Substance Use Disorders Substance Use Disorders (SUD)(SUD)

Cost $67 bill/yr in crime/↓ workCost $67 bill/yr in crime/↓ workRates past year:Rates past year:

Alcohol (ETOH)- 8%Alcohol (ETOH)- 8% Cocaine~ 1%Cocaine~ 1% Opiates- 1%Opiates- 1%

2© AMSP 2011

Cocaine Especially ProblematicCocaine Especially Problematic >2 million in U.S. cocaine dependent>2 million in U.S. cocaine dependent Serious consequencesSerious consequences

Medical: heart attack, stroke, seizureMedical: heart attack, stroke, seizure Psychological: psychosis, mood disturbancePsychological: psychosis, mood disturbance Legal: possession, trafficking, theftLegal: possession, trafficking, theft ER visits ER visits ↑↑ ~ 50% in past 10 yrs ~ 50% in past 10 yrs

3© AMSP 2011

This Lecture ReviewsThis Lecture Reviews DefinitionsDefinitions Tx options & limitationsTx options & limitations Biology of cocaine use disorder Biology of cocaine use disorder

(CUD)(CUD) How vaccines (vax) work & How vaccines (vax) work &

application to CUDapplication to CUD

4© AMSP 2011

Abuse & DependenceAbuse & Dependence Abuse ≥1 of:Abuse ≥1 of:

Failure in major Failure in major obligationsobligations

Hazardous situations Hazardous situations useuse

Legal problemsLegal problems Social or interpersonal Social or interpersonal

problemsproblems

Dependence ≥3 of:Dependence ≥3 of: ToleranceTolerance WithdrawalWithdrawal Unable Unable ↓↓use or quituse or quit ↑ ↑ time find, use, & time find, use, &

recover recover ↑ ↑ aamount & time usingmount & time using Stop important Stop important

activitiesactivities Use despite Use despite

consequencesconsequences

5© AMSP 2011

Clinical VignetteClinical Vignette 38 yo, married, wm attorney in ER38 yo, married, wm attorney in ER

Suicidal thoughts (e.g.,withdrawal)Suicidal thoughts (e.g.,withdrawal) $30 crack cocaine/d$30 crack cocaine/d Binges $1000/weekend Binges $1000/weekend

(e.g.,tolerance)(e.g.,tolerance) Paranoia after binge Paranoia after binge

(e.g.,consequence)(e.g.,consequence)

6© AMSP 2011

Clinical VignetteClinical VignetteDiagnosis: cocaine dep Diagnosis: cocaine dep

ToleranceToleranceWithdrawalWithdrawalPsychological problemsPsychological problems

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This Lecture ReviewsThis Lecture ReviewsDefinitions Definitions √√Tx options & limitationsTx options & limitationsBiology of CUDBiology of CUDHow vax work & application How vax work & application

to CUDto CUD

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Limited Medications for Limited Medications for ETOHETOH

Disulfiram (Antabuse 250 mg/d)Disulfiram (Antabuse 250 mg/d) Inhibits aldehyde dehydrogenaseInhibits aldehyde dehydrogenase Causes physical symptomsCauses physical symptoms ↓ ↓ ETOH use in highly motivated ETOH use in highly motivated

patients patients Many side effectsMany side effects Placebo control studies rarePlacebo control studies rare

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Limited Medications for Limited Medications for ETOHETOH

Naltrexone (Revia 50mg/d)Naltrexone (Revia 50mg/d)Opioid receptor antagonistOpioid receptor antagonistReceptors key in rewardReceptors key in rewardMay May ↓ ↓ reward of drinkreward of drink↓ ↓ heavy ETOH useheavy ETOH use

10© AMSP 2011

Limited Medications for Limited Medications for ETOHETOH

Acamprosate (Campral 1-2 g/d)Acamprosate (Campral 1-2 g/d) NMDA receptor antagonistNMDA receptor antagonist Receptors Receptors ↑ ↑ activity after abstinentactivity after abstinent NMDA NMDA ↑ ↑ anxiety & insomniaanxiety & insomnia ↓ ↓ start drink & start drink & ↓ ↓ quantity of ETOHquantity of ETOH

Overall, Overall, ↑ ↑ outcome 15%outcome 15%

11© AMSP 2011

Limited Medications for Limited Medications for OpioidsOpioids

Methadone (Methadone ≥ 80mg/d)Methadone (Methadone ≥ 80mg/d) Long acting opioid receptor agonistLong acting opioid receptor agonist Daily dosing Daily dosing → → no withdrawalno withdrawal Blunts euphoria if take opioidsBlunts euphoria if take opioids ↑↑abstinence, abstinence, ↑↑employment, employment, ↓↓crimecrime ↓↓relapserelapse

12© AMSP 2011

Limited Medications for Limited Medications for Opioids Opioids

Buprenorphine (Subutex 16-Buprenorphine (Subutex 16-20mg/d)20mg/d)Long acting opioid partial Long acting opioid partial

agonistagonist↑↑abstinence & abstinence & ↓↓relapserelapse

13© AMSP 2011

Limited Medications for Limited Medications for OpioidsOpioids

Naltrexone (Revia 50-100mg/d)Naltrexone (Revia 50-100mg/d)Opioid receptor antagonistOpioid receptor antagonistBlocks opioid highBlocks opioid high↑↑aabstinence & bstinence & ↓↓relapserelapse

All need motivation to takeAll need motivation to take ↑ ↑ modest outcomemodest outcome

14© AMSP 2011

Limited Medications for Limited Medications for NicotineNicotine

Nicotine replacement (gum, patch, spray, etc)Nicotine replacement (gum, patch, spray, etc) 2X quit rate 2X quit rate

Buproprion SR (Zyban 150mg BID)Buproprion SR (Zyban 150mg BID) Inhibits DA & NE reuptakeInhibits DA & NE reuptake 2X quit rate2X quit rate

Varenicline (Chantix 1mg/BID)Varenicline (Chantix 1mg/BID) Selective nicotine receptor partial agonistSelective nicotine receptor partial agonist 3X quit rate3X quit rate

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Limited Tx Options for CUDLimited Tx Options for CUDNo effective meds for CUDNo effective meds for CUDHigh noncompliance & High noncompliance &

relapserelapse Drop out~ 50% from txDrop out~ 50% from tx Relapse- 52% 1 yr after txRelapse- 52% 1 yr after tx

16© AMSP 2011

Behavioral InterventionsBehavioral Interventions Cognitive behavioral therapy (CBT)Cognitive behavioral therapy (CBT)

Emphasizes skills trainingEmphasizes skills trainingHelps recognize consequences Helps recognize consequences

LegalLegalMedical Medical Occupational Occupational

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CBT (cont’d)CBT (cont’d) Recognize dysfunctional thinkingRecognize dysfunctional thinking Substitute w/ rational thoughtsSubstitute w/ rational thoughts Develop coping skillsDevelop coping skills

Anticipate triggersAnticipate triggers Incorporate strategies to cope w/ Incorporate strategies to cope w/

triggerstriggers Abstinence @ 17wks: CBT (40%) vs. tx Abstinence @ 17wks: CBT (40%) vs. tx

as usual (TAU) (23%)as usual (TAU) (23%)

18© AMSP 2011

Contingency Management Contingency Management (CM)(CM)

Reinforced behaviors more likely repeatedReinforced behaviors more likely repeated

Received vouchers for goods w/ Received vouchers for goods w/ ↓ ↓ cocaine cocaine useuse

↑↑compliance: CM (50%) vs. no tx (5%)compliance: CM (50%) vs. no tx (5%)

↓↓continued use: CM (52%) vs. TAU (27%)continued use: CM (52%) vs. TAU (27%)

19© AMSP 2011

Behavioral InterventionsBehavioral Interventions Combination Combination tx-tx- abstinence @ 3 wks: abstinence @ 3 wks:

CBT (35%); CM (60%); Combo (70%) CBT (35%); CM (60%); Combo (70%)

Novel tx approaches neededNovel tx approaches needed Understanding CUD impact on CNSUnderstanding CUD impact on CNS Technological advances Technological advances → → new new

approaches (e.g., vax)approaches (e.g., vax)

20© AMSP 2011

This Lecture ReviewsThis Lecture Reviews

Definitions Definitions √√Tx options & limitations Tx options & limitations √√Biology of CUDBiology of CUDHow vax work & application to How vax work & application to

CUDCUD

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Biology of CUDBiology of CUDCoke Coke ↑ ↑ DA in CNSDA in CNS

Blocks DA reuptake Blocks DA reuptake transportertransporter

↑ ↑ DA DA → → reinforcing effectsreinforcing effectsCoke- small molecule crosses Coke- small molecule crosses

blood brain barrier (BBB)blood brain barrier (BBB)22© AMSP 2011

Biology of CUDBiology of CUD Route of administration = onset of Route of administration = onset of

CNS effectsCNS effects Smoking- 6-8 secs in modest amtsSmoking- 6-8 secs in modest amts IV-15 secs in large amtsIV-15 secs in large amts Intranasal- minutes in lower amtsIntranasal- minutes in lower amts More delay & More delay & ↓ ↓ amts amts → ↓ → ↓ reinforcereinforce

23© AMSP 2011

This Lecture ReviewsThis Lecture Reviews

Definitions Definitions √√Tx options & limitations Tx options & limitations √√Biology of CUD Biology of CUD √√How vax work & application to How vax work & application to

CUDCUD24

© AMSP 2010

How vax workHow vax workDefinitionsDefinitions

Antigens (Ags): substances Antigens (Ags): substances → → immune responseimmune response

Antibodies (Abs): proteins Antibodies (Abs): proteins made in antigen responsemade in antigen response

25© AMSP 2011

Active ImmunityActive Immunity

Active Immunity (AI) Active Immunity (AI) → → specific Abspecific Ab Confers longer immunity (memory)Confers longer immunity (memory) ↓ ↓ cost vs. monoclonal Abs (mAbs) cost vs. monoclonal Abs (mAbs) Requires time for Ab productionRequires time for Ab production Inter-individual variabilityInter-individual variability

26© AMSP 2011

Passive Immunity Passive Immunity Passive immunity (PI)Passive immunity (PI)

Immediate onset Immediate onset ↑↑ expensive than AIexpensive than AI Shorter immunity than AIShorter immunity than AI ↓↓ inter-individual variabilityinter-individual variability

Both types of immunotherapy must:Both types of immunotherapy must: Elicit immune responseElicit immune response Produce Abs specific to cokeProduce Abs specific to coke

27© AMSP 2011

Vax Strategies Vax Strategies Goal: prevent coke entering CNSGoal: prevent coke entering CNS ↑ ↑ iimmune response mmune response → → Abs productionAbs production Abs bind to cokeAbs bind to coke Ab-coke complex large:Ab-coke complex large:

Cannot cross BBBCannot cross BBBCannot cross placentaCannot cross placenta

28© AMSP 2011

Tetanus (1µg/mL) vs. coke (40µg/mL)Tetanus (1µg/mL) vs. coke (40µg/mL) ↑↑Abs = Abs = ↑↑coke binding coke binding → ↓→ ↓coke in coke in

CNSCNS Efficacy = 80% bindingEfficacy = 80% binding Blunted response = 50% bindingBlunted response = 50% binding Not interfere w/ coke metabolismNot interfere w/ coke metabolism ↓↓metabolism = metabolism = ↑↑coke fx in peripherycoke fx in periphery

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Development of AIDevelopment of AI

Types of Clinical TrialsTypes of Clinical TrialsPreclinicalPreclinical

In vivo or vitroIn vivo or vitroMechanism of action, toxicityMechanism of action, toxicity

Phase 0Phase 0Not efficacy = use low doseNot efficacy = use low doseAbsorption & metabolismAbsorption & metabolism

30© AMSP 2011

Types of Clinical TrialsTypes of Clinical Trials Phase I (human tolerability)Phase I (human tolerability)

Multiple ascending dosesMultiple ascending doses Observe reactionObserve reaction

Phase II (↑ subjects)Phase II (↑ subjects) Selected or randomized w/ controlSelected or randomized w/ control Phase IIa- assess dosing Phase IIa- assess dosing Phase IIb- assess efficacyPhase IIb- assess efficacy

31© AMSP 2011

Types of Clinical TrialsTypes of Clinical Trials Phase III (large randomized Phase III (large randomized

controlled multicenter trials)controlled multicenter trials) Phase IIIa (effectiveness)Phase IIIa (effectiveness)

Vs. placeboVs. placeboVs. “gold standard” tx Vs. “gold standard” tx

Phase IIIb ( effectiveness beyond Phase IIIb ( effectiveness beyond original approvaloriginal approval))

32© AMSP 2011

Types of Clinical TrialsTypes of Clinical Trials

Two successful Phase III Two successful Phase III trials for FDA approvaltrials for FDA approval

Phase IV- post marketing Phase IV- post marketing surveillancesurveillance

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Results of Vax StudiesResults of Vax StudiesPhase I (human tolerability)Phase I (human tolerability)

Significant Ab response to Significant Ab response to cokecoke

Well toleratedWell toleratedNo serious adverse fxNo serious adverse fx

34© AMSP 2011

Results of Vax StudiesResults of Vax Studies Phase IIa (18 pts over 14 wks) (doses)Phase IIa (18 pts over 14 wks) (doses)

100µg x 4 injections 100µg x 4 injections 400µg x 5 injections400µg x 5 injections Well toleratedWell tolerated No allergyNo allergy Individual variability (30%-low Ab)Individual variability (30%-low Ab) Higher doses Higher doses → ↑→ ↑clean & clean & ↓↓euphoriaeuphoria

38© AMSP 2011

Results of Vax StudiesResults of Vax Studies Phase IIb (115 pts over 24 wks)Phase IIb (115 pts over 24 wks)

Randomized- five 360µg injectionsRandomized- five 360µg injections Controlled- five saline injectionsControlled- five saline injections All pts received CBTAll pts received CBT Ab levels ≥43µg/mL =Ab levels ≥43µg/mL = ↓ ↓ euphoriaeuphoria ↑ ↑ Ab levels = Ab levels = ↓ ↓ coke usecoke use

53% (≥43µg/mL) vs. 23% (≤43µg/mL) 53% (≥43µg/mL) vs. 23% (≤43µg/mL) abstinent @ wks 8-20abstinent @ wks 8-20

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Results (cont’d)Results (cont’d)

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Limitations of VaxLimitations of Vax Variability in Abs responseVariability in Abs response Abs diminish over time ~ 6 mosAbs diminish over time ~ 6 mos Able to override w/ Able to override w/ ↑ ↑ cocaine usecocaine use Able to use other stimulantsAble to use other stimulants Vax not address cravings & withdrawalVax not address cravings & withdrawal No long term dataNo long term data Vax available possibly by 2015Vax available possibly by 2015

38© AMSP 2010

Clinical Vignette RevisitedClinical Vignette Revisited 38 yo, married, wm attorney in ER38 yo, married, wm attorney in ER

Suicidal thoughts (e.g.,withdrawal)Suicidal thoughts (e.g.,withdrawal) Using $30 crack /dUsing $30 crack /d Binges on $1000 crack/weekend Binges on $1000 crack/weekend

(e.g., tolerance)(e.g., tolerance) Paranoia after binge Paranoia after binge

(e.g.,consequence)(e.g.,consequence)

39© AMSP 2011

Treatment w/ VaxTreatment w/ Vax First line tx = behavioral interventions First line tx = behavioral interventions Likely to relapse b/c of cravingsLikely to relapse b/c of cravings Route of administration Route of administration → → rapid & intense rapid & intense

euphoriaeuphoria Vax attenuates euphoria Vax attenuates euphoria ↓ ↓ euphoria = euphoria = ↓ ↓ reinforcementreinforcement ↓ ↓ reinforcement reinforcement →→ prevents full relapse prevents full relapse ↑ ↑ vax effectiveness if pt well motivatedvax effectiveness if pt well motivated Goal may be Goal may be ↓↓use rather than abstinenceuse rather than abstinence

40© AMSP 2011

ConclusionsConclusions CUD costly to individuals & societyCUD costly to individuals & society CUD no effective pharmacotherapyCUD no effective pharmacotherapy Coke’s properties appropriate for vax Coke’s properties appropriate for vax Vax blocks coke’s reinforcing fxVax blocks coke’s reinforcing fx Early data support potential Early data support potential

effectiveness of vaxeffectiveness of vax Vax has limitationsVax has limitations

41© AMSP 2011

This Lecture ReviewsThis Lecture ReviewsDefinitions Definitions √√Tx options & limitations Tx options & limitations √√Biology of CUD Biology of CUD √√How vax work How vax work & application to & application to

CUD CUD √√

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© AMSP 2011