1. Benjamin Nordstrom MD, PhD VP, Medical Director for Program Development Phoenix House Foundation

2.  Understand how buprenorphine, methadone, and naltrexone work  Understand clinical evidence for these drugs  Understand dosing rationale for methadone and buprenorphine

3.  Drug use starts out because it is pleasurable and/or helps avoid pain  Drug use pursued in such a way that negative consequences follow  Drug use persists in the face of negative consequences and the desire to quit (i.e. after it no longer “makes sense”)

4.  Reinforcement ↑ the frequency of a behavior  Positive reinforcement  behavior makes a good feeling start  Negative reinforcement  behavior makes a bad feeling stop

5.  Tolerance develops quickly  Use gets perpetuated by….  Positive reinforcement  Get euphoria (high)  Negative reinforcement  Get withdrawal when wears off  Withdrawal is pretty unpleasant

6.  Full agonists  Bind to the receptor and activate the receptor  Increasing doses of the drug produce increasing effects until a maximum effect is achieved (receptor is fully activated)  Most abused opioids are full agonists

8.  Partial agonists  Bind to the receptor and activate the receptor  Increasing the dose does not lead to as great an effect as does increasing the dose of a full agonist- less of a maximal effect is achieved

10.  Antagonists  Bind to the receptor, but don’t activate the receptor  Block the receptor from being bound by a full agonist or partial agonist  Like putting gum in a lock, or…

12. 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)

13. Works on the same receptor (mu opioid receptors) as heroin and other abused opioids Can use it to taper people down Build a “chemical staircase” for them to walk down Can use it to maintain people as well Put on same dose of methadone as heroin Stops withdrawal Ratchet up dose to way past how much heroin they used Price it out of reach Stops positive and negative reinforcement

14.  Methadone overdoses are common  Frequently occur during the first couple of weeks of methadone treatment (Buster et al 2002)  Likely due to the pharmacokinetics of methadone  Tolerance needs to build  Induces own metabolism  Long half-life

16.  Methadone  Half-life = 27 +/- 12 hours  Tmax = about 3 hours  Buprenorphine  Half-life = 2.33 +/- 0.24 hours  BUT slow dissociation  Tmax SL route = 0.7 +/- 0.1 hours

18.  Recommendations (Srivastava and Kahan,2006)  Initial dose ≤ 30 mg (10-20 mg if high risk)  Dose increase 5 mg q 3-5 days  Can increase 10-15mg if low risk and in w/d all day  High risk  65 or older  Respiratory disease (e.g. COPD)  Liver problems  Using sedating medications  On CYP 3A4 inhibitors

19.  Under dosing (i.e. less than 60 mg a day) has historically been a problem (D’Aunno and Vaughn 1992, D’Aunno and Pollack 2002)  In 2005:  44% patients got ≥ 80 mg  35% got < 60 mg a day  17% got < 40 mg a day  Lower doses in clinics w/ African Americans and Hispanics and w/ NA oriented leadership (Pollack and D’Aunno 2005)

20.  Methadone  Retains in tx > PBO at 20-30 mg (e.g. Strain 1993)  Dose dependent decrease in illicit opioid use (Strain et al 1999)

21.  Donny et al 2002  Stabilized volunteers on 30, 60, and 120 mg methadone x 3 weeks each  Challenged w/ heroin  Found that lower 2 doses blocked w/d, but only 120 mg completely blocked effects of heroin  Donny et al 2005  Stabilized volunteers on 50, 100, and 150 mg  Worked to self-administer vs alternate reinforcer  Found > 100 mg suppressed self-administration

22. Buprenorphine, Methadone, LAAM: Treatment Retention Percent Retained 0 20 40 60 80 100 1234567891011121314151617 20% Lo Meth (20mg/d) 58% Bup (32mg TIW) 73% Hi Meth (100mg/d) ) 53% LAAM (equiv 100mg/d) Study Week Adapted from Johnson, et al., 2000

23. Buprenorphine, Methadone, LAAM: Opioid Urine Results Mean % Negative 1357911131517 0 20 40 60 80 100 Hi Meth (100mg/d) Bup (32mg TIW) ) LAAM (equiv 100mg/d) Lo Meth (20mg/d) Study Week Adapted from Johnson, et al., 2000

24.  “Peak” = highest concentration in blood  “Trough” = lowest concentration in blood  Trough levels ≥ 200 ng/mL are usually sufficient to prevent withdrawal  Maintenance peak:trough usually are 2:1 to 4:1 (Foster et al 2001)  Consider split dosing in indicated

28.  Clinically significant if > 500 ms  Can lead to torsade de pointes  Mean dose in one study was 231 mg (Justo et al 2006)  29% cases reported to FDA dose = 60 -100 mg (Pearson and Woosley 2005)  Cochrane Review says not clearly established link (Pani et al 2013)  Consider screening EKG esp if high dose or on other meds than lengthen QTc

29.  High affinity for the mu opioid receptor  Competes with other opioids and blocks their effects  Prevents positive reinforcement  Slow dissociation from the mu opioid receptor  Prolonged therapeutic effect for opioid dependence treatment  Long half life (20-44 hours)  Prevents negative reinforcement

30. Zubieta et al., 2000

31. 321620 0 2 4 6 8 10 12 14 16 18 Buprenorphine Dose (mg/day) Change in Total Score (post-HYD minus Post-BUP) * *

32.  Buprenorphine 16 mg = methadone 60 mg  Fareed et al, J. Addict. Dis. 2012, 31(1)  Meta-analysis of 21 studies  Found that doses of at least 16 mg predicted better retention in treatment, and that retention in treatment predicted less opioid use

33.  Schedule II  Dispensed at Opioid Treatment Programs (OTP)  Staffing and practices directed by Federal law  42 CFR Part 8  Compared to psychosocial interventions alone  Increased treatment retention  Decreased opioid use

34.  Schedule III  Office-Based Opioid Treatment (OBOT) or OTP  DATA 2000  Addiction specialist (3 kinds)  8 hour course  Compared to psychosocial interventions alone  Improve treatment retention  Reduce opioid use

35.  Patient preference typically decides which  No factors predict better outcome for one vs. the other (Marsch et al 2005)  Some studies show they are the same  Some studies show  Methadone retains better  Buprenorphine reduces opioid use better  Cochrane meta-analysis:  Methadone retains better  Equal at reducing opioid use

36.  Not a controlled substance  Any licensed provider can Rx  Oral or long-acting injection  Compliance is a problem

37.  No solid empirical evidence to answer  Oft cited case control study (Stimmel et al 1977)  Guidance from TIP 43 is “at least 2 years”  Stability in multiple domains of life  Social  Occupational  Family