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 Pharmacological treatment options within drug classes: –Alcohol –Opioids –Nicotine –Stimulants Clinical implications of co-occurring psychiatric disorders

3. 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) Thorough evaluation and diagnosis essential

4. Addiction Risk Factors

5. Neurobiology of Addiction Reward system: mesolimbic dopamine pathway –Natural vs. drug rewards –Dopamine release: pleasure and reinforcement 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 “Hypo-frontality”: impaired decision-making, loss of control (orbitofrontal cortex, anterior cingulate) 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 psychiatric symptoms or co- occurring disorders Reduction of cravings and urges Substitution therapy Prevention

9. Medications for Alcohol Dependence FDA-Approved: –Disulfuram (Antabuse) –PO naltrexone (Revia) –IM naltrexone (Vivitrol) –Acamprosate (Campral) Non-FDA-approved: –Topiramate (Topamax) –Ondansetron (Zofran)

10. Disulfuram (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

11. Disulfuram (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 Neiderhofer and Staffen ’03a: increased abstinence with disulfuram in adolescent alcoholics

12. Naltrexone (Revia) FDA approved 1994 Dosing: 50 mg PO qd (start at 25 mg qd) Mechanism: mu-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 Deas et al., ’05: pilot study in adolescent alcoholics

13. IM Naltrexone (Vivitrol) FDA approved 2006 Dose: 380 mg IM q 4 weeks No need for oral lead-in Stop drinking 7 days prior (ideal) Mechanism: opioid antagonist Results: Decreased heavy drinking days, decreased frequency of drinking

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

15. Acamprosate (Campral) Start post-detox (ideal) Side effects: diarrhea, abdominal discomfort Results: increased time to relapse, increased total abstinence, reduced drinking days Niederhofer and Staffen ’03: increased abstinence in adolescents with AUDs relative to placebo

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

19. 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

20. 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

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

22. 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

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

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

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

27. 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

28. 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

30. 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

31. Bupropion SR (Zyban) Dose: 150 mg PO bid -if < 90 lbs, 150 mg qd max Start 5-7 days before quit date Mechanism: -NE and dopamine reuptake inhibition -Nicotinic receptor antagonism Side effects: headache, insomnia Contraindications: seizures, eating disorders Muramoto et al., ’07: efficacy of 300 mg dose relative to placebo in adolescents

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

33. Stimulants CRACK METHAMPHETAMINE COCAINE

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

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

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

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

38. 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) Perform comprehensive psychiatric evaluation including SUD screening Obtain info from multiple sources Have a high index of suspicion for SUD co- morbidity when patient not responding to tx

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

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

41. Medication Management in COD For patients with anxiety d/o’s and SUDs: –Try to avoid BDZs –Consider: SSRIs, buspirone, mirtazapine, trazodone, low-dose quetiapine For patients with ADHD and SUD, consider: –Atomoxetine (Strattera) –Bupropion SR or XL (Wellbutrin) –Modafinil (Provigil) –If stimulant necessary: Long-acting formulations (e.g., Concerta) Lisdexamphetamine Daytrana patch

42. 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 Emerging literature supports use of meds in youth with SUDs and psychiatric comorbidity

43. References Deas D, May MP, Randall C, Johnson N, and Anton R, 2005. Naltrexone treatment of adolescents: an open-label pilot study. J Child Adol Psychopharmacol 15(5):723-8. Killen JD, Robinson TN, Ammerman S, Hayward C, Rogers J, Stone C, Samuels D, Levin SK, Green S, and Schatzberg AF, 2004. Randomized clinical trial of the efficacy of bupropion combined with nicotine patch in the treatment of adolescent smokers. J Consult Clin Psychol 72(4): 729- 35. Marsch LA, Bickel WK, Badger GJ, Stothart ME, Quesnel KJ, Stanger C, and Brooklyn J, 2005. Comparison of pharmacological treatments for opioid-dependent adolescents: a randomized controlled trial. Arch Gen Psychiatry 62(10): 1165. Monuteaux MC, Spencer TJ, Faraone SV, Wilson AM, and Biederman J, 2007. A randomized, placebo-controlled trial of bupropion for the prevention of smoking in children and adolescents with ADHD. J Clin Psychiatry 68(7): 1094-101.

44. References Muramoto ML, Leischow SJ, Sherrill D, Matthews E, and Strayer LJ, 2007. Randomized, double-blind, placebo-controlled trial of 2 dosages of sustained-release bupropion for adolescent smoking cessation. Arch Pediatr Adolesc Med 161(11): 1068-74. Newton TF, Roache JD, De La Garza R 2 nd, Fong T, Wallace CL, Li SH, Elkashef A, Chiang N, and Kahn R, 2006. Bupropion reduces methamphetamine-induced subjective effects and cue-induced craving. Neuropsychopharmacology 31(7):1537-44. Niederhofer H and Staffen W, 2003a. Acamprosate and its efficacy in treating alcohol dependent adolescents. Eur Child Adolesc Psychiatry 12(3):144-8. Niederhofer H and Staffen W, 2003b. Comparison of disulfuram and placebo in treatment of alcohol dependence in adolescents. Drug and Alcohol Rev 22:295-97. Kreek MJ, Schlussman SD, Bart J, LaForge KS, and Butelman ER, 2004. Evolving perspectives on neurobiological research on the addictions: celebration of the 30 th anniversary of NIDA. Neuropharmacology 47 Suppl 1:324-44.

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