Medication Assisted Therapy for Opioid Addiction:
Methadone and Buprenorphine
Andrew J. Saxon, M.D.Veterans Affairs Puget Sound Health Care System
and
University of WashingtonSeattle, WA
Disclosures
Supported by: National Institute on Drug AbuseClinical 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 Pharmacokineticsand 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 StudyBefore
Experimental Group(Methadone)
Control Group(No Methadone)
Gunne & Gronbladh, 1981
Swedish Methadone Study After 2 Years
Experimental Group(Methadone)
Control Group(No Methadone)
Gunne & Gronbladh, 1981
d
a b
c
d d
a Sepsisb Sepsis and Endocarditisc Leg Amputationd 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)
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)
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
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.
Treatment duration (days)
Rem
aini
ng in
tre
atm
ent
(nr
)
0
5
10
15
20
0 50 100 150 200 250 300 350
Detox/placebo
Buprenorphine
Maintenance vs. Detoxification: Retention
c2=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.
Buprenorphine Implants for Opioid Addiction
Ling et al., 2010
START Study Schema
1920 Number screened for participation
1269 Randomized
740 Buprenorphine/Naloxone 529 Methadone
340 Evaluable400 Failed to remain on assigned
medication for 24 wks0 Failed to provide ≥ 4 LT
samples
391 Evaluable 136 Failed to remain on assigned
medication for 24 wks2 Failed to provide ≥ 4 LT samples
261 Completed 32-week follow-up 330 Completed 32-week follow-up
Treatment Retention
0
0.2
0.4
0.6
0.8
10 20 40 60 80 10
0
120
140
160
168
Surv
ival
Days in treatment during 24 weeks
Buprenorphine (n=738) Methadone (n=529)
Survival Curves for Buprenorphine Versus Methadone
1
Treatment Retention by Dose
0-40 41-60 61-80 81-120 121+
0%
20%
40%
60%
80%
100%
0-10 12-14 16-20 22-28 30-32
mg methadone (max)
% of
comp
letion
mg buprenorphine (max)
Comparing Retention at 24 Weeks by Maximum Dose of Medication Prescribed
Buprenorphine (% = % of buprenorphine participants prescribed in that dose range)
Methadone (% = % of methadone participants prescribed in that dose range)
27.9%26.8%
27.6%15.3%
11.8%
5.8%8.7%
23.4% 35.6%
17.0%
Opiate Positives by Dose
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Week in Treatment
Buprenorphine dose (n=738) Opiate positive among BUP patientsMethadone dose (n=529) Opiate positive among MET patients
Average Weekly Dose and Positive Opiate over Weeks in Treatment (n=1,267)
3
HIV Injection Risk Behavior
Risk Behavior Survey completed at baseline, week 12, week 24
Needle Sharing in Past 30 Daysamong 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 24Multiple Sexual Partners in Past 30
Daysamong 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 AddictionMethadone 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
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