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Pharmacotherapy of Alcohol Dependence

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  1. Pharmacotherapy of Alcohol Dependence Department of Surgery Grand Rounds St. Luke’s and Roosevelt Hospitals New York, Wednesday, September 7, 2005 Petros Levounis, M.D. Director, The Addiction Institute of New York Chief, Division of Addiction Psychiatry at St. Luke’s and Roosevelt Hospitals www.AddictionInstituteNY.org

  2. 4 HANDOUTS • Mayo-Smith, M.F. (2003). Management of Alcohol Intoxication and Withdrawal. In A. W. Graham, T. K. Shultz, M. F. Mayo-Smith, R. K. Ries, & B. B. Wilford (Eds.), Principles of Addiction Medicine (3rd ed., pp. 621-631). Chevy Chase, Maryland: American Society of Addiction Medicine. • Fundamentals of Addiction Medicine • Addiction Institute Brochure • These slides

  3. OUTLINE • Introduction • Alcohol Intoxication • Alcohol Withdrawal • Relapse Prevention • Co-Occurring Disorders • New Directions

  4. 1 INTRODUCTION

  5. Epidemiology • 207 million = US Population • 18 million = Alcohol Use Disorders (9%) • 8 million = Alcohol Dependence (45%) • 2 million = Ever treated (24%) • 1.2 million = Ever seen an M.D. (60%) • .6 million = Ever given meds (50%) Grant BF et al. Arch Gen Psychiatry. 2004;61:807-816. http://imshealth.com

  6. Neurotransmitter Systems • GABA → CNS Inhibition • Glutamate → CNS Excitation • Opioid → Euphoria/Reward • Dopamine → Addiction • Serotonin → Impulsivity

  7. 2 ALCOHOL INTOXICATION

  8. Characteristics • 0-100 mg/dL Well-being • 100-200 mg/dL Incoordination • 200-300 mg/dL Ataxia • 300-400 mg/dL Stage I Anesthesia • 400-600 mg/dL Coma • 600-800 mg/dL Death

  9. Pharmacotherapy • Use IV thiamine and glucose • Do not use ipecac, activated charcoal, caffeine, amphetamines, or flumazenil. • Treatment is supportive.

  10. 3 ALCOHOL WITHDRAWAL

  11. Characteristics 1 • Following the last drink: • 6 to 24 hours: Autonomic Hyperactivity • 24 to 48 hours: Seizures • 48 to 96 hours: Delirium tremens • “Kindling effect” for seizures. • Older patients are at higher risk of DTs. • Typically mild, occasionally severe, rarely fatal.

  12. Characteristics 2 • Autonomic Hyperactivity with: • Reduced GABA activity and • Enhanced glutamate activity.

  13. Characteristics 3 • Early signs of withdrawal: • Tachycardia • Blood pressure elevation • Sweating • Hyperthermia • Tremor (6 to 8 cycles per second)

  14. Assessment • Clinical Institute Withdrawal Assessment for Alcohol (revised). Mayo-Smith MF. JAMA. 1997;278:144-51.

  15. CIWA-Ar Categories[ Range of Scores: 0-7* ] Adapted from www.asam.org

  16. Practice Guidelines Adapted from Mayo-Smith MF. JAMA. 1997;278:144-51.

  17. Pharmacotherapy 1 • Long-acting benzodiazepines (e.g., chlordiazepoxide) are the treatment of choice. • Short-acting benzodiazepines (e.g., lorazepam) are preferred in liver damage and the elderly. • Anticonvulsants are being studied. Holbrook AM et al. Can Med Assoc J. 1999;160:649-55. Bonnet U et al. J Clin Psychopharmacol. 2003;23:514-9.

  18. Pharmacotherapy 2 • For symptom triggered medication, administer every hour when CIWA-Ar >= 9: • Chlordiazepoxide 50 to 100 mg • Lorazepam 2 to 4 mg • Diazepam 10 to 20 mg Mayo-Smith MF. JAMA. 1997;278:144-51.

  19. Pharmacotherapy 3 • For standing po chlordiazepoxide: • Day 1: 50 mg Q 4 hours • Day 2: 50 mg Q 6 hours • Day 3: 25 mg Q 4 hours • Day 4: 25 mg Q 6 hours Garbutt JC et al. JAMA. 1999;281:1318-25.

  20. Pharmacotherapy 4 • For delirium tremens: • 2 to 4 mg IV lorazepam followed by • 1 to 2 mg IV lorazepam every 5 minutes until patient is calm. • Taper slowly over 4 to 5 days. Adopted from Garbutt JC et al. JAMA. 1999;281:1318-25.

  21. Pharmacotherapy 5 • In general, for severe withdrawal: • Titrate to light sedation. • Have flumazenil ready. • Calculate daily dose. • Decrease dose by 25% daily.

  22. 4 RELAPSE PREVENTION

  23. DISULFIRAM Introduced in 1954

  24. Mechanism of Action • Alcohol → Acetaldehyde → Acetate • Disulfiram irreversibly binds to acetaldehyde dehydrogenase inhibiting the metabolism of acetaldehyde to acetate. • Acetaldehyde accumulates resulting in a violent reaction (nausea, vomiting, flushing).

  25. Efficacy • Double-blind, placebo-control study design is not helpful as both the medication and the placebo pills may (or may not) result in fear of drinking. • Most studies are negative, but disulfiram may be helpful in highly structured settings. Fuller RK et al. JAMA. 1986;256:1449-55.

  26. Dosing and Safety • 250-500 mg daily. • Medication costs approximately $40 a month. • Some liver toxicity; liver function should monitored. • Inhibits hepatic microsomal enzymes and increases drug levels. Physician’s Desk Reference. 59th ed. Pp 2442-3.

  27. NALTREXONE Introduced in 1995

  28. Mechanism of Action • Reduces positive reinforcement (reward craving). • The patient does not experience the full euphorogenic/reinforcing effect of alcohol. • Prevents a slip from becoming a full-blown relapse.

  29. Efficacy • Effective in reducing relapse to heavy drinking ( >4 in men, >3 drinks/day in women). • The Srisurapanont (2005) meta-analysis found efficacy up to 12 weeks but not after 12 weeks. • Medication compliance may be a limiting factor in treatment. Mason BJ. Eur Neuropsychopharmacol. 2003;13:469-475. Srisurapanont M & Jarusuraisin N. Cochrane Database Syst Rev 2005.

  30. Dosing and Safety • 50 mg daily. • Medication costs $103 a month. • Liver toxicity; liver function should monitored closely. • Otherwise safe and well-tolerated. • No significant drug-drug interactions. http://ncadi.samhsa.gov/govpubs/BKD268/28c.aspx

  31. ACAMPROSATE Introduced in 2005

  32. Mechanism of Action • Reduces negative reinforcement (abstinence craving). • Neuroadaptation and upregulation of the glutamate system in alcoholism. • Acamprosate interferes with the glutamatergic system.

  33. Efficacy • Effective in improving abstinence. • The Mann et al (2004) meta-analysis found a 50% improvement in 6-month abstinence (36% acamprosate vs. 23% placebo). • Three times a day dosing may compromise compliance. Sass et al. Arch Gen Psychiatry. 1996;53:673-680. Mann K et al. Alcohol Clin Exp Res. 2004;28:51-63.

  34. Dosing and Safety • 666 mg three times a day. • Medication costs $110 a month. • Excreted by the kidneys - No liver metabolism. • Mild diarrhea (16% acamprosate vs. 10% placebo). • No drug-drug interactions. Physician’s Desk Reference. 59th ed. Pp 3428-30.

  35. 5 CO-OCCURRING DISORDERS

  36. In General • Co-occurring alcohol dependence and other psychiatric disorder(s) typically require treatment for both (all). • Treating patients under one roof improves both addiction and mental health outcomes. Mariani JJ, Levin FR. Harvard Rev Psychiatry. 2004;12:351-66. Kranzler HR, Jaffe JH. In: Graham TK et al, eds. Principles of Addition Medicine. 3rd ed. Chevy Chase, MD: American Society of Addition Medicine. 2003:701-19.

  37. Depression • Antidepressants typically improve depressive symptoms. • However, they have limited impact on alcohol use. Nunez EV, Levin FR. JAMA. 2004;291:1887-96.

  38. Antidepressants’ Effect on Depression From Nunez EV, Levin FR. JAMA. 2004;291:1893.

  39. Antidepressants’ Effect on Substance Use From Nunez EV, Levin FR. JAMA. 2004;291:1893.

  40. 6 NEW DIRECTIONS

  41. New Delivery Systems • Long-acting naltrexone injection: 100 μm diameter microspheres composed of naltrexone and PLG polymeric matrix. • Nausea, headache, and fatigue are the prominent adverse effects. • FDA decision expected in late ‘05. http://www.fda.gov Please note: This agent is not approved by the FDA for use in alcohol dependence.

  42. Injectable Naltrexone • Heavy drinking days rates during a 24 week treatment trial with injectable naltrexone 190 mg and 380 mg Qmonth. • Injectable naltrexone reduced the rate of heavy drinking by 25% (P=.02). Adapted from Garbutt et al. JAMA. 2005;293:1622.

  43. New Combinations • Acamprosate and naltrexone have different mechanisms of action and may work synergistically. • The COMBINE trial (n=1,375; 11 sites) will assess the medication combination and two behavioral interventions for a total of 9 possible treatment formulations. COMBINE Study Research Group. Alcohol Clin Exp Res. 2003;27:1123-1131.

  44. Naltrexone/Acamprosate • Abstinence rates during a 12-week treatment trial with naltrexone 50 mg QD and acamprosate 666 mg TID. • The combination of the two medications helped alcoholics stay abstinent (P=0.002) better than each drug alone. Adapted from Kiefer F et al. Arch Gen Psychiatry. 2003;60:96.

  45. New Pharmacological Agents • Anticonvulsants • Topiramate • Carbamazepine • Valproic Acid • GABA agonist • Baclofen • Selective Serotonin Reuptake Inhibitors • Serotonin (5-HT3) antagonist • Ondansetron Please note: These agents are not approved by the FDA for use in alcohol dependence.

  46. Where you can find us • You can request an addiction consultation by contacting: • Galen Cooper, Ph.D., x38409/pgr 35864 at Roosevelt, or • Raisa Montalvo, M.A., x31743/pgr 39046 at St. Luke’s. • Our website: www.AddictionInstituteNY.org • Our 24-hour-line: 212-523-6491