buprenorphine: an introduction walter ling md integrated substance abuse programs ucla los angeles,...
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Buprenorphine: An Introduction
Walter Ling MD
Integrated Substance Abuse Programs
UCLALos Angeles, CA
April 21st 2006
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