the biology of addic/on and its medical treatment: an overview

Thebiologyofaddic/onanditsmedicaltreatment:anoverview

JoshuaSonkiss,MD

ChiefMedicalOfficer

AnchorageCommunityMentalHealthServices

October16,2017

Disclosurestatement

Ihavenorelevantfinancialintereststodisclose.

Iwilldiscussoff-labeluseofsomemedica/ons.

2JoshuaSonkissMD|AnchorageCommunityMentalHealthServices

LearningObjec/vesAQerpar/cipa/nginthisac/vity,prac//onersshouldbeableto:

•  Explaintwobiomedicalmodelsforaddic/on.

•  Namethreesubstanceusedisordersforwhichthereareevidence-basedpharmacologicinterven/ons.

•  Befamiliarwithmedica/onsmostoQenusedtotreatsubstanceusedisorders.

•  Knowwhentoreferpa/entsforpharmacologictreatmentofaddic/on.

JoshuaSonkissMD|AnchorageCommunityMentalHealthServices 3

Outline

•  Ingredientsofaddic/on•  Neuroanatomyoftherewardcircuit•  Modelsofcogni/veimpairment•  Researchonexecu/vefunc/oninginaddic/on•  Pharmacologictreatmentforaddic/on•  Whentorefer


Whybiology?


Theingredientsofaddic/on

•  Tolerance•  Withdrawal•  Dependence

•  Andali_lesomethingmore


Tolerance

•  Toleranceistheneedtotakemoreofadrugtogetthesameeffect.


WhatCausesTolerance?•  Thebrainmakesadjustmentssoitfunc/onsnormallywhenthedrugispresent,andabnormallywhenit’snot.

•  Thinkoftolerancelikedrivingwiththebrakeson—youhavetopushharderonthegastogetuptohighwayspeed.


Imagingstudies

10

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.

JoshuaSonkissMD|AnchorageCommunityMentalHealthServices

Withdrawal

iswhathappenswhenthegaspedalisallthewaytothefloor–andyousuddenlytakeyourotherfootoffthebrake.


Dependence

Tolerance+Withdrawal

----------------------Dependence

KostenTR.Theneurobiologyofopioiddependence:implica/onsfortreatment.SciPractPerspect.2002Jul;1(1):13-20


Isdependencethesameasaddic/on?


No.


Isdependencethesameasaddic/on?

Youneedsomethingmore.Addic&on:achronic,relapsingbraindiseasethatischaracterizedbycompulsivedrugseekinganduse,despiteharmfulconsequences.

15

Na&onalIns&tuteonDrugAbuse:www.drugabuse.gov


Howdoesaddic/ongetstarted?

16

Dopamineincreasesinresponsetonaturalrewardssuchasfood.JoshuaSonkissMD|AnchorageCommunityMentalHealthServices

DiChiaraetal.Neuroscience.1999Mar;89(3):637-41.DifiorinoandPhillips.JNeurosci.1997Jun15;17(12):4849-55

17

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

Whatsustainsaddic/on?

Condi/oningbasedonmemoriesofintensepleasure18JoshuaSonkissMD|AnchorageCommunityMentalHealthServices

Whatsustainsaddic/on?

•  Salienceofdrugseclipsesothers/muli,includingnaturalconsequences



20

PhotocopyrightSureshEswaren.Nochangesmade.h_ps://crea/vecommons.org/licenses/by-nc-nd/4.0/legalcode


Salienceinthehealthybrain

21

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Salienceintheaddictedbrain

22

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BenowitzNL.MedClinNorthAm.1992Mar;76(2):415-37

Thenico/necycle:runningawayfromwithdrawal

Therewardcircuit•  Prefrontalcortex:theseatofwill

§  Glutamate:inhibi/on(thoughexcitatoryNT)•  Nucleusaccumbens:theseatofpleasure

§  Dopamine:desire§  Serotonin:sa/etyandinhibi/on

•  Ventraltegmentalarea:theseatofreward§  Dopamine:pleasure

•  Locuscoeruleus:theseatofarousal§  Norepinephrine:sympathe/cresponse


Therewardcircuit



Biomedicalmodelsofaddic/on

•  ChangedsetpointOpioidusecausespermanentstructuralandchemicalchangesthatcreateanewbiologicalandbehavioralbaselinefortheaddict.



Biomedicalmodelsofaddic/on

•  Cogni.vedeficitsOpioidusedegradesprefrontalcor/calinhibi/onofthedrivetouse,underminingtheaddictedperson’swillataneurologicallevel.



Cogni/vedeficitmodel


x


Domainsofcogni/veimpairment•  Impulsiveness

I’mnotgoingtothinktoomuchdecidingtogethigh.

•  Rewardhypersensi/vityIwanttogethighmorethananythingelse.

•  Harmhyposensi/vityIforgothowbaditfeltthelast&meIwenttojail.

•  Increasedrisk-takingMyproba&onofficerprobablywon’tfindout.

•  Outcomemyopia(i.e.temporaldiscoun/ng)Mykidsmightgettakenaway,butnotrightnow.


IGTandabs/nenceinmethamphetamineusers


Wangetal.Effectsoflengthofabs/nenceondecision-makingandcravinginmethamphetamineabusers.PLoSOne.2013Jul24;8(7):e68791.

Decision-makingabilityontheIowaGamblingTask(IGT)inMETHabusersatdifferentabs/nence/mesandhealthycontrolsover100cardchoices.

Decision-makinginopioidusers


Biernackietal.Decision-makingabilityincurrentandpastusersofopiates:Ameta-analysis.NeurosciBiobehavRev.2016Sep17;71:342-351.

Awordaboutdetoxifica/on•  Notatreatment—medically-assistedwithdrawal

•  Usefulasabridgetopsychosocialorpharmacologictreatment

•  Veryhighrelapserateswhenusedalone•  Withopioids,elevatedriskofoverdosedeathwithinonemonthofanydetoxprotocol

NosykBetal.Acallforevidence-basedmedicaltreatmentofopioiddependence.HealthAff(Millwood).2013Aug;32(8):1462-9.


Tobacco



*

*OnewaytodothisistorecommendcallingtheQuitLine.

Aroadmapforquiung

TheQuitLine


Medica/onsforTUD

•  Nico/neReplacementTherapy(NRT)§  Increasesquitratesby50-70%regardlessofse?ng

§  FDA-approved,safe§  Patch,gum,lozenge,spray§  QuitLine


Medica/onsforTUD•  Bupropion(Zyban)

§  Increasesdopamine,norepinephrineandserotonin§  Doubles6-monthquitratecomparedtoplacebo§  An/depressant§  FDA-approved

•  Varenicline(Chan/x)§  Partlyblocksnico/nereceptor§  Morethandoublesquitratecomparedtoplacebo§  FDA-approved§  Suicide?Psychosis?


Gonazlesital.ClinPharmacolTher.2001;69:438-444.Jorenbyetal.JAMA.2006Jul5;296(1):56-63

Medica/onsforTUD

•  Nortriptyline(Pamelor)§  Tricyclic(oldschool)an/depressant§  NotFDA-approved

•  Clonidine(Minipress)§  Bloodpressuremedicine§  NotFDA-approved


Medica/onsforAUD

•  Disulfiram(Antabuse)§  “Theonethatmakesyousickwhenyoudrink”§  Blocksaldehydedehydrogenase§  Ethicalconcerns§ Maybeeffec/vewhenobserved§  Rarelyused§  FDA-approved


Medica/onsforAUD

•  Acamprosate(Campral)§  RestoresbalancebetweenGABAandNMDAneurotransmission

§  Reducesrelapsebyhalfcomparedwithplacebo§  666mgthree/mesdaily§  Reducescravings§  FDA-approved


Medica/onsforAUD

•  Naltrexone(Revia)§  Blocksopioidreceptors§  30-40%reduc/oninrelapsetoheavydrinking§  Reducesthepleasureassociatedwithdrinking§  Reducescravings§  Four-weekinjec/onavailable(Vivitrol)§  FDA-approved


SrisurapanontM,JarusuraisinN.CochraneDatabaseSystRev2005;(1):CD001867

EmergingAUDtreatments(notFDA-approved)

•  Gabapen/n(Neuron/n)§  Effec/veforanxiety§  Abusable§ MaybeFDA-approvedsoon

•  Topiramate(Topamax)§  “Stupamax,”“Dopamax”§ Weightloss

•  Baclofen(Gablofen,Lioresal)


BenzodiazepinesandAUD

•  Benzosincludeclonazepam(Klonepin),lorazepam(A/van),alprazolam(Xanax)andmanyothers

•  Importantfordetox•  Cross-tolerant•  Cancauserelapse•  Cancauserespiratorydepression/arrest


Opioids


ORTORTNotORT

FullAgonistTreatment(ORT)

•  Methadone§  Spectacularresultssince1965§  Fullagonistbutlonghalf-life§  Administeredonlyinspeciallylicensedmethadoneclinicswhenusedforaddic/ontreatment

§  Canbeusedforpaintreatment§  FDA-approved


Par/alAgonistTreatment(ORT)

•  Buprenorphine(Suboxone,Subutex,etc.)§  Par/alagonist—hardertooverdose§  PrescribersneedspecialtrainingandDEAcer/ficate,butintheorycanbeadministeredinanyprescriber’soffice.

§  Canbeusedforpaintreatment,nospecialtrainingrequired

§  FDA-approved


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.


DisadvantagesofORT

•  Poten/alforabuseanddiversionofmedica/on

•  Lifelongtreatmentformany—upto95percentrelapsewhentapera_empted

•  SomepeopleseeORTas“subs/tu/ngoneaddic/onforanother.”

NosykBetal.Acallforevidence-basedmedicaltreatmentofopioiddependence.HealthAff(Millwood).2013Aug;32(8):1462-9.


WhyuseORT?


Maucketal.Methadonemaintenancetherapyversusnoopioidreplacementtherapyforopioiddependence.CochraneDatabaseSystRev.2009Jul8;(3):CD002209.

AntagonistTreatment(notORT)

•  Oralorlong-ac/nginjectablenaltrexone(Vivitrol)

•  Advantages:•  Blockshighfromopioids•  Avoidss/gmaofORT(doesn’t“replaceoneaddic/onwithanother”)

•  Appealstopolicymakerswhofavorabs/nence•  Can’tbeabusedordiverted


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


PregnancyandOUD•  Opioiduseandopioidwithdrawalhaveadverseeffectsonfetus.

•  Withdrawalisusuallymoreserious(prematuredelivery,s/llbirth).

•  Therefore,abs/nence-basedtreatmentisnotrecommendedduringpregnancyforanyonewhoisac/velyusingopioids.


KampmanandJarvis.AmericanSocietyofAddic/onMedicine(ASAM)Na/onalPrac/ceGuidelinefortheUseofMedica/onsintheTreatmentofAddic/onInvolvingOpioidUse.JAddictMed2015;9358-367

PregnancyandOUD•  Opioidreplacementtherapyisthestandardofcareinpregnancy.

•  Medically-assistedwithdrawalisnotrecommended.

•  Neonatalabs/nencesyndromeistreatableandusuallyresolvesinseveralweeks.


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


Substanceswithli_leornoevidencetosupportpharmacologictreatment•  Seda/ve-hypno/cs

§ Medicallymanagedwithdrawal

•  S/mulants§  Con/ngencymanagement

•  Cannabisandsynthe/ccannabinoids§  Counseling,12-step

•  Hallucinogens§  Notaddic/ve


Whenshouldyourefertoanaddic/onmedicinespecialist?

•  Whenpharmacologictreatmentsexistforthesubstanceyourpa/entisusing

•  Whenpsychosocialinterven/onsalonehavenotbeensuccessful

•  Whenapa/entasksforareferral•  Wheneverapa/enthasopioidusedisorder•  Ifyourpa/entispregnant


Learningassessment

1.Whichofthefollowingistrueaboutpsychosocialinterven/onsinaddic/on?a.Accordingtorecentstudies,theyofferli_lebenefitforopioidusedisorder.

b.Researchhasshownsomepsychosocialinterven/onsareworsethandoingnothing.

c.Theyarethecornerstoneoftreatmentforcannabisusedisorder.

d.aandbonlye.alloftheabove


Learningassessment

2.Whichofthefollowingneurotransmi_ersplaysacentralroleinalladdic/ons?a.GABAb.Norepinephrinec.Serotonind.Dopaminee.Dynorphins


Learningassessment

3.Whichofthefollowingaretrueaboutabs/nence-basedtreatmentforOUD?a.Itincreasestheriskofoverdosedeath.b.ItshouldalwaysbetriedbeforeORT.c.Itworksforasmallminorityofpa/ents.d.aandconlye.alloftheabove


Learningassessment

4.Whatisthesafesttreatmentforpregnantwomenwithopioidusedisorder?a.Opioidreplacementtherapyb.Rapiddetoxifica/onc.Slowdetoxifica/ond.aandconlye.alloftheabove


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.


Ques/ons?

JoshuaSonkissMD|AnchorageCommunityMentalHealthServices 66PhotobySylvainPedneault

the biology of addic/on and its medical treatment: an overview

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