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