Medication Assisted Treatment for Alcohol

and Opioid Dependence

Larissa Mooney, M.D.Assistant Professor of Psychiatry

UCLA Integrated Substance Abuse Programs

April 25, 2012

Objectives Introduction to addictive disorders

(SUDs) Epidemiology Neurobiology

Health effects of alcohol and opioid use disorders

Pharmacological treatments within drug classes: Alcohol Opioids

Introduction

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

Pharmacotherapy as part of multimodal treatment plan

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

Social)

12-Month and Lifetime Prevalence

Rates - NESARC Alcohol dependence

12 Mo: 4.3% Lifetime: 12% (30% for AUDs) Annual mortality: ~100,000

Other (non-nicotine) drug dependence 12 Mo: 0.6% Lifetime: 2.7% Annual mortality: 17,000

Hasin et al., 2007; Compton et al., 2007

Addiction Risk Factors

Neurobiology of Addiction

Reward system: dopamine pathway Natural vs. drug rewards Dopamine release: pleasure and reinforcement

Dopamine projections to brain reward centers and prefrontal cortex (PFC)

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

Impaired decision-making, loss of control Altered neurobiology: relapse risk even

after extended periods of abstinence

Reward pathway -- mesolimbic dopamine system

Pharmacotherapy in Substance Use Disorders

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

co-occurring disorders Reduction of cravings and urges Substitution therapy

Alcohol-Related Impacts

3rd leading cause of preventable death 15-30% of primary care and hospitalized 40% trauma patients with BAL = 0.1

Trauma is leading cause of death < age 40 40% of MVA deaths 2,000,000 injuries Life span of AUD cut by 15 years 15% will develop ETOH cirrhosis

Cardiovascular Consequences of Alcohol

Hypertension Cardiomyopathy (enlarged heart) Coronary heart disease (CHD), CHF Arrhythmias Low/moderate use: protective

Hepatic Consequences of Alcohol

Fatty liver Alcoholic hepatitis Cirrhosis Women: earlier onset of illness

Other Medical Consequences

Pancreatitis Anemia Neuropathy Osteoperosis Wernicke-Korsakoff (thiamine

deficiency) Fetal Alcohol Syndrome (spectrum

disorder) Cancers: breast, head and neck,

stomach, esophageal, colon, liver

Alcohol Effects: Neurotransmitters

dopamine

makes you

happy

-glutamate

the main excitatory

neurotransmitter: speeds

you up

+GABA the main inhibitory

neurotransmitter:slows you down

endogenous

opioids

make you euphoric and feel no pain

Medications for Alcohol Dependence

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

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

Disulfiram (Antabuse)

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

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

dyspnea, diaphoresis, headache, palpitations

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

Disulfiram (Antabuse)

Reactions may occur 1-2 weeks after last dose

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

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

Most likely to benefit: highly motivated and directly observed patients

Naltrexone (Revia)

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

qd) Mechanism: μ-opioid antagonist

Decreases positive reinforcing effects

Decreases cue- and alcohol-induced cravings

Side effects: nausea, dysphoria, increased LFTs

Results: fewer drinking days, less alcohol consumed, decreased craving

Research on Naltrexone

Results: Two studies submitted for FDA approval. In both studies, participants treated with naltrexone had a greater reduction in relapse during the entire study than those treated with placebo.

23%

54%

0%

10%

20%

30%

40%

50%

60%

Percentage of

Participants Who

Relapsed During the

Study

naltrexone group placebo group

Reduction in Relapse - Volpicelli et al. Study*

* statistically significant

IM Naltrexone (Vivitrol)

FDA approved 2006 Dose: 380 mg IM q 4 weeks Enhanced compliance Stop drinking 7 days prior (ideal) Mechanism: opioid antagonist Results: Decreased heavy drinking

days, decreased frequency of drinking

Acamprosate (Campral)

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

GABA Mechanism: NMDA

receptor modulation Restores GABA-

glutamate balance Blocks “negative”

reinforcement

Acamprosate (Campral) Start post-detox

(ideal) Side effects:

diarrhea, abdominal discomfort

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

Research on Acamprosate

Results: In all three studies, participants treated with acamprosate were able to maintain complete abstinence more frequently than those treated with placebo

38%

13%

28%

13%

16%

9%

0%

5%

10%

15%

20%

25%

30%

35%

40%

Percentage of Participants

Who Consumed No Alcohol During

the Entire

13-WeekStudy (Pelc)*

48-WeekStudy (Sass)*

52-WeekStudy

(Paille)*

Complete Abstinence

acamprosate

placebo

* statistically significant

Study

Results: In all three studies, participants treated with acamprosate had a greater reduction in the number of drinking days during the entire study than those treated with placebo.

67%

29%

74%

38%

85%

67%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Percentage of Days Abstinent

13-WeekStudy (Pelc)*

48-WeekStudy (Sass)*

52-WeekStudy

(Paille)*

Reduction in Drinking Days

acamprosate

placebo

* statistically significant

Research on Acamprosate

Results: In all three studies, participants treated with acamprosate were able to regain complete abstinence after one relapse more frequently than those treated with placebo.

11%

8%

18%

7%

11%

3%

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Percentage of Participants

Who Regained Complete

Abstinence for the Reminder of the Study after First

13-WeekStudy (Pelc)*

48-WeekStudy

(Sass)*

52-WeekStudy

(Paille)*

Regained Complete Abstinence after First Relapse

acamprosate

placebo

* statistically significant

Relapse

Research on Acamprosate

Public Health & Risk Behavior Problems

Tuberculosis IDUs high risk

STDs Gonorrhea, chlamydia, syphilis,

herpes HIV/AIDS HBV HCV

Opioid Dependence: Needle-Related Problems

Abcess Cellulitis Subacute bacterial

endocarditis Necrotizing fasciitis Botulism

Treating Opioid Dependence: Aims

Detoxification: Opioid-based (methadone, buprenorphine) Non-opioid based (clonidine, supportive meds) “Rapid detox”

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

Lifestyle and behavior change

Opioid Detoxification

Medications used to alleviate withdrawal symptoms:

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

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

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

muscle relaxants, BDZs

Opioid Substitution Goals

Reduce symptoms & signs of withdrawal

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

and non-drug lifestyle

OOH O

N

OH

CH3 CH2CH2 CH N

CH3CH3

CH3

O

Methadone: Clinical Properties

Orally active synthetic μ agonist Action: CNS depressant/ Analgesic Long half-life, slow elimination Effects last 24 hours; once-daily dosing

maintains constant blood level Prevents withdrawal, reduces craving

and use Facilitates rehabilitation Clinic dispensing limits availability

CH3 CH2CH2 CH N

CH3CH3

CH3

O

Buprenorphine for Opioid Dependence

FDA approved 2002, age 16+ Mandatory certification from DEA

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

Buprenorphine Formulations

Sublingual administration Subutex (Buprenorphine)

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

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

IM Naltrexone (Vivitrol)

FDA approved 2010 Dose: 380 mg IM q 4 weeks Enhanced compliance Must be opioid-free for 7-10 days Mechanism: opioid antagonist

Blocks effects of opioids for 4 weeks

Challenges for Dually Diagnosed

Patients with CODs are more likely to have: Increased severity of mental illness Medication noncompliance Worse treatment prognosis (more

severe course, etc.) Lower income and resources Worse physical health Increased risk of incarceration

Buckley 2006, J Clin Psychiatry; SAMHSA 2007

Traditional Treatment Models

Mental health and substance use disorders treated separately

“I can’t treat your depression until you take care of your alcohol problem”

Sequential treatment of SUD/psychiatric d/o

Parallel treatment More recent evidence: supports

integrated treatment

In Conclusion

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

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

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

Thank you!

Larissa Mooney, M.D.UCLA Integrated Substance Abuse

Programslmooney@mednet.ucla.edu