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Treatment of Addiction as HIV Prevention

Treatment of Addiction as HIV Prevention. August 6, 2008 Charles P. O’Brien, MD, PhD University of Pennsylvania. Disclosures. Consultant to Forest (Campral) Alkermes/Cephalon (Naltrexone) Merck (medication development). HIV Infection Rates by Treatment Status at Time of Enrollment.

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Treatment of Addiction as HIV Prevention

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  1. Treatment of Addiction as HIV Prevention August 6, 2008 Charles P. O’Brien, MD, PhD University of Pennsylvania

  2. Disclosures • Consultant to • Forest (Campral) • Alkermes/Cephalon (Naltrexone) • Merck (medication development)

  3. HIV Infection Rates by Treatment Status at Time of Enrollment

  4. Fig. 1

  5. Prevalence of IV drug users (%) among HIV positive individuals registered within a year

  6. Prevalence of HIV positive individuals (%) among drug addicts

  7. Drug Categories Heroin Stimulants cocaine methamphetamine Alcohol Nicotine Sedatives Marijuana Anabolic Steroids Inhalants Club Drugs

  8. New Medications Buprenorphine Bup/Naloxone (Suboxone) LAAM Naltrexone for alcoholism Depot Naltrexone Acamprosate Topiramate, Baclofen, GVG Rimonabant Ondansatron Modafinil Bupropion

  9. Manual Guided Therapies Cognitive Behavioral (CBT) Drug Counseling (DC) Twelve Step Facilitation (TSF) Motivation Enhancement Therapy (MET) BRENDA (Biopsychosocial, Nurse) Interpersonal Therapy (IPT) Family Therapy Group Therapy

  10. Drug Free TherapeuticCommunity Expensive Not widely available nor covered by insurance Many addicts not willing to participate Those who graduate have 50% relapse rate in one year

  11. Opiate Receptors Post-Synaptic Neuron N NOC Kappa Mu Delta .. .. .. .. TX MOR MOR TX MOR TX MOR Affinity for Receptor KappaMuDelta Naltrexone 406 108 54 Morphine 1 1 1

  12. Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone) 100 90 Full Agonist (Methadone) 80 70 Intrinsic Activity 60 Partial Agonist 50 (Buprenorphine) 40 30 20 10 Antagonist (Naloxone) 0 -10 -9 -8 -7 -6 -5 -4 Log Dose of Opioid

  13. Methadone Maintenance

  14. Methadone Maintenance <45 mg 27.9% positive 46 mg - 80 5.4%

  15. Impact of Methadone Maintenance Treatment on IV Drug Use of 388 Male Methadone Patients in Six Programs . . Last Addiction Period 100% In-Treatment Period . 81.4% 63.3% . 41.7% . 28.9% Admission Pre-Admission 1st Year 2nd Year 3rd Year 4th Year period

  16. Relapse to IV Drug Use after Methadone Maintenance Treatment of 105 Male Patients who left Treatment 82.1% 72.7% 57.6% 45.5% 28.9% In-Treatment Rate Months Since Drop Out

  17. Co-occurring mental disorders • Depression • Anxiety • Schizophrenia • Bipolar disorder • TREATMENT: Psychotherapy + Psychoactive medication

  18. “Dose” of Psychotherapy • Hold methadone dose constant • Randomize among • 1. No counseling • 2. Standard counseling • 3. Enhanced counseling

  19. Opiate Positive Urines 69% terminated

  20. Percent Meeting Protective Termination Criterion

  21. Buprenorphine Partial agonist Very safe Combined with naloxone (Suboxone) New law allows treatment in physician’s office

  22. ”How much do you feel the drug?” Buprenorphine Analog Score (cm) Time (minutes) S. Walsh, et al 1994, Clinical Pharmacology & Experimental Therapeutics

  23. Naltrexone Complete antagonist Blocks receptors Also blocks alcohol high “IMPOSSIBLE” to relapse on naltrexone Available as a monthly injection

  24. 2.1 Million Americans in prison Philadelphia prison system 18 % of parolees have history of opiate addiction Relapse should/could result in re-incarceration Approximately 1 Million opiate addicts in US Most support habit by crime

  25. Mean Percent Positive Urines Substance Oral Nltx Control Sig. (N=34) (N=17) Opiate 8% 30% p<.05 Cocaine 33% 49% NS Amphetamine 0% 1% NS Benzodiazepine 2% 6% NS Marijuana 13% 19% NS Alcohol 2% 4% NS

  26. 100% 80% 56% Percent Subjects 60% P<.05 40% 26% 20% 0% NALTREXONE CONTROL Re-Incarceration at 6 months

  27. New delivery system One injection each month Slow release Blocks opiates and endogenous opioids for one month Alcoholism: FDA approved 2006 Opiate addiction: in clinical trial

  28. A new delivery systemBetter adherenceLower monthly doseSteady brain levels *Garbutt et al 2005

  29. Plasma Concentrations Dean RL. Front Biosci. 2005 Jan 1;10:643-655. Dunbar JL, et al. Alc Clin Exp Res. 2006;30:480-490. Data on File, Alkermes, Inc.

  30. Baseline Placebo Vivitrex 190 mg Vivitrex 380 mg Results: Heavy Drinking Days 75th Percentile 30 25th Percentile 25 21.5 19.3 19.3 20 15 Median Heavy Drinking Days per Month 10 7.0 5.9 5.6 5.4 4.9 4.4 4.0 5 3.1 2.1 0 Overall Male Female

  31. Retention in treatment by study week and treatment group Comer, S. D. et al. Arch Gen Psychiatry 2006;63:210-218

  32. Percentage of urine samples negative for various drugs of interest Comer, S. D. et al. Arch Gen Psychiatry 2006;63:210-218

  33. Medications for Cocaine Addiction • GABA-ergic medications • Vigabatrin • Baclofen • Topiramate • Block cocaine withdrawal • Methylphenidate - negative • Amphetamine - negative • Modafinil - positive studies, also blocks cocaine euphoria

  34. Modafinil Blunts Cocaine Euphoria Cocaine-induced euphoria was (ARCI Amphetamine Scale) was significantly blunted (P = 0.02) after modafinil pretreatment (n=6) Dackis CA, et al.: Modafinil and Cocaine: A Double-Blind, Placebo-Controlled Drug Interaction Study. Drug & Alcohol Dependence 70:29-37, 2003

  35. Results: Abstinence (Urine Testing) Study Week Longitudinal GEE models showed a significant main effect for cocaine abstinence in the modafinil group (odds ratio = 2.41, 95% CI 1.09-5.31, p = 0.03) • Dackis, C.A., et al., A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology, 2005. 30(1): p. 205-11.

  36. Results: Prolonged Abstinence More of the modafinil-treated subjects (33% v. 13%; p < 0.05) provided 9 consecutive clean urines (perfect attendance)

  37. Results: Abstinence at Study End More of the modafinil-treated subjects (67% v. 22%) provided 3 consecutive clean urines at the end of their medication trial • Dackis, C.A., et al., A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology, 2005. 30(1): p. 205-11.

  38. Results: Abuse / Overuse Return rate in modafinil & placebo groups was not different (chi2 = 0.01, p = 0.93) Dackis et al. A Double-Blind, Placebo-Controlled Trial of Modafinil for Cocaine Dependence. Neuropsychopharmacology (in press).

  39. 6 5 4 3 2 1 -1 0 1 2 3 4 5 6 7 8 Abuse Potential of Modafinil Amphetamine 15 mg Modafinil 300 mg Caffeine 300 mg Placebo ARCI:amphetaminescale Hours post-dose Warot. Eur Psychiatry. 1993;8:201

  40. Penn/VA Center Team Arthur Alterman James McKay Wade Berrettini A. Thomas McLellan John Cacciola David Metzger Anna Rose Childress David Oslin James Cornish Helen Pettinati Charles Dackis Michael Stromberg Ronald Ehrman Elmer Yu Teresa Franklin George Woody Kyle KampmanJoe Volpicelli obrien@mail.trc.upenn.edu http://www.uphs.upenn.edu/trc

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