Buprenorphine: An Introduction

Walter Ling MD

Integrated Substance Abuse Programs

UCLALos Angeles, CA

April 21st 2006

lwalter@ucla.edu

www.uclaisap.org

Buprenorphine in the Treatment ofOpioid Addiction

• Buprenorphine as a medication– Development: Historical perspective– Pharmacology: Safety and efficacy

• Buprenorphine as a Treatment – Philosophical, societal and policy implications– The role of the clinicians

Classification of Addicts and Recommended Treatment

Types of Addicts• Correctional cases

• Mental defectives (degenerates)

• Social misfits

• Otherwise normal

Treatment• Internment camps

• Sterilization

• Vocational guidance

• Psychoanalysis

Forty years later :Methadone

• Long acting

• Orally active opiate agonist capable of reducing or eliminating withdrawal signs and symptoms

• Reducing drug craving

• Normalizing physiological function

47%

23%

17%

12.5%

6%

0%

10%

20%

30%

40%

50%Not in Tx

Currently in Tx

In Tx 5 years

C&D

No needle use since admission to Tx

A B C D

The Effect of Methadone Treatments on HIV Seropositivity Rates

All subjects were male, heterosexual IV drug users in NYC. Treatment

provided was methadone maintenance.

Novick et al., Presented at CPDD, 1985

Naltrexone

OOH O

N

OH

Naltrexone: The Perfect Drug

• Orally Effective• Rapid onset of action• Long duration of action• Safe• Few side effects• Completely blocks effects of heroin• Non-addicting• No tolerance• No dependence• No withdrawal

One reason not to take naltrexone:

Can’t get high!

Naltrexone:The Perfect Drug “victimless cure”

It’s like taking nothing.

The Opioid Receptor Family

Potentially lethal dosePositive effect

=

addictive

potential

Negative effect

Full agonist -morphine/heroin

hydromorphone

Antagonist - naltrexone

dose

Antagonist + agonist/partial agonist

Agonist + partial agonist

Super agonist -fentanyl

Partial agonist - buprenorphine

Mu efficacy and opiate addictionMu efficacy and opiate addiction

Buprenorphine as a Medication: Pharmacological Characteristics

Partial Agonist• high safety profile/ceiling effect

• low dependence

Tight Receptor Binding• long duration of action

• slow onset mild abstinence

Good Effect

0

20

40

60

80

100

p 0.5 2 8 16 32

Buprenorphine (mg)

Pea

k S

core

3.75 15 60

Methadone (mg)

Respiration

02468

1012141618

p 1 2 4 8 16 32

Buprenorphine (mg)

Bre

ath

s/m

inu

te

Intensity of abstinence

60

50

40

30

20

10

0

Him

mel

sbac

h s

core

s

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Buprenorphine

Morphine

Days after drug withdrawal

Study # 999A: Buprenorphine’sEffect on Opiate Use

0

5

10

15

20

25

% S

s W

ith

13

Con

secu

tive

Op

iate

Fre

e U

rin

es

Buprenorphine dose (mg)

1

4

8

16

Buprenorphine Maintenance Treatment of Opiate Dependence: A Multicenter

Randomized Clinical Trial

Mean Heroin Craving: 16 week completers

15

20

25

30

35

40

45

50

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Week of Study

Mea

n C

ravi

ng

Sco

re

1 mg

4 mg

8 mg

16 mg

Joint Probability

N remaining in treatment

X

Total N of subjects

N giving drug free urinesN remaining in treatment

Figure A: A Comparison of Buprenorphine doses from four studies using Joint Probability

0

10

20

30

40

50

Join

t P

roba

bili

ty S

core

Week 8 Week 17

Schottenfeld, et al. 1997 -4 mg

Johnson et al. 1992 - 8 mg

Ling et al. 1996- 8 mg

Strain et al. 1994 (8 variable)

Schottenfeld et al. 1997 -12 mg

A Comparison of Methadone from Four Studies Using Joint Probability

0

10

20

30

40

50

60

70

80

Week 8 Week 17

ARC 20 mg

Schottenfeld 20 mg

LA 30 mg

Strain (50 variable)

ARC 60 mg

Schottenfeld 65 mg

LA 80 mg

Buprenorphine Made Safer:Addition of Naloxone Reduces Abuse

• Naloxone will block buprenorphine’s effects by the IV but not the sublingual route

• Sublingual absorption of buprenorphine @ 70%; naloxone @ 10%

• If injected, BUP/NX will precipitate withdrawal in a moderately to severely dependent addict

Buprenorphine made Safer:Buprenorphine/Naloxone Combination

4 part buprenorphine: 1 part naloxoneSublingual: Opiate agonist effect from

buprenorphine

Intravenous: Opiate antagonist effect from naloxone

Discourage IV use

Diminish street value

Diminish diversion

Allow for flexible dosing

Buprenorphine as Treatment strategy:The First CTN Protocols

• Inpatient detoxification:– Buprenorphine/naloxone vs clonidine– (CTN 0001)

• Outpatient detoxification:– Buprenorphine/naloxone vs clonidine– (CTN 0002)

Study Design

Buprenorphine/Naloxone13 days detoxification

Clonidine13 days detoxification

Open Randomized StudyBup/Nx:Clonidine = 2:1

Joint Probability

N remaining in treatment

X

Total N of subjects

N giving drug free urinesN remaining in treatment

Percent Present and Clean0001 (Inpatient)

0

10

20

30

40

50

60

70

80

90

100

Day 3 or 4 Day 7 or 8 Day 10 or 11 Day 13 or 14

ClonidineBup/Nx

Percent Present and Clean0002 (Outpatient)

0

5

10

15

20

25

30

35

40

45

50

Day 3 or 4 Day 7 or 8 Day 10 or 11 Day 13 or 14

ClonidineBup/Nx

NNT: Number Needed to TreatCTN 0001 (Inpatient)

• NNT for Bup/Nx 77/59 = 1.31 • NNT for Clonidine 36/8 = 4.5

NNT Clonidine : BupNx = 3.44

CTN 0002 (Outpatient)• NNT for Bup/Nx: 157/46 = 3.4 • NNT for Clonidine: 74/4 = 18.5

NNT Clonidine : Bup/Nx = 5.44

  NNT= Number of patients needed to treat to achieve 1 treatment success

Drug Addiction Treatment Act of 2000 An Amendment to the Controlled Substances Act

(October, 2000)

• Subutex and Suboxone approved October 8, 2002 and marketed in January 2003

• Qualified physicians can treat up to 30 patients with the Buprenorphine products ( sublingual tablets)

• Physicians become qualified by training in sessions from designated organizations- APA, ASAM, AAAP, or over the internet; or if otherwise qualified

• Physicians can treat patients in their usual medical practice setting; able to provide or refer for psychosocial treatment.

Our Treatment Philosophy

Addicts are sick; they need help

They also sin; don’t treat them too well

Treatment of Opiate Dependence

• Detoxification

• Maintenance

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12

In Treatment

Rate

28.9%

Months Since Drop Out

1-3Months

Later

4-6Months

Later

45.5%

57.6%

72.7%

82.1%

7-9Months

Later

10-12Months

Later

Ball, JC, Ross A. The Effectiveness of Methadone Maintenance Treatment, Springer-Verlag, New York, 1991

Pe

rce

nt

IV U

se

rs

Relapse to IV Drug Use After Termination of Methadone Maintenance Treatment

Detoxification

Detoxification is good for a lot of things; staying off drugs is not one of them.

Pharmacotherapy and Recovery

• “Medication is not recovery”?

• Addiction is chemistry went wrong

• You can change the brain with experience or with medication; they are the same thing

How People Change

• “You can change the brain with biological treatment or with behavioral treatment”

• Alan Leshner, Former head NIDA

• “You can change someone’s life by altering his genes; but you also do that by paying off his credit card”

• James Watson

Summary: Will Buprenorphine be a Success?

• Not a new medication but a vehicle for a new treatment philosophy

• Not just to change patients but to change us

• New attitude from community leaders like us should lead to new societal attitude towards addiction and change the way we treat and view those afflicted

Thanks to

National Institute on Drug Abuse

NIDA Clinical Trials Network Staff

CTN Publications Committee

Participating CTN Nodes and CTPs

Reckitt Benckiser

Participating Patients

You the audience