1. Medication Assisted Therapy for Opioid Addiction: Methadone and Buprenorphine Andrew J. Saxon, M.D. Veterans Affairs Puget Sound Health Care System and University of Washington Seattle, WA

2. Disclosures Supported by: National Institute on Drug Abuse Clinical Trials Network Supported by: National Institute on Drug Abuse Clinical Trials Network Scientific Advisory Board, Alkermes, Inc. Scientific Advisory Board, Alkermes, Inc. Speaker, ReckittBenckiser, Inc. Speaker, ReckittBenckiser, Inc.

3. Medication Assisted Treatment Methadone and Buprenorphine –Pharmacology –Efficacy Starting Treatment with Agonist Replacement Therapies (START) Study –Comparing methadone and buprenorphine on Treatment retention Illicit opioid use HIV risk reduction

4. Methadone Pharmacokinetics and Dosing Rapidly absorbed Peak Levels in 4 hours t 1/2 =24 hours Metabolized in liver (p450 3A/4) Doses should be individualized but higher doses generally more effective

5. Kyle et al., 1999

6. Swedish Methadone Study Before Experimental Group (Methadone) Control Group (No Methadone) Gunne & Gronbladh, 1981

7. Swedish Methadone Study After 2 Years Experimental Group (Methadone) Control Group (No Methadone) Gunne & Gronbladh, 1981 d ab c dd a Sepsis b Sepsis and Endocarditis c Leg Amputation d In Prison

8. Methadone Side Effects Minimal sedation once tolerance achieved Constipation Increased Appetite/Weight Gain Lowered Libido; May decrease gonadal hormone levels Exhaustively studied in all other organ systems with no evidence of chronic harm

9. Properties of Buprenorphine, a µ -Opioid Partial Agonist Ceiling effect on respiratory depression High affinity for µ-opioid receptor Slowly dissociates from µ-opioid receptors Ameliorates withdrawal once underway Can precipitate withdrawal if given in temporal proximity to full agonist opioids

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

11. Buprenorphine Pharmacology Poor oral bioavailability; given sublingually (subcutaneous implants: experimental; patch: for pain) Slow onset (Peak effects 3-6 hrs.) Long duration (24 - 48 hours) Slow offset Half life > 24 hours

12. Zubieta et al., 2000

13. No. Assessed for Eligibility: 84 No. Randomized: 40 No. Excluded: 44 Not Meeting Inclusion Criteria: 41 Refused to Participate: 2 Other Reasons: 1 Allocated to Buprenorphine: 20 Received Buprenorphine: 20 Allocated to Detox/placebo: 20 Received Detox/Placebo:20 Included in Analysis:20 Excluded from Analysis: 0 Included in Analysis * :20 Excluded from Analysis: 0 All Patients: Group CBT Relapse Prevention Weekly Individual Counseling Three times Weekly Urine Screens Buprenorphine Maintenance vs. Detoxification Kakko J et al. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomized, placebo-controlled trial. Lancet 361(9358):662-8, 2003.

14. Treatment duration (days) Remaining in treatment (nr) 0 5 10 15 20 050100150200250300350 Detox/placebo Buprenorphine Maintenance vs. Detoxification: Retention

15.  2 =5.9; p=0.0150/20 (0%)4/20 (20%)Dead Cox regressionBuprenorphineDetox/Placebo Maintenance vs. Detoxification: Mortality Kakko J et al. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomized, placebo-controlled trial. Lancet 361(9358):662-8, 2003.

16. Buprenorphine Implants for Opioid Addiction Ling et al., 2010

17. START Study Schema 1920Number screened for participation 1269Randomized 740Buprenorphine/Naloxone529Methadone 340Evaluable 400 Failed to remain on assigned medication for 24 wks 0Failed to provide ≥ 4 LT samples 391Evaluable 136Failed to remain on assigned medication for 24 wks 2Failed to provide ≥ 4 LT samples 261 Completed 32-week follow-up330 Completed 32-week follow-up

18. Treatment Retention

19. Treatment Retention by Dose

20. Opiate Positives by Dose

21. HIV Injection Risk Behavior Risk Behavior Survey completed at baseline, week 12, week 24 Risk Behavior Survey completed at baseline, week 12, week 24 Needle Sharing in Past 30 Days among Week 24 Completers: Baseline (%)Week 24 (%)p Bup/Nx (n=340)14.42.4<.0001 MET (n=391)14.14.8<.0001

22. HIV Sexual Risk Behavior Risk Behavior Survey completed at baseline, week 12, week 24 Risk Behavior Survey completed at baseline, week 12, week 24 Multiple Sexual Partners in Past 30 Days among Week 24 Completers: Baseline (%)Week 24 (%)p Bup/Nx (n=340)6.85.2<.04 MET (n=391)8.25.1<.04

23. MAT for Opioid Addiction Methadone and Buprenorphine Conclusions Relapse rates are high without MAT Relapse rates are high without MAT Methadone and Buprenorphine both efficacious and reduce mortality Methadone and Buprenorphine both efficacious and reduce mortality Methadone and Buprenorphine both reduce HIV risk behaviors Methadone and Buprenorphine both reduce HIV risk behaviors