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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 • Stimulants • Nicotine • Clinical implications of co-occurring 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) • Baclofen

  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

  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

  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 Acamprosate (Campral)

  15. Clinical Case #1 • 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 • Mother has found hidden bottles of vodka • 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) • Admits to drinking or taking a pill to help her sleep

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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

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

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

  24. Clinical Case #2 • 34 y/o female with 3-year history of Vicodin use • Using 10-12 pills/day for back pain suffered in an automobile accident • No history of heroin or other opioid use • 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

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

  26. Clinical Case #3 • 18 y/o unemployed male with a two year history of intravenous heroin use • Criminal convictions for shoplifting • 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 • Reports that he has done well on methadone though has difficulty obtaining the funds to remain in treatment

  27. Stimulants COCAINE CRACK METHAMPHETAMINE

  28. 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

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

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

  31. Clinical Case #4 • 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 • 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. • 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

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

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

  34. 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

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

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

  37. 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

  38. 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 patients with SUDs and psychiatric comorbidity

  39. References • Anton RF, O’Malley SS, Ciraulo DA, Cisoler RA, Couper D, Donovan DM, et al., 2006. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study. JAMA 295(17):2003-17. • Dackis CA, Kampman KM, Lynch KG, Pettinati HM, & O’Brien, CP, 2005. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacol 30:205-11. • Elkashef A, Vocci F, Hanson G, White J, Wickes W, & Tiihonen J, 2008. Pharmacotherapy of methamphetamine addiction: an update. Subst Abus 29(3):31-49. • Garbutt JC, 2009. The state of pharmacotherapy for the treatment of alcohol dependence. J Subst Abuse Treat 36(1): S15-23.

  40. References • Garbutt JC, Kranzler HR, O’Malley SS, Gastfriend DR, Pettinati HM, Loewy JW, et al., 2005. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA 293(13):1617-25. • 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. Neuropharmacol 47 Suppl 1:324-44. • Newton TF, Roache JD, De La Garza R 2nd, Fong T, Wallace CL, Li SH, et al., 2006. Bupropion reduces methamphetamine-induced subjective effects and cue-induced craving. Neuropsychopharmacol 31(7):1537-44. • Vigezzi P, Guglielmino L, Marzorati P, Silenzio R, DeChiara M, Corrado F, et al., 2006. Multimodal drug addiction treatment: a field comparison of methadone and buprenorphine among heroin- and cocaine-dependent patients. J Subst Abuse Treat 31(1):3-7. • Vocci FJ, Acri J, and Elkashef A, 2005. Medication development for addictive disorders: the state of the science. Am J Psychiatry 162(8): 1432-40.

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

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