Download USING RECOVERY MEDICATIONS:

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
Disclosures

Supported by:
National Institute on Drug Abuse
Clinical Trials Network

Scientific Advisory Board, Alkermes, Inc.

Speaker, ReckittBenckiser, Inc.
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
Methadone Pharmacokinetics
and Dosing
• Rapidly absorbed
• Peak Levels in 4 hours
• t1/2=24 hours
• Metabolized in liver (p450 3A/4)
• Doses should be individualized but higher
doses generally more effective
Kyle et al., 1999
Swedish Methadone Study
Experimental Group
(Methadone)
Gunne & Gronbladh, 1981
Before
Control Group
(No Methadone)
Swedish Methadone Study
Experimental Group
(Methadone)
After 2 Years
Control Group
(No Methadone)
a
b
c
d
d
d
Gunne & Gronbladh, 1981
a
b
c
d
Sepsis
Sepsis and Endocarditis
Leg Amputation
In Prison
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
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
Efficacy: Full Agonist (Methadone) Partial Agonist
(Buprenorphine), Antagonist (Naloxone)
100
Full Agonist
(Methadone)
90
80
70
%
60
Efficacy
50
Partial Agonist
(Buprenorphine)
40
30
20
Antagonist
(Naloxone)
10
0
-10
-9
-8
-7
Log Dose of Opioid
-6
-5
-4
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
Zubieta et al., 2000
Buprenorphine Maintenance vs.
Detoxification
No. Assessed for
Eligibility: 84
All Patients:
No. Excluded:
44
Not Meeting Inclusion Criteria:
41
Group CBT Relapse Prevention
Weekly Individual Counseling
Refused to Participate:
Three times Weekly Urine
Screens
No. Randomized:
40
Other Reasons:
2
1
Allocated to Buprenorphine:
20
Allocated to Detox/placebo:
20
Received Buprenorphine:
20
Received Detox/Placebo:20
Included in Analysis:
Included in Analysis*:
Excluded from Analysis:
20
0
Excluded from Analysis:
20
0
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.
Remaining in treatment (nr)
Maintenance vs. Detoxification: Retention
20
15
10
Detox/placebo
5
Buprenorphine
0
0
50
100
150
200
250
Treatment duration (days)
300
350
Maintenance vs. Detoxification: Mortality
Detox/Placebo Buprenorphine Cox regression
Dead
4/20 (20%)
0/20 (0%)
c2=5.9; p=0.015
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.
Buprenorphine Implants for Opioid Addiction
Ling et al., 2010
START Study Schema
1920
Number screened for participation
1269
740 Buprenorphine/Naloxone
340 Evaluable
400 Failed to remain on assigned
medication for 24 wks
0
Failed to provide ≥ 4 LT samples
261 Completed 32-week follow-up
Randomized
529 Methadone
391 Evaluable
136 Failed to remain on assigned
medication for 24 wks
2 Failed to provide ≥ 4 LT samples
330 Completed 32-week follow-up
Treatment Retention
Survival Curves for Buprenorphine Versus Methadone
Buprenorphine (n=738)
1
Methadone (n=529)
0.6
0.4
0.2
168
160
140
120
100
80
60
40
20
0
0
Survival
0.8
Days in treatment during 24 weeks
1
Treatment Retention by Dose
Comparing Retention at 24 Weeks by Maximum Dose of
Medication Prescribed
0-40
mg methadone (max)
41-60
61-80
81-120
100%
121+
17.0%
23.4%
35.6%
% of completion
80%
60%
40%
20%
15.3%
8.7%
27.9%
26.8%
27.6%
5.8%
11.8%
0%
0-10
12-14
16-20
22-28
mg buprenorphine (max)
30-32
Buprenorphine (% = % of buprenorphine participants prescribed in that dose range)
Methadone (% = % of methadone participants prescribed in that dose range)
Opiate Positives by Dose
Average Weekly Dose and Positive Opiate over Weeks in Treatment
(n=1,267)
Buprenorphine dose (n=738)
Opiate positive among BUP patients
Methadone dose (n=529)
Opiate positive among MET patients
100
80
60
40
20
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
0
Week in Treatment
HIV Injection Risk Behavior

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)
14.4
2.4
<.0001
MET (n=391)
14.1
4.8
<.0001
HIV Sexual Risk Behavior

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)
6.8
5.2
<.04
MET (n=391)
8.2
5.1
<.04
MAT for Opioid Addiction
Methadone and Buprenorphine
Conclusions

Relapse rates are high without MAT

Methadone and Buprenorphine both efficacious
and reduce mortality

Methadone and Buprenorphine both reduce
HIV risk behaviors