Benjamin Nordstrom MD, PhD
VP, Medical Director for Program
Development
Phoenix House Foundation

Understand how buprenorphine, methadone,
and naltrexone work

Understand clinical evidence for these drugs

Understand dosing rationale for methadone
and buprenorphine

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”)

Reinforcement ↑ the frequency of a
behavior

Positive reinforcement
 behavior

makes a good feeling start
Negative reinforcement

behavior makes a bad feeling stop




Tolerance develops quickly
Use gets perpetuated by….
Positive reinforcement
 Get euphoria (high)
Negative reinforcement
 Get withdrawal when wears off
 Withdrawal is pretty unpleasant

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

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

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…
Efficacy: Full Agonist (Methadone) Partial Agonist
(Buprenorphine), Antagonist (Naloxone)
100
Full Agonist
(Methadone)
90
80
70
%
Efficacy
60
Partial Agonist
(Buprenorphine)
50
40
30
20
Antagonist
(Naloxone)
10
0
-10
-9
-8
-7
Log Dose of Opioid
-6
-5
-4



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



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

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



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


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)

Methadone

Retains in tx > PBO at 20-30 mg (e.g.
Strain 1993)

Dose dependent decrease in illicit opioid
use (Strain et al 1999)

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
Buprenorphine, Methadone, LAAM:
Treatment Retention
Percent Retained
100
80
73% Hi Meth (100mg/d)
60
58% Bup (32mg TIW)
40
53% LAAM (equiv 100mg/d)
20
20% Lo Meth (20mg/d)
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Study Week
Adapted from Johnson, et al., 2000
Buprenorphine, Methadone, LAAM:
Opioid Urine Results
100
Mean % Negative
80
LAAM (equiv 100mg/d)
60
Bup (32mg TIW)
Hi Meth (100mg/d)
40
Lo Meth (20mg/d)
20
0
1
3
5
7
9
11
Study Week
13
15
17
Adapted from Johnson, et al., 2000

“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






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

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

Zubieta et al., 2000
18
16
14
Change in
Total Score
(post-HYD
minus
Post-BUP)
12
10
8
6
*
*
4
2
0
32
16
2
Buprenorphine Dose (mg/day)
0

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

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




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

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
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

Not a controlled substance

Any licensed provider can Rx

Oral or long-acting injection

Compliance is a problem

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