1. Pharmacological Treatment of Addictive Disorders Larissa Mooney, M.D. Assistant Professor of Psychiatry UCLA Integrated Substance Abuse Programs

2. Objectives Introduction to medication treatment approaches for addictive disorders Introduction to medication treatment approaches for addictive disorders Pharmacological treatment options within drug classes: Pharmacological treatment options within drug classes: Alcohol Alcohol Opioids Opioids Stimulants Stimulants Nicotine Nicotine Clinical implications of co-occurring disorders Clinical implications of co-occurring disorders

3. 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) Thorough evaluation and diagnosis essential Thorough evaluation and diagnosis essential

4. Addiction Risk Factors

5. Neurobiology of Addiction Reward system: mesolimbic dopamine pathway Reward system: mesolimbic dopamine pathway Natural vs. drug rewards Natural vs. drug rewards Dopamine release: pleasure and reinforcement Dopamine release: pleasure and reinforcement Dopaminergic projections from ventral tegmental area (VTA) to nucleus accumbens (NA), amygdala, and prefrontal cortex (PFC) Dopaminergic projections from ventral tegmental area (VTA) to nucleus accumbens (NA), amygdala, 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 “Hypo-frontality”: impaired decision-making, loss of control (orbitofrontal cortex, anterior cingulate) “Hypo-frontality”: impaired decision-making, loss of control (orbitofrontal cortex, anterior cingulate) Altered neurocircuitry: relapse risk even after extended periods of abstinence Altered neurocircuitry: relapse risk even after extended periods of abstinence

6. Reward pathway -- mesolimbic dopamine system

7. 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 Prevention Prevention

9. Medications for Alcohol Dependence 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

10. Disulfuram (Antabuse) Disulfuram (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

11. Disulfuram (Antabuse) Disulfuram (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

12. 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: mu-opioid antagonist Mechanism: mu-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

13. IM Naltrexone (Vivitrol) FDA approved 2006 FDA approved 2006 Dose: 380 mg IM q 4 weeks Dose: 380 mg IM q 4 weeks No need for oral lead-in No need for oral lead-in 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

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

15. 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

16. Clinical Case #1 42 y.o. female who lives with her mother and 12 y.o. son 42 y.o. female who lives with her mother and 12 y.o. son Reports daily use of alcohol and occasional use of other substances Reports daily use of alcohol and occasional use of other substances Mother has found hidden bottles of vodka Mother has found hidden bottles of vodka Reports feeling tired, depressed, anxious, and difficulty “motivating to do anything” Reports feeling tired, depressed, anxious, and difficulty “motivating to do anything” Reports nightmares and difficulty sleeping at night related to trauma (h/o sexual abuse) Reports nightmares and difficulty sleeping at night related to trauma (h/o sexual abuse) Admits to drinking or taking a pill to help her sleep Admits to drinking or taking a pill to help her sleep

17. Evaluation and Management What further evaluation and workup would you recommend? What further evaluation and workup would you recommend? What is the differential diagnosis? What is the differential diagnosis? What medications would you consider? What medications would you consider?

20. Treating Opioid Dependence: Aims Detoxification: Detoxification: Opioid-based agonist (methadone, buprenorphine) Opioid-based agonist (methadone, 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

21. 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

22. 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

23. Methadone: Clinical Properties Orally active synthetic μ agonist Orally active synthetic μ agonist Action: CNS depressant/ Analgesic Action: CNS depressant/ Analgesic Quick absorption, slow elimination, long half-life Quick absorption, slow elimination, long half-life 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

24. 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

25. 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

26. Buprenorphine: Pharmacological Characteristics Partial Agonist (ceiling effect) -less euphoria -less euphoria -safer in overdose -safer in overdose High Receptor Affinity -long duration of action -long duration of action -1 st dose given during withdrawal -1 st dose given during withdrawal

27. Clinical Case #2 34 y/o female with 3-year history of Vicodin use 34 y/o female with 3-year history of Vicodin use Using 10-12 pills/day for back pain suffered in an automobile accident Using 10-12 pills/day for back pain suffered in an automobile accident No history of heroin or other opioid use No history of heroin or other opioid use Sometimes takes more than prescribed by her physician, but would like to stop taking all medications Sometimes takes more than prescribed by her physician, but would like to stop taking all medications Employed, lives with her husband and two children, and has private insurance Employed, lives with her husband and two children, and has private insurance

28. Evaluation and Management What further evaluation would you recommend? What further evaluation would you recommend? What treatment options would you consider? What treatment options would you consider?

29. Clinical Case #3 18 y/o unemployed male with a two year history of intravenous heroin use 18 y/o unemployed male with a two year history of intravenous heroin use Criminal convictions for shoplifting Criminal convictions for shoplifting Has attempted outpatient detox on two previous occasions; most recent period of sobriety lasted 4 months Has attempted outpatient detox on two previous occasions; most recent period of sobriety lasted 4 months Lives with his parents who are unaware of his dependence Lives with his parents who are unaware of his dependence Reports that he has done well on methadone though has difficulty obtaining the funds to remain in treatment Reports that he has done well on methadone though has difficulty obtaining the funds to remain in treatment

30. Stimulants CRACK METHAMPHETAMINE COCAINE

31. Methamphetamine vs. Cocaine Methamphetamine synthetic synthetic high lasts 8-24 hours high lasts 8-24 hours T ½: 12 hours T ½: 12 hours mechanism: both DA reuptake and release mechanism: both DA reuptake and release limited medical uses limited medical uses neurotoxicity neurotoxicity Cocaine plant-derived high lasts 20-30 minutes T ½: 1 hour mechanism: mainly DA reuptake used medically not directly neurotoxic

32. Medications Considered for Cocaine Negative Results+/Under Consideration Desipramine* Modafinil Desipramine* Modafinil Amantadine*Disulfuram Amantadine*Disulfuram Gabapentin Propanolol (WD) Gabapentin Propanolol (WD) Bupropion*Topiramate Bupropion*Topiramate AripiprazoleBaclofen AripiprazoleBaclofen TA-CD Vaccine DHEA

33. Medications considered for Methamphetamine Negative Results+/Under Consideration ImipramineBupropion ImipramineBupropion DesipramineModafinil DesipramineModafinil TyrosineTopirimate TyrosineTopirimate OndansetronDisulfiram OndansetronDisulfiram FluoxetineLobeline FluoxetineLobeline AripiprazoleGabapentin AripiprazoleGabapentin Sertraline Sertraline

34. Clinical Case #4 21 y/o marginally-housed male with a history of bipolar D/O and methamphetamine dependence 21 y/o marginally-housed male with a history of bipolar D/O and methamphetamine dependence History of prior psychiatric admissions, suicide attempt three years ago, and prior treatment with lamictal and depakote; currently off medications History of prior psychiatric admissions, suicide attempt three years ago, and prior treatment with lamictal and depakote; currently off medications Previously employed in entertainment industry Previously employed in entertainment industry Attending a mandated 3-day/wk outpatient drug treatment program after receiving a citation for “solicitation of sex” and arrest for DWI. Attending a mandated 3-day/wk outpatient drug treatment program after receiving a citation for “solicitation of sex” and arrest for DWI. After 2 weeks of nonattendance, currently reports insomnia, “racing thoughts”, and intermittent AH After 2 weeks of nonattendance, currently reports insomnia, “racing thoughts”, and intermittent AH Has visible excoriations on face; described episodes of picking due to sensations of “pebbles” under his skin Has visible excoriations on face; described episodes of picking due to sensations of “pebbles” under his skin

35. Evaluation and Management What further evaluation and workup would you recommend? What further evaluation and workup would you recommend? What is the differential diagnosis? What is the differential diagnosis? What treatment options would you consider? What treatment options would you consider?

36. FDA-Approved Meds Lacking There are no FDA-approved medications for the following addictive disorders: There are no FDA-approved medications for the following addictive disorders: Cocaine Cocaine Methamphetamine Methamphetamine Marijuana Marijuana Pathological Gambling Pathological Gambling Sexual Addiction Sexual Addiction Compulsive shopping Compulsive shopping

37. Co-Occurring Psychiatric D/O and SUD in Adolescents “Potential problems with the diagnostic process increase almost exponentially when substance use disorders and psychiatric disorders occur together.” (Schukit, 2006) “Potential problems with the diagnostic process increase almost exponentially when substance use disorders and psychiatric disorders occur together.” (Schukit, 2006) Perform comprehensive psychiatric evaluation including SUD screening Perform comprehensive psychiatric evaluation including SUD screening Obtain info from multiple sources Obtain info from multiple sources Have a high index of suspicion for SUD co- morbidity when patient not responding to tx Have a high index of suspicion for SUD co- morbidity when patient not responding to tx

38. Clinical Management of CODs Individualize and integrate treatment for CODs whenever possible Individualize and integrate treatment for CODs whenever possible Consider random drug testing Consider random drug testing Consider need for higher level of care Consider need for higher level of care Consult addiction medicine specialist if necessary Consult addiction medicine specialist if necessary

39. Medication Management in COD Ambivalence is common re: use of meds in patients with SUDs. Ambivalence is common re: use of meds in patients with SUDs. Q: When to initiate pharmacotherapy when diagnosis is unclear? Q: When to initiate pharmacotherapy when diagnosis is unclear? With psychosis, moderate to severe depression, or mania, treat sooner With psychosis, moderate to severe depression, or mania, treat sooner Strategies include: Strategies include: -Verbalize clear expectations re: medication outcomes -Assume potential for misuse and drug interactions -Schedule frequent follow-ups

40. Medication Management in COD For patients with anxiety d/o’s and SUDs: For patients with anxiety d/o’s and SUDs: Try to avoid BDZs Try to avoid BDZs Consider: SSRIs, buspirone, mirtazapine, trazodone, low- dose quetiapine Consider: SSRIs, buspirone, mirtazapine, 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 patch Daytrana patch

41. 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 Emerging literature supports use of meds in patients with SUDs and psychiatric comorbidity Emerging literature supports use of meds in patients with SUDs and psychiatric comorbidity

43. Medications for Nicotine Dependence FDA approved in adults: FDA approved in adults: - Nicotine replacement therapies Patch, gum, lozenge, inhaler Patch, gum, lozenge, inhaler - Bupropion SR (Zyban) - Varenicline (Chantix) Some efficacy but not FDA approved: Some efficacy but not FDA approved: - Nortriptyline - Clonidine

44. Nicotine Patch OTC Dosing: 7, 14, and 21 mg > 10 cig’s/day: 21 mg < 10 cig’s/day: 14 mg 24 or 16 hour dosing Stop smoking at onset Side effects: skin reaction, insomnia

45. Nicotine Gum OTC 2mg if < 25 cig’s/day 4mg if > 25 cig’s/day Use q 1-2 h “Park” and chew method Slow, buccal absorption Avoid eating/drinking Side effects: mouth/throat soreness

47. Nicotine Lozenge OTC 2mg if 1 st cigarette > 30 min after waking 4mg if 1 st cigarette < 30 min after waking Up to 20 lozenges/day More discrete than gum

48. Bupropion SR (Zyban) Bupropion SR (Zyban) Dose: 150 mg PO bid Dose: 150 mg PO bid -if < 90 lbs, 150 mg qd max Start 5-7 days before quit date Start 5-7 days before quit date Mechanism: Mechanism: -NE and dopamine reuptake inhibition -Nicotinic receptor antagonism Side effects: headache, insomnia Side effects: headache, insomnia Contraindications: seizures, eating disorders Contraindications: seizures, eating disorders

49. Varenicline (Chantix) Varenicline (Chantix) Dosing: Starter Pak, Continuing Pak (0.5 mg qd to 1 mg bid) for 12 weeks Dosing: Starter Pak, Continuing Pak (0.5 mg qd to 1 mg bid) for 12 weeks Start 7 days before quit date Start 7 days before quit date Mechanism: partial nicotinic agonist Mechanism: partial nicotinic agonist Attenuates withdrawal Attenuates withdrawal Decreases Craving Decreases Craving Side effects: nausea, headache, insomnia Side effects: nausea, headache, insomnia Renal clearance (primary) Renal clearance (primary) Caution: risk of mood disturbance, suicidality Caution: risk of mood disturbance, suicidality

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52. Thank you! Larissa Mooney, M.D. UCLA Integrated Substance Abuse Programs lmooney@mednet.ucla.edu