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Pharmacological Treatment of Addictive Disorders

Pharmacological Treatment of Addictive Disorders. Larissa Mooney, M.D. Assistant Professor of Psychiatry UCLA Integrated Substance Abuse Programs. Objectives. Introduction to medication treatment approaches for addictive disorders Pharmacological treatment options within drug classes:

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Pharmacological Treatment of Addictive Disorders

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  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

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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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 Acamprosate (Campral)

  14. 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 Acamprosate (Campral)

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

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

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

  22. 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

  23. 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 Nicotine Patch

  24. 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 Nicotine Gum

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

  26. 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

  27. 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

  28. Stimulants COCAINE CRACK METHAMPHETAMINE

  29. 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 Methamphetamine vs. Cocaine

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

  31. Medications considered for Methamphetamine Negative Results +/Under Consideration • Imipramine Bupropion • Desipramine Modafinil • Tyrosine Topirimate • Ondansetron Disulfiram • Fluoxetine Lobeline • Aripiprazole Gabapentin

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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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.

  39. 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 2nd, 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 30th anniversary of NIDA. Neuropharmacology 47 Suppl 1:324-44.

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

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