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) Introduction to addictive disorders (SUDs) Epidemiology Epidemiology Neurobiology Neurobiology Health effects of alcohol and opioid use disorders Health effects of alcohol and opioid use disorders Pharmacological treatments within drug classes: Pharmacological treatments within drug classes: Alcohol Alcohol Opioids Opioids

Introduction Addiction is a chronic, relapsing brain disease characterized by compulsive use despite harmful consequences Addiction is a chronic, relapsing brain disease characterized by compulsive use despite harmful consequences Pharmacotherapy as part of multimodal treatment plan Pharmacotherapy as part of multimodal treatment plan Treatment approaches: Treatment approaches: Medications (Bio) Medications (Bio) Therapy, lifestyle changes (Psycho-Social) 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 Reward system: dopamine pathway Natural vs. drug rewards Natural vs. drug rewards Dopamine release: pleasure and reinforcement Dopamine release: pleasure and reinforcement Dopamine projections to brain reward centers and prefrontal cortex (PFC) Dopamine projections to brain reward centers and prefrontal cortex (PFC) Process of addiction causes dysfunctional learning and memory and maladaptive behavioral patterns Process of addiction causes dysfunctional learning and memory and maladaptive behavioral patterns Impaired decision-making, loss of control Impaired decision-making, loss of control Altered neurobiology: relapse risk even after extended periods of abstinence 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 withdrawal (“detox”) Treatment of psychiatric symptoms or co-occurring disorders Treatment of psychiatric symptoms or co-occurring disorders Reduction of cravings and urges Reduction of cravings and urges Substitution therapy Substitution therapy

Alcohol-Related Impacts 3 rd leading cause of preventable death 3 rd leading cause of preventable death 15-30% of primary care and hospitalized 15-30% of primary care and hospitalized 40% trauma patients with BAL = % trauma patients with BAL = 0.1 Trauma is leading cause of death < age 40 Trauma is leading cause of death < age 40 40% of MVA deaths 40% of MVA deaths 2,000,000 injuries 2,000,000 injuries Life span of AUD cut by 15 years Life span of AUD cut by 15 years 15% will develop ETOH cirrhosis 15% will develop ETOH cirrhosis

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

Hepatic Consequences of Alcohol Fatty liver Fatty liver Alcoholic hepatitis Alcoholic hepatitis Cirrhosis Cirrhosis Women: earlier onset of illness Women: earlier onset of illness

Other Medical Consequences Pancreatitis Pancreatitis Anemia Anemia Neuropathy Neuropathy Osteoperosis Osteoperosis Wernicke-Korsakoff (thiamine deficiency) Wernicke-Korsakoff (thiamine deficiency) Fetal Alcohol Syndrome (spectrum disorder) Fetal Alcohol Syndrome (spectrum disorder) Cancers: breast, head and neck, stomach, esophageal, colon, liver 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: FDA-Approved: Disulfiram (Antabuse) Disulfiram (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) Quetiapine (Seroquel) Quetiapine (Seroquel) Baclofen Baclofen

Disulfiram (Antabuse) Disulfiram (Antabuse) FDA approved 1951 FDA approved 1951 Dosing: 250mg-500mg qd Dosing: 250mg-500mg qd Mechanism: inhibits aldehyde dehydrogenase, causing buildup of acetaldehyde with alcohol ingestion: Mechanism: inhibits aldehyde dehydrogenase, causing buildup of acetaldehyde with alcohol ingestion: Flushing, nausea, vomiting, dizziness, dyspnea, diaphoresis, headache, palpitations Flushing, nausea, vomiting, dizziness, dyspnea, diaphoresis, headache, palpitations In severe cases: arrhythmias, seizures, coma, cardiovascular collapse In severe cases: arrhythmias, seizures, coma, cardiovascular collapse

Disulfiram (Antabuse) Disulfiram (Antabuse) Reactions may occur 1-2 weeks after last dose Reactions may occur 1-2 weeks after last dose Caution: “hidden” alcohol in perfumes, mouthwash, cough medicines, desserts, sauces, salad dressings Caution: “hidden” alcohol in perfumes, mouthwash, cough medicines, desserts, sauces, salad dressings Side effects: fatigue, headache, hepatitis, psychosis (dopamine), neuritis, rash, aftertaste Side effects: fatigue, headache, hepatitis, psychosis (dopamine), neuritis, rash, aftertaste Most likely to benefit: highly motivated and directly observed patients Most likely to benefit: highly motivated and directly observed patients

Naltrexone (Revia) Naltrexone (Revia) FDA approved 1994 FDA approved 1994 Dosing: 50 mg PO qd (start at 25 mg qd) Dosing: 50 mg PO qd (start at 25 mg qd) Mechanism: μ-opioid antagonist Mechanism: μ-opioid antagonist Decreases positive reinforcing effects Decreases positive reinforcing effects Decreases cue- and alcohol-induced cravings Decreases cue- and alcohol-induced cravings Side effects: nausea, dysphoria, increased LFTs Side effects: nausea, dysphoria, increased LFTs Results: fewer drinking days, less alcohol consumed, decreased craving 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. 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. * statistically significant

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

Acamprosate (Campral) FDA Approved 2004 FDA Approved 2004 Dose: 666mg PO tid Dose: 666mg PO tid Renal excretion Renal excretion Structural analog of GABA Structural analog of GABA Mechanism: NMDA receptor modulation Mechanism: NMDA receptor modulation Restores GABA-glutamate balance Restores GABA-glutamate balance Blocks “negative” reinforcement Blocks “negative” reinforcement

Acamprosate (Campral) Start post-detox (ideal) Start post-detox (ideal) Side effects: diarrhea, abdominal discomfort Side effects: diarrhea, abdominal discomfort Results: increased time to relapse, increased total abstinence, reduced drinking days 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 Results: In all three studies, participants treated with acamprosate were able to maintain complete abstinence more frequently than those treated with 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. 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. * 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. 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. * statistically significant Relapse Research on Acamprosate

Public Health & Risk Behavior Problems Tuberculosis Tuberculosis IDUs high risk IDUs high risk STDs STDs Gonorrhea, chlamydia, syphilis, herpes Gonorrhea, chlamydia, syphilis, herpes HIV/AIDS HIV/AIDS HBV HBV HCV HCV

Opioid Dependence: Needle- Related Problems Abcess Abcess Cellulitis Cellulitis Subacute bacterial endocarditis Subacute bacterial endocarditis Necrotizing fasciitis Necrotizing fasciitis Botulism Botulism

Treating Opioid Dependence: Aims Detoxification: Detoxification: Opioid-based (methadone, buprenorphine) Opioid-based (methadone, buprenorphine) Non-opioid based (clonidine, supportive meds) Non-opioid based (clonidine, supportive meds) “Rapid detox” “Rapid detox” Relapse prevention: Relapse prevention: Agonist maintenance (methadone) Agonist maintenance (methadone) Partial agonist maintenance (buprenorphine) Partial agonist maintenance (buprenorphine) Antagonist maintenance (naltrexone, Vivitrol) Antagonist maintenance (naltrexone, Vivitrol) Lifestyle and behavior change Lifestyle and behavior change

Opioid Detoxification Medications used to alleviate withdrawal symptoms: Medications used to alleviate withdrawal symptoms: - Opioid agnonists (methadone, buprenorphine) - Opioid agnonists (methadone, buprenorphine) - Clonidine (alpha-2 agonist) Dose: 0.1 mg PO tid (increase as tolerated) Dose: 0.1 mg PO tid (increase as tolerated) Caution: hypotension Caution: hypotension - Other supportive meds anti-diarrheals, anti-emetics, ibuprofen, muscle relaxants, BDZs anti-diarrheals, anti-emetics, ibuprofen, muscle relaxants, BDZs

Opioid Substitution Goals Opioid Substitution Goals Reduce symptoms & signs of withdrawal Reduce symptoms & signs of withdrawal Reduce or eliminate craving Reduce or eliminate craving Block effects of illicit opioids Block effects of illicit opioids Restore normal physiology Restore normal physiology Promote psychosocial rehabilitation and non-drug lifestyle Promote psychosocial rehabilitation and non-drug lifestyle

Methadone: Clinical Properties Orally active synthetic μ agonist Orally active synthetic μ agonist Action: CNS depressant/ Analgesic Action: CNS depressant/ Analgesic Long half-life, slow elimination Long half-life, slow elimination Effects last 24 hours; once-daily dosing maintains constant blood level Effects last 24 hours; once-daily dosing maintains constant blood level Prevents withdrawal, reduces craving and use Prevents withdrawal, reduces craving and use Facilitates rehabilitation Facilitates rehabilitation Clinic dispensing limits availability Clinic dispensing limits availability

Buprenorphine for Opioid Dependence FDA approved 2002, age 16+ FDA approved 2002, age 16+ Mandatory certification from DEA (100 pt. limit) Mandatory certification from DEA (100 pt. limit) Mechanism: partial mu agonist Mechanism: partial mu agonist Office-based, expands availability Office-based, expands availability Analgesic properties Analgesic properties Ceiling effect Ceiling effect Lower abuse potential Lower abuse potential Safer in overdose Safer in overdose

Buprenorphine Formulations Sublingual administration Sublingual administration Subutex (Buprenorphine) Subutex (Buprenorphine) -2mg, 8mg Suboxone (4:1 Bup:naloxone) Suboxone (4:1 Bup:naloxone) -2mg/0.5 mg, 8mg/2mg Dose: 2mg-32mg/day Dose: 2mg-32mg/day

IM Naltrexone (Vivitrol) FDA approved 2010 FDA approved 2010 Dose: 380 mg IM q 4 weeks Dose: 380 mg IM q 4 weeks Enhanced compliance Enhanced compliance Must be opioid-free for 7-10 days Must be opioid-free for 7-10 days Mechanism: opioid antagonist Mechanism: opioid antagonist Blocks effects of opioids for 4 weeks Blocks effects of opioids for 4 weeks

Challenges for Dually Diagnosed Patients with CODs are more likely to have: Patients with CODs are more likely to have: Increased severity of mental illness Increased severity of mental illness Medication noncompliance Medication noncompliance Worse treatment prognosis (more severe course, etc.) Worse treatment prognosis (more severe course, etc.) Lower income and resources Lower income and resources Worse physical health Worse physical health Increased risk of incarceration Increased risk of incarceration Buckley 2006, J Clin Psychiatry; SAMHSA 2007

Traditional Treatment Models Mental health and substance use disorders treated separately Mental health and substance use disorders treated separately “I can’t treat your depression until you take care of your alcohol problem” “I can’t treat your depression until you take care of your alcohol problem” Sequential treatment of SUD/psychiatric d/o Sequential treatment of SUD/psychiatric d/o Parallel treatment Parallel treatment More recent evidence: supports integrated treatment More recent evidence: supports integrated treatment

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