Pharmacological Pharmacological Treatment of Treatment of

Addictive DisordersAddictive DisordersLarissa Mooney, M.D.Larissa Mooney, M.D.Assistant Professor of Psychiatry Assistant Professor of Psychiatry

UCLA Integrated Substance Abuse UCLA Integrated Substance Abuse ProgramsPrograms

ObjectivesObjectives

Introduction to medication treatment Introduction to medication treatment approaches for addictive disorders approaches for addictive disorders

Pharmacological treatment options within Pharmacological treatment options within drug classes:drug classes: AlcoholAlcohol OpioidsOpioids StimulantsStimulants NicotineNicotine

Clinical implications of co-occurring Clinical implications of co-occurring disordersdisorders

IntroductionIntroduction

Addiction is a chronic, relapsing brain Addiction is a chronic, relapsing brain disease characterized by compulsive use disease characterized by compulsive use despite harmful consequencesdespite harmful consequences

Pharmacotherapy as part of Pharmacotherapy as part of multimodalmultimodal treatment plantreatment plan

Treatment approaches:Treatment approaches: Medications (Bio) Medications (Bio) Therapy, lifestyle changes (Psycho-Social)Therapy, lifestyle changes (Psycho-Social)

Thorough evaluation and diagnosis Thorough evaluation and diagnosis essentialessential

Addiction Risk FactorsAddiction Risk Factors

Neurobiology of Neurobiology of AddictionAddiction

Reward system: mesolimbic dopamine pathwayReward system: mesolimbic dopamine pathway Natural vs. drug rewardsNatural vs. drug rewards Dopamine release: pleasure and reinforcementDopamine release: pleasure and reinforcement

Dopaminergic projections from ventral Dopaminergic projections from ventral tegmental area (VTA) to nucleus accumbens tegmental area (VTA) to nucleus accumbens (NA), amygdala, and prefrontal cortex (PFC) (NA), amygdala, and prefrontal cortex (PFC)

Process of addiction causes dysfunctional Process of addiction causes dysfunctional learning and memory and maladaptive learning and memory and maladaptive behavioral patterns behavioral patterns

““Hypo-frontality”: impaired decision-making, Hypo-frontality”: impaired decision-making, loss of control (orbitofrontal cortex, anterior loss of control (orbitofrontal cortex, anterior cingulate)cingulate)

Altered neurocircuitry: relapse risk even after Altered neurocircuitry: relapse risk even after extended periods of abstinence extended periods of abstinence

Reward pathway -- mesolimbic Reward pathway -- mesolimbic dopamine systemdopamine system

Pharmacotherapy in Pharmacotherapy in Substance Use DisordersSubstance Use Disorders

Treatment of withdrawal (“detox”) Treatment of withdrawal (“detox”) Treatment of psychiatric symptoms or Treatment of psychiatric symptoms or

co-occurring disorders co-occurring disorders Reduction of cravings and urgesReduction of cravings and urges Substitution therapySubstitution therapy Prevention Prevention

Medications for Alcohol Medications for Alcohol DependenceDependence

FDA-Approved: FDA-Approved: Disulfuram (Antabuse)Disulfuram (Antabuse) PO naltrexone (Revia)PO naltrexone (Revia) IM naltrexone (Vivitrol)IM naltrexone (Vivitrol) Acamprosate (Campral)Acamprosate (Campral)

Non-FDA-approved:Non-FDA-approved: Topiramate (Topamax) Topiramate (Topamax) Ondansetron (Zofran)Ondansetron (Zofran) Baclofen Baclofen

Disulfuram Disulfuram (Antabuse)(Antabuse)

FDA approved 1951FDA approved 1951 Dosing: 250mg-500mg qdDosing: 250mg-500mg qd Mechanism: inhibits aldehyde Mechanism: inhibits aldehyde

dehydrogenase, causing buildup of dehydrogenase, causing buildup of acetaldehyde with alcohol ingestion:acetaldehyde with alcohol ingestion: Flushing, nausea, vomiting, dizziness, Flushing, nausea, vomiting, dizziness,

dyspnea, diaphoresis, headache, dyspnea, diaphoresis, headache, palpitations palpitations

In severe cases: arrhythmias, seizures, In severe cases: arrhythmias, seizures, coma, cardiovascular collapsecoma, cardiovascular collapse

Disulfuram Disulfuram (Antabuse)(Antabuse)

Reactions may occur 1-2 weeks after Reactions may occur 1-2 weeks after last doselast dose

Caution: “hidden” alcohol in perfumes, Caution: “hidden” alcohol in perfumes, mouthwash, cough medicines, desserts, mouthwash, cough medicines, desserts, sauces, salad dressingssauces, salad dressings

Side effects: fatigue, headache, Side effects: fatigue, headache, hepatitis, psychosis (dopamine), hepatitis, psychosis (dopamine), neuritis, rash, aftertaste neuritis, rash, aftertaste

Most likely to benefit: highly motivated Most likely to benefit: highly motivated and directly observed patients and directly observed patients

Naltrexone (Revia)Naltrexone (Revia)

FDA approved 1994FDA approved 1994 Dosing: 50 mg PO qd (start at 25 mg Dosing: 50 mg PO qd (start at 25 mg

qd)qd) Mechanism: mu-opioid antagonistMechanism: mu-opioid antagonist

Decreases positive reinforcing effectsDecreases positive reinforcing effects Decreases cue- and alcohol-induced Decreases cue- and alcohol-induced

cravingscravings Side effects: nausea, dysphoria, Side effects: nausea, dysphoria,

increased LFTsincreased LFTs Results: fewer drinking days, less Results: fewer drinking days, less

alcohol consumed, decreased craving alcohol consumed, decreased craving

IM Naltrexone (Vivitrol)IM Naltrexone (Vivitrol)

FDA approved 2006FDA approved 2006 Dose: 380 mg IM q 4 weeksDose: 380 mg IM q 4 weeks No need for oral lead-inNo need for oral lead-in Stop drinking 7 days prior (ideal)Stop drinking 7 days prior (ideal) Mechanism: opioid antagonistMechanism: opioid antagonist Results: Decreased heavy drinking Results: Decreased heavy drinking

days, decreased frequency of days, decreased frequency of drinking drinking

Acamprosate (Campral)Acamprosate (Campral)

FDA Approved 2004FDA Approved 2004 Dose: 666mg PO tidDose: 666mg PO tid Renal excretion Renal excretion Structural analog of Structural analog of

amino acid taurine and amino acid taurine and GABAGABA

Mechanism: NMDA Mechanism: NMDA receptor modulationreceptor modulation Restores GABA-Restores GABA-

glutamate balanceglutamate balance Blocks “negative” Blocks “negative”

reinforcementreinforcement

Acamprosate (Campral)Acamprosate (Campral) Start post-detox (ideal)Start post-detox (ideal) Side effects: diarrhea, Side effects: diarrhea,

abdominal discomfortabdominal discomfort Results: increased Results: increased

time to relapse, time to relapse, increased total increased total abstinence, reduced abstinence, reduced drinking days drinking days

Clinical Case #1Clinical Case #1

42 y.o. female who lives with her mother and 42 y.o. female who lives with her mother and 12 y.o. son 12 y.o. son

Reports daily use of alcohol and occasional use Reports daily use of alcohol and occasional use of other substancesof other substances

Mother has found hidden bottles of vodkaMother has found hidden bottles of vodka Reports feeling tired, depressed, anxious, and Reports feeling tired, depressed, anxious, and

difficulty “motivating to do anything”difficulty “motivating to do anything” Reports nightmares and difficulty sleeping at Reports nightmares and difficulty sleeping at

night related to trauma (h/o sexual abuse)night related to trauma (h/o sexual abuse) Admits to drinking or taking a pill to help her Admits to drinking or taking a pill to help her

sleepsleep

Evaluation and Evaluation and ManagementManagement

What further evaluation and workup What further evaluation and workup would you recommend?would you recommend?

What is the differential diagnosis?What is the differential diagnosis? What medications would you What medications would you

consider? consider?

Treating Opioid Treating Opioid Dependence: AimsDependence: Aims

Detoxification:Detoxification: Opioid-based agonist (methadone, Opioid-based agonist (methadone,

buprenorphine)buprenorphine) Non-opioid based (clonidine, supportive meds)Non-opioid based (clonidine, supportive meds) Antagonist-based (naltrexone: “rapid”)Antagonist-based (naltrexone: “rapid”)

Relapse prevention: Relapse prevention: Agonist maintenance (methadone)Agonist maintenance (methadone) Partial agonist maintenance (buprenorphine)Partial agonist maintenance (buprenorphine) Antagonist maintenance (naltrexone) Antagonist maintenance (naltrexone)

Lifestyle and behavior change Lifestyle and behavior change

Opioid Detoxification Opioid Detoxification

Medications used to alleviate Medications used to alleviate withdrawal symptoms:withdrawal symptoms:

- Opioid agnonists (methadone, - Opioid agnonists (methadone, buprenorphine) buprenorphine) - Clonidine (alpha-2 agonist)- Clonidine (alpha-2 agonist)

Dose: 0.1 mg PO tid (increase as tolerated)Dose: 0.1 mg PO tid (increase as tolerated) Caution: hypotensionCaution: hypotension

- Other supportive meds- Other supportive meds anti-diarrheals, anti-emetics, ibuprofen, anti-diarrheals, anti-emetics, ibuprofen,

muscle relaxants, BDZs muscle relaxants, BDZs

Opioid Substitution GoalsOpioid Substitution Goals

Reduce symptoms & signs of Reduce symptoms & signs of withdrawalwithdrawal

Reduce or eliminate cravingReduce or eliminate craving Block effects of illicit opioidsBlock effects of illicit opioids Restore normal physiologyRestore normal physiology Promote psychosocial rehabilitation Promote psychosocial rehabilitation

and non-drug lifestyleand non-drug lifestyle

OOH O

N

OH

CH3 CH2CH2 CH N

CH3CH3

CH3

O

Methadone: Methadone: Clinical PropertiesClinical Properties

Orally active synthetic μ agonist Orally active synthetic μ agonist Action: CNS depressant/ Analgesic Action: CNS depressant/ Analgesic Quick absorption, slow elimination, long Quick absorption, slow elimination, long

half-lifehalf-life Effects last 24 hours; once-daily dosing Effects last 24 hours; once-daily dosing

maintains constant blood level maintains constant blood level Prevents withdrawal, reduces craving and Prevents withdrawal, reduces craving and

use use Facilitates rehabilitationFacilitates rehabilitation Clinic dispensing limits availability Clinic dispensing limits availability

CH3 CH2CH2 CH N

CH3CH3

CH3

O

Buprenorphine for Buprenorphine for Opioid DependenceOpioid Dependence

FDA approved 2002, age 16+FDA approved 2002, age 16+ Mandatory certification from DEA Mandatory certification from DEA

(100 pt. limit)(100 pt. limit) Mechanism: partial mu agonistMechanism: partial mu agonist Office-based, expands availabilityOffice-based, expands availability Analgesic propertiesAnalgesic properties Ceiling effect Ceiling effect Lower abuse potential Lower abuse potential Safer in overdose Safer in overdose

Buprenorphine Buprenorphine FormulationsFormulations

Sublingual administration Sublingual administration Subutex (Buprenorphine)Subutex (Buprenorphine)

-2mg, 8mg-2mg, 8mg Suboxone (4:1 Bup:naloxone) Suboxone (4:1 Bup:naloxone)

-2mg/0.5 mg , 8mg/2mg -2mg/0.5 mg , 8mg/2mg Dose: 2mg-32mg/dayDose: 2mg-32mg/day

Buprenorphine: Buprenorphine: Pharmacological Pharmacological CharacteristicsCharacteristics

Partial Agonist Partial Agonist (ceiling effect)(ceiling effect)

-less euphoria-less euphoria -safer in overdose-safer in overdose

High Receptor High Receptor AffinityAffinity

-long duration of -long duration of actionaction

-1-1stst dose given dose given during withdrawalduring withdrawal 0

2468

1012141618

p 1 2 4 8 16 32

Buprenorphine (mg)

Bre

aths

/min

ute

0

20

40

60

80

100

Buprenorphine (mg)

Pea

k S

core

3.75 15 60

Methadone (mg)

Clinical Case #2Clinical Case #2

34 y/o female with 3-year history of 34 y/o female with 3-year history of Vicodin useVicodin use

Using 10-12 pills/day for back pain Using 10-12 pills/day for back pain suffered in an automobile accidentsuffered in an automobile accident

No history of heroin or other opioid useNo history of heroin or other opioid use Sometimes takes more than prescribed Sometimes takes more than prescribed

by her physician, but would like to stop by her physician, but would like to stop taking all medicationstaking all medications

Employed, lives with her husband and Employed, lives with her husband and two children, and has private insurance two children, and has private insurance

Evaluation and Evaluation and ManagementManagement

What further evaluation would you What further evaluation would you recommend? recommend?

What treatment options would you What treatment options would you consider?consider?

Clinical Case #3Clinical Case #3 18 y/o unemployed male with a two year 18 y/o unemployed male with a two year

history of intravenous heroin use history of intravenous heroin use Criminal convictions for shopliftingCriminal convictions for shoplifting Has attempted outpatient detox on two Has attempted outpatient detox on two

previous occasions; most recent period of previous occasions; most recent period of sobriety lasted 4 months sobriety lasted 4 months

Lives with his parents who are unaware of Lives with his parents who are unaware of his dependence his dependence

Reports that he has done well on Reports that he has done well on methadone though has difficulty obtaining methadone though has difficulty obtaining the funds to remain in treatment the funds to remain in treatment

StimulantsStimulantsCRACK

METHAMPHETAMINE

COCAINE

Methamphetamine vs. Methamphetamine vs. CocaineCocaine

MethamphetaminMethamphetaminee

syntheticsynthetic high lasts 8-24 hourshigh lasts 8-24 hours T ½: 12 hoursT ½: 12 hours mechanism: both DA mechanism: both DA

reuptake and releasereuptake and release limited medical useslimited medical uses

neurotoxicity neurotoxicity

CocaineCocaine plant-derivedplant-derived high lasts 20-30 high lasts 20-30

minutesminutes T ½: 1 hourT ½: 1 hour mechanism: mainly mechanism: mainly

DA reuptake DA reuptake used medicallyused medically not directly not directly

neurotoxicneurotoxic

Medications Considered for Medications Considered for CocaineCocaine

Negative ResultsNegative Results +/Under Consideration+/Under Consideration Desipramine* Desipramine* ModafinilModafinil Amantadine*Amantadine* DisulfuramDisulfuram Gabapentin Gabapentin Propanolol (WD)Propanolol (WD) Bupropion*Bupropion* TopiramateTopiramate AripiprazoleAripiprazole BaclofenBaclofen

TA-CD VaccineTA-CD VaccineDHEADHEA

Medications considered Medications considered for Methamphetaminefor Methamphetamine

Negative ResultsNegative Results +/+/Under Under ConsiderationConsideration

ImipramineImipramine BupropionBupropion DesipramineDesipramine ModafinilModafinil TyrosineTyrosine TopirimateTopirimate OndansetronOndansetron DisulfiramDisulfiram FluoxetineFluoxetine LobelineLobeline AripiprazoleAripiprazole GabapentinGabapentin Sertraline Sertraline

Clinical Case #4Clinical Case #4 21 y/o marginally-housed male with a history of 21 y/o marginally-housed male with a history of

bipolar D/O and methamphetamine dependencebipolar D/O and methamphetamine dependence History of prior psychiatric admissions, suicide History of prior psychiatric admissions, suicide

attempt three years ago, and prior treatment with attempt three years ago, and prior treatment with lamictal and depakote; currently off medications lamictal and depakote; currently off medications

Previously employed in entertainment industryPreviously employed in entertainment industry Attending a mandated 3-day/wk outpatient drug Attending a mandated 3-day/wk outpatient drug

treatment program after receiving a citation for treatment program after receiving a citation for “solicitation of sex” and arrest for DWI. “solicitation of sex” and arrest for DWI.

After 2 weeks of nonattendance, currently reports After 2 weeks of nonattendance, currently reports insomnia, “racing thoughts”, and intermittent AHinsomnia, “racing thoughts”, and intermittent AH

Has visible excoriations on face; described Has visible excoriations on face; described episodes of picking due to sensations of “pebbles” episodes of picking due to sensations of “pebbles” under his skinunder his skin

Evaluation and Evaluation and ManagementManagement

What further evaluation and workup What further evaluation and workup would you recommend?would you recommend?

What is the differential diagnosis?What is the differential diagnosis? What treatment options would you What treatment options would you

consider? consider?

FDA-Approved Meds FDA-Approved Meds LackingLacking

There are no FDA-approved There are no FDA-approved medications for the following medications for the following addictive disorders: addictive disorders: Cocaine Cocaine Methamphetamine Methamphetamine MarijuanaMarijuana Pathological GamblingPathological Gambling Sexual AddictionSexual Addiction Compulsive shopping Compulsive shopping

Co-Occurring Psychiatric Co-Occurring Psychiatric D/O and SUD in AdolescentsD/O and SUD in Adolescents ““Potential problems with the diagnostic Potential problems with the diagnostic

process increase almost exponentially when process increase almost exponentially when substance use disorders and psychiatric substance use disorders and psychiatric disorders occur together.”disorders occur together.” (Schukit, 2006) (Schukit, 2006)

Perform comprehensive psychiatric Perform comprehensive psychiatric evaluation including SUD screeningevaluation including SUD screening

Obtain info from multiple sourcesObtain info from multiple sources Have a high index of suspicion for SUD co-Have a high index of suspicion for SUD co-

morbidity when patient not responding to morbidity when patient not responding to txtx

Clinical Management of Clinical Management of CODsCODs

Individualize and integrate Individualize and integrate treatment for CODs whenever treatment for CODs whenever possiblepossible

Consider random drug testingConsider random drug testing Consider need for higher level of Consider need for higher level of

carecare Consult addiction medicine Consult addiction medicine

specialist if necessaryspecialist if necessary

Medication Management in Medication Management in CODCOD

Ambivalence is common re: use of meds in Ambivalence is common re: use of meds in patients with SUDs. patients with SUDs.

Q: When to initiate pharmacotherapy when Q: When to initiate pharmacotherapy when diagnosis is unclear? diagnosis is unclear? With psychosis, moderate to severe depression, or With psychosis, moderate to severe depression, or

mania, treat soonermania, treat sooner Strategies include:Strategies include:

-Verbalize clear expectations re: medication -Verbalize clear expectations re: medication outcomesoutcomes

-Assume potential for misuse and drug -Assume potential for misuse and drug interactionsinteractions

-Schedule frequent follow-ups-Schedule frequent follow-ups

Medication Management in Medication Management in CODCOD

For patients with anxiety d/o’s and SUDs:For patients with anxiety d/o’s and SUDs: Try to avoid BDZsTry to avoid BDZs Consider: SSRIs, buspirone, mirtazapine, Consider: SSRIs, buspirone, mirtazapine,

trazodone, low-dose quetiapine trazodone, low-dose quetiapine For patients with ADHD and SUD, consider:For patients with ADHD and SUD, consider:

Atomoxetine (Strattera)Atomoxetine (Strattera) Bupropion SR or XL (Wellbutrin)Bupropion SR or XL (Wellbutrin) Modafinil (Provigil) Modafinil (Provigil) If stimulant necessary:If stimulant necessary:

Long-acting formulations (e.g., Concerta) Long-acting formulations (e.g., Concerta) Lisdexamphetamine Lisdexamphetamine Daytrana patchDaytrana patch

In ConclusionIn Conclusion

Addiction is a serious, chronic and relapsing Addiction is a serious, chronic and relapsing disorder, but treatments are available disorder, but treatments are available

Medications should be considered as part of Medications should be considered as part of a comprehensive treatment plan, addressing a comprehensive treatment plan, addressing both disordered physiology and disrupted both disordered physiology and disrupted liveslives

Medications should be considered for Medications should be considered for treatment of: psychiatric sx’s, addictive d/o’s, treatment of: psychiatric sx’s, addictive d/o’s, and co-occurring d/o’sand co-occurring d/o’s

Emerging literature supports use of meds in Emerging literature supports use of meds in patients with SUDs and psychiatric patients with SUDs and psychiatric comorbiditycomorbidity

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Thank you! Thank you!

Larissa Mooney, M.D.Larissa Mooney, M.D.

UCLA Integrated Substance Abuse UCLA Integrated Substance Abuse ProgramsPrograms

lmooney@mednet.ucla.edulmooney@mednet.ucla.edu