(doesn’t“replaceoneaddic/onwithanother”)
• Appealstopolicymakerswhofavorabs/nence• Can’tbeabusedordiverted
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AntagonistTreatment(notORT)
• Disadvantages:• Oralnaltrexonenobe_erthanplaceboMinozziSetal,CochraneDatabaseSystRev2011
• Long-ac/nginjectablenaltrexone(Vivitrol)promising,butlimitedevidence
LeeJetal.Extended-ReleaseNaltrexonetoPreventOpioidRelapseinCriminalJus/ceOffenders.NEnglJMed.2016Mar31;374(13):1232-42KrupitskyEetal.Injectableextended-releasenaltrexone(XR-NTX)foropioiddependence:long-termsafetyandeffec/veness.Addic/on.2013Sep;108(9):1628-37
• Hightreatmentdropoutrates• Mayinterferewithpaintreatment
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PregnancyandOUD• Opioiduseandopioidwithdrawalhaveadverseeffectsonfetus.
• Withdrawalisusuallymoreserious(prematuredelivery,s/llbirth).
• Therefore,abs/nence-basedtreatmentisnotrecommendedduringpregnancyforanyonewhoisac/velyusingopioids.
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KampmanandJarvis.AmericanSocietyofAddic/onMedicine(ASAM)Na/onalPrac/ceGuidelinefortheUseofMedica/onsintheTreatmentofAddic/onInvolvingOpioidUse.JAddictMed2015;9358-367
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PregnancyandOUD• Opioidreplacementtherapyisthestandardofcareinpregnancy.
• Medically-assistedwithdrawalisnotrecommended.
• Neonatalabs/nencesyndromeistreatableandusuallyresolvesinseveralweeks.
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Behavioraladdic/ons
• Sexualaddic/ons§ SSRIan/depressants(e.g.fluoxe/nehaveshownbenefit
§ Cau/onwiths/mulants,benzodiazepines,bupropion
• Gamblingaddic/on§ Naltrexone(Revia,Vivitrol)hasshownbenefit§ SSRIshaveshownbenefit§ Cau/onwiths/mulants,somean/psycho/cs
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Substanceswithli_leornoevidencetosupportpharmacologictreatment• Seda/ve-hypno/cs
§ Medicallymanagedwithdrawal
• S/mulants§ Con/ngencymanagement
• Cannabisandsynthe/ccannabinoids§ Counseling,12-step
• Hallucinogens§ Notaddic/ve
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Whenshouldyourefertoanaddic/onmedicinespecialist?
• Whenpharmacologictreatmentsexistforthesubstanceyourpa/entisusing
• Whenpsychosocialinterven/onsalonehavenotbeensuccessful
• Whenapa/entasksforareferral• Wheneverapa/enthasopioidusedisorder• Ifyourpa/entispregnant
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Learningassessment
1.Whichofthefollowingistrueaboutpsychosocialinterven/onsinaddic/on?a.Accordingtorecentstudies,theyofferli_lebenefitforopioidusedisorder.
b.Researchhasshownsomepsychosocialinterven/onsareworsethandoingnothing.
c.Theyarethecornerstoneoftreatmentforcannabisusedisorder.
d.aandbonlye.alloftheabove
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Learningassessment
2.Whichofthefollowingneurotransmi_ersplaysacentralroleinalladdic/ons?a.GABAb.Norepinephrinec.Serotonind.Dopaminee.Dynorphins
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Learningassessment
3.Whichofthefollowingaretrueaboutabs/nence-basedtreatmentforOUD?a.Itincreasestheriskofoverdosedeath.b.ItshouldalwaysbetriedbeforeORT.c.Itworksforasmallminorityofpa/ents.d.aandconlye.alloftheabove
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Learningassessment
4.Whatisthesafesttreatmentforpregnantwomenwithopioidusedisorder?a.Opioidreplacementtherapyb.Rapiddetoxifica/onc.Slowdetoxifica/ond.aandconlye.alloftheabove
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Learningassessment
5.Whichofthefollowingistrueaboutsmokingcessa/ondrugs?a.TheQuitLineofferscoachingonly.b.E-cigare_esareeffec/veforsmokingcessa/on.c.Varenicline(Chan/x)causessuicide.d.NRTshouldneverbecombinedwithvarenicline(Chan/x)orbupriopion(Zyban).
e.NRTincreasesquitratesby50-70%regardlessofpsychosocialtreatment.
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Ques/ons?
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