Transcript Buprenorphine and Naloxone: Clinical Pharmacology Abuse

Buprenorphine and Naloxone:
Clinical Pharmacology
Abuse Liability
John Mendelson MD
California Pacific Medical Research Institute
and the
University of California at San Francisco
Presentation Goals
 Review Buprenorphine Pharmacology
– Basic Pharmacology
– Sublingual pharmacokinetics
 Review Rational for Suboxone
(Buprenorphine Naloxone combo tablet)
– Predicted effects in
Buprenorphine treated patients
MMT patients
Untreated Heroin Addicts
Onward
 Review Buprenorphine Pharmacology
– Basic Pharmacology
– Sublingual pharmacokinetics
 Review Rational for Suboxone
(Buprenorphine Naloxone combo tablet)
– Predicted effects in
Buprenorphine treated patients
MMT patients
Untreated Heroin Addicts
Buprenorphine Pharmacology
 Semisynthetic, highly lipophylic
Thebaine derivative
 25 to 50 times more potent than
morphine
 Partial µ-agonist
 Some kappa antagonist effects
– Clinical significance unclear
Pharmacotherapy with
Buprenorphine
 Used as parenteral analgesic in Europe
(1º England) for cancer pain and in
obstetrics
 Never caught on in USA
 May produce less respiratory
depression than traditional µ-agonists
Analgesia
Buprenorphine vs. Morphine
 0.4 mg Buprenorphine IM equianalgesic
with 10 mg Morphine IM
 Analgesia lasts longer (6 hours)
 Maximal effects occur later
– Peak respiratory depression at 3
hours
– Peak miosis at 6 hours
Pharmacological Properties
 Partial agonist effects suggested by
– Ceiling on analgesic effects
– Antagonizes fentanyl induced
respiratory depression without
complete loss of anesthesia
Indicates high affinity for µ-receptor
– Can precipitate opiate withdrawal in
highly µ-dependent people
Advantages of Buprenorphine
 Tolerable dose range (4 to 32 mg SL
daily to every 3rd day) for addiction
pharmacotherapy
 Partial agonist
– Ceiling effects so safer in overdose
– Less/absent effects in µ-dependent
addicts
 Kappa antagonist
– Less euphoria
Disadvantages of Buprenorphine
 Can be abused
– Risk may be greatest in new abusers
 Is only a partial agonist
– not suitable for addicts with high
levels of dependence or
– for pain patients on high doses of
analgesic opiates
 Poor oral absorption
Receptor Affinity - Clinical
Implications
 High affinity for µ receptor means
buprenorphine is not easily displaced
from µ receptors. Therefore
– If you precipitate withdrawal, it will be
hard to reverse
– agonist effects are not reversible with
Naloxone
Naloxone is effective if given before
buprenorphine but not after
Dosing Issues
 Review Buprenorphine Pharmacology
– Basic Pharmacology
– Sublingual pharmacokinetics
 Review Rational for Suboxone
(buprenorphine Naloxone combo tablet)
– Predicted effects in
Buprenorphine treated patients
MMT patients
Untreated Heroin Addicts
Absorption and Distribution of
Buprenorphine
 Sublingual bioavailability of 30 to 50 %
(liquid) to 15 to 25 % (tablets)
 Poor oral bioavailability
– In one study oral bioavailability of an
analgesic dose of 0.4 mg was 16%
– Little data on larger buprenorphine
doses
Buprenorphine and Naloxone
Tablets
 Tablets are much easier than liquids to
dose.
 But, the available tablets can require up
to 10 minutes to dissolve
 This can make dosing difficult
– If you don’t think so try not to swallow for
the remainder of this talk. (Better yet,
because not swallowing can be distracting,
wait until the next talk to try this
experiment)
Buprenorphine Pharmacokinetics
 Absorption
– Poor oral absorption due to extensive
first pass metabolism
Metabolism in gut wall
High hepatic extraction
– Adequate sublingual absorption
Bioavailability of Sublingual and
Oral Buprenorphine/Naloxone
 Determined the absolute and relative
bioavailability of oral and sublingual
Buprenorphine and Naloxone tablets
 Measured pharmacodynamic effects of
oral and sublingual Buprenorphine and
Naloxone tablets
The Hope
 Oral administration would be as good as
sublingual administration
 Ease of dosing would be improved
Methods
 9 opiate experienced subjects but not
dependent.
– 6 men, 3 women
 3 session (PO, SL, IV), open label,
double-blind, balanced 3X3 Latin
Square crossover design
 PO and SL dosing placebo controlled
Buprenorphine and Naloxone
Doses
 IV dose:
– Buprenorphine 2 mg and Naloxone
0.5 mg
 PO and SL doses:
– Buprenorphine 8 mg and Naloxone 2
mg
 PO and IV dosing:
– IV dose administered over 15 minutes
– PO dose administered with 240 ml H2O
Sublingual Dosing
 Highly controlled, totally different from how
patients will dose
– After saliva pH measured, tablet placed
in midportion of lateral sublingual space
– Sublingual space inspected at 5 minutes
– Instructed to swallow if tablet dissolved,
continue holding if not dissolved
– Dosing terminated at 10 minutes with
swallowing
Pharmacokinetic Measures
 Plasma and urine concentrations of
Buprenorphine and Norbuprenorphine
(and conjugates) and Naloxone (and
conjugates)
 For Buprenorphine and Naloxone
– AUC (extrapolated and unextrapolated)
– Peak Plasma Concentration and Peak
Time
 Bioavailability determined by AUC Ratio
Plasma Buprenorphine Levels
3
2.5
É
É
É
ng/ml
2
1.5 É
É
1 J É
J
É
0.5 J
É
J
É
J
É
J
J
J
J J J
J
É
0 É
J
0
6
12
3
ÉÉÉ
É
2
É
É
É
1 J
J
J J
J J J
J
0 É
JÉ
0 2 4
É
J
É
J
É
J
É
J
6
8
10 12
É
J
É
J
18
24
30
Time (hours)
36
É
J
É
J
42
48
J
PO
É
SL
Plasma Buprenorphine Levels
3
2.5
É
É
É
ng/ml
2
1.5 É
É
1 J É
J
É
0.5 J
É
J
É
J
É
J
J
J
J J J
J
É
0 É
J
0
6
12
3
ÉÉÉ
É
2
É
É
É
1 J
J
J J
J J J
J
0 É
JÉ
0 2 4
É
J
É
J
É
J
É
J
J
PO
6 8 10 12
SL
Sublingual
F >> Éthan
Oral
be due
to
É
J
either gut or hepatic
18
24
30
36
42
48
Time (hours) metabolism
É
J
Could
É
É
J
J
Plasma Buprenorphine Levels
100
ng/ml (log scale)
H
10
H
H
H
JH
JJH
J H
J H
JH H
1
J H
J
J H
J
H
J
H
J
H
H
J
J
0.1
0
6
12
18
24
30
Time (hours)
36
42
48
H
IV
J
SL
Plasma Buprenorphine Levels
100
ng/ml (log scale)
H
10
H
H
H
JH
JJH
J H
J
1 B JH H H
B
J H
B
B
J JH
BB
J B
BB B
BB
0.1
0
6
12
H
J
B
H
H
H
J
B
J
B
18
24
30
Time (hours)
36
JB
42
48
H
IV
J
SL
B
PO
Oral vs Sublingual:
Absolute and Relative F
Oral Buprenorphine
Sublingual Buprenorphine
Absolute Relative
6.4%
44%
14.7%
Oral Naloxone
Sublingual Naloxone
0%
3%
SL dosing yields 2.5 times more
buprenorphine than PO dosing
No difference in metabolite generation
Plasma Norbuprenorphine Levels
1.6
1.6
1.2
ng/ml
1.2
0.8 J
ÉJÉ
JJ
É JÉÉ
JÉ
J
0.4
J
É
J JÉ JÉ É
J
É
0 É
J
0
6
12
0.8
JJ
É
JJ
JÉÉÉ
ÉÉ
J É
J
0.4
J
É
0 É
J
0 2 4
É
J
JÉ
J
É
J
PO
6
8 10 12
É
SL
É
J
É
J
É
J
18
24
30
Time (hours)
36
É
J
JÉ
42
48
Plasma Norbuprenorphine Levels
1.6
1.6
1.2
ng/ml
1.2
0.8 J
ÉJÉ
JJ
É JÉÉ
JÉ
J
0.4
J
É
J JÉ JÉ É
J
É
0 É
J
0
6
12
0.8
JJ
É
JJ
JÉÉÉ
ÉÉ
J É
J É J J J
0.4
J É É É
J
É
0 É
J
0 2 4 Metabolite
6 8 10 12
É
J
É
J
18
24
30
Time (hours)
J
PO
É SL
levels
after PO and SL
É
É
administration
are
J
J
identical
36
42
48
Suggests
a high
hepatic extraction
Pharmacology of Oral Naloxone
 Low systemic availability but
pharmacologically active
 Can reverse the GI effects of opiates
– Need doses that are 20% (or more) of
daily morphine dose
 More than 5 mg/day can precipitate
opiate withdrawal
Plasma Naloxone levels
0.5
0.5
0.4
ng/ml
0.25
É
0.3
0 JÉ
0
0.2
É
J
J
0.5
É
J
É
0.1
É
0 JÉ J J
0
0.5
É
J
1
É
J
JÉ
1.5
2
2.5
Time (hours)
JÉ
3
PO
É
SL
1
É
É
J
3.5
JÉ
4
Plasma Naloxone levels
ng/ml
0.5
Subnanogram
levels indicate
0.4
almost no
systemic
0.3
absorption
0.5
0.25
É
0 JÉ
0
0.2
É
J
J
0.5
É
J
É
0.1
É
0 JÉ J J
0
0.5
É
J
1
É
J
JÉ
1.5
2
2.5
Time (hours)
JÉ
3
PO
É
SL
1
É
É
J
3.5
JÉ
4
Naloxone Pharmacokinetics
 After IV dose all subjects had
measurable Naloxone levels
 Almost no Naloxone detectable in
plasma with either PO or SL doses
– Naloxone found in only 4 of 144
samples after PO, 6 of 144 after SL
– Estimated SL F is only 3%, oral F
approaches 0
Pharmacodynamic Measures
 Physiologic Measures
– Heart Rate, Blood Pressure, Respiratory
Rate, Pupil Size
 Subjective Effects
– Verbally rated Global Intoxication and
Withdrawal.
– Visual Analog Good drug, Bad drug, Drug
liking and Sickness
– Opiate Agonist and Withdrawal Scales
Subject and observer rated
Subjective Intoxication
Intoxication Rating (0-100)
60
H
H
H
50
H
H
40
H
J
H
J
30
H
J
20
10
J
J
B
B
B
J
B
H
B
J
B
B
J
B
J
0 H
J B
B
0
1
B
2
PO
3
Time (hours)
J
SL
4
5
H
6
IV
Respiratory rate
16 J
Inhalations/min
H
14 B JB JB
H
12
JB JB
HH
B
H
10
B
J
J
H
B
JB
H
B
J
J
H
H
H
2
3
Time (hours)
4
8
0
1
B
PO
J
SL
5
H
6
IV
No differences in
 Heart Rate, Blood Pressure
 Global withdrawal rating
 VA Bad drug or sickness ratings
 Opiate agonist and withdrawal scales
Conclusions
 Sublingual Buprenorphine is always
better than Oral Buprenorphine
 Sublingual doses produce:
– Larger AUC’s and Cmax’s
– More intoxication, good drug effect
and drug liking
– Greater respiratory depression,
smaller pupils
Why isn’t the Bioavailability of
Buprenorphine (or Naloxone) better?
 Buprenorphine and first pass effects
– Oral Buprenorphine Clearance = 61±29
L/hr
– Oral hepatic extraction ratio = 0.7
 Naloxone and first pass effects
– Estimated Naloxone Clearance = 216±30
L/hr
– This is greater than hepatic and renal
blood flow
Implications
 Sublingual dosing is the best method
 Clinically significant Naloxone
absorption unlikely
 Better tablets may improve drug
delivery
Liquid-tablet differences in
bioavailability
 Bioavailability is usually greater with liquid
formulations. Why?
– Drug fully dissolved, none sequestered in
tablet matrix
– Liquid is buffered to neutral pH
– Absorption starts before reaching the gut
 Can usually compensate by increasing the
dose
Liquid-tablet kinetics
Parameter
CMax (ng/ml)
TMax (hours)
AUCunexp (h-ng/ml )
Tablet
2.9 ± 0.5
1.2 ±0.3
13.0 ± 5.9
Solution
7.1 ± 2.8
0.9 ± 0.3
30.5 ± 11.2
ANOVA
p< 0.02
p< 0.05
p<0.04
SL Buprenorphine 8 mg for 5 minutes, N=6
Nath et al J. Clin Pharmacol 199;39:619-23
Suboxone
 Review Buprenorphine Pharmacology
– Basic Pharmacology
– Sublingual pharmacokinetics
 Review Rational for Suboxone
(Buprenorphine Naloxone combo tablet)
– Predicted effects in
Buprenorphine treated patients
MMT patients
Untreated Heroin Addicts
The Basic Idea Behind Suboxone
 Drug is good when taken as
directed
 Drug is bad when taken any other
way
 Dose preparation safe and effective
for take home dosing
Rational for Suboxone
 When taken sublingually
– Buprenorphine will be well absorbed
– Naloxone absorption will be minimal
 If taken intravenously
– Naloxone now100% bioavailable
– Precipitated withdrawal occurs
 Purchasers of Suboxone will find seller
and expresses displeasure
Does it work?
 Sublingual Suboxne effective
– No precipitated withdrawal seen in
Buprenorphine stabilized patients in
multiple clinical trials
 Excellent withdrawal produced in
human laboratory models with
parenteral administration
Populations of Opiate Abusers
 There is a continuum of opiate abuse
 Infrequent use escalates to regular
abuse and addiction
 At some point user becomes dependent
 Suboxone works because Naloxone
precipitates withdrawal
– Therefore, will only be effective in µopiate dependent people
Evaluation of Efficacy
 For Suboxone to work there should be:
– an aversive reaction with parenteral
administration
– no aversive reaction with sublingual
administration
People who might abuse
Suboxone
 Treated Opiate Addicts
–Buprenorphine treated patients
–Methadone Maintenance Patients
 Untreated Opiate Addicts
 New Opiate Abusers
Effects of B/N in Buprenorphine
Treated Patients
 Research Question
– Does sublingual Naloxone interfere
with Buprenorphine therapy
 Laboratory study of 9 Buprenorphine
stabilized heroin addicts
– Buprenorphine 8 mg/day for 10 days
 Challenged with SL and IV
Buprenorphine and Naloxone
Results - SL Buprenorphine
8 mg SL Buprenorphine rapidly
stabilizes withdrawal
Results - SL Naloxone
Withdrawal not increased by addition of
sublingual Naloxone 2, 4 or 8mg
Results - IV Bup/Nal
No precipitated withdrawal with slow IV
infusion of Buprenorphine 4 mg with
Naloxone 4 mg
Buprenorphine Discontinuation
After abrupt discontinuation of SL
Buprenorphine resulted in only minimal
withdrawal for about 5 days
Conclusions
 Sublingual Buprenorphine (8 mg liquid)
effective in stabilizing withdrawal
 Sublingual Naloxone does not diminish
Buprenorphine effects
 Slowly administered IV Naloxone (4 mg
over 30 minutes) does not precipitate
opiate withdrawal
Clinical Implications
 Buprenorphine stabilized addicts will not
experience any adverse effects if they
inject Suboxone
 Fortunately (or unfortunately, depending
on your perspective) they will not have
much more pleasurable effects either
 Suggests low abuse liability in this
population
Effects in Treated Addicts
 Review Buprenorphine Pharmacology
– Basic Pharmacology
– Sublingual pharmacokinetics
 Review Rational for Suboxone
(Buprenorphine Naloxone combo tablet)
– Predicted effects in
Buprenorphine treated patients
MMT patients
Untreated Heroin Addicts
Effects in Methadone Patients
 Highly µ dependent people
 Often withdrawal phobic
 Usually continue to abuse heroin
and other opiates
Our Study
 We studied 6 men on stable methadone
doses of 45 to 60 mg/day
 Challenged IV with
– Buprenorphine 0.2 mg
– Naloxone 0.1 mg
– Buprenorphine 0.2 and Naloxone 0.1 mg
– Placebo

80
60
40
Bad Drug
100
80
60
40
20
20
0
0
A
B
C
D
A Buprenorphine placebo, Naloxone placebo
B Buprenorphine 0.2 mg, Naloxone placebo
Sickness Scale (0-100)
100
Bad Drug Effect (0-100)
PEAK EFFECTS - MEANS (±SD)
Sickness
A
B
C
D
C Buprenorphine placebo, Naloxone 0.1 mg
D Buprenorphine 0.2 mg, Naloxone 0.1 mg
Conclusion, Clinical Implications
 Buprenorphine produced only minimal
opiate agonist effects
 A small dose of Naloxone is highly
aversive in this population
 The Buprenorphine and Naloxone
combination behaves like Naloxone
 Abuse potential of Suboxone probably
very low in MMT patients
Effects in Street Addicts
 Review Buprenorphine Pharmacology
– Basic Pharmacology
– Sublingual pharmacokinetics
 Review Rational for Suboxone
(Buprenorphine Naloxone combo tablet)
– Predicted effects in
Buprenorphine treated patients
MMT patients
Untreated Heroin Addicts
Effects in Untreated Addicts
 This is the group most likely to abuse
Suboxone
 Difficult people to study
– In and out of withdrawal
– Chaotic lifestyle
– Co-morbid medical and psychiatric
disease
Effects in Untreated Addicts
 8 male daily heroin injectors
 Studied after overnight abstinence from
heroin
 Challenged with
– Buprenorphine 2 mg
– Naloxone 2 mg
– Buprenorphine 2 mg and Naloxone 2
mg
– Placebo
Intoxication (0-
50
40
30
J
Withdrawal (0-100)
28
24 H H
20
H
16
12
8
B
4
B
B
F
F
J
J FB J J
0 FH
0 15
JJ
H
B
F
J
30
J
H
H H
B H B
B
B H H
B H
B
B
B
F
J
45
F F F F F
J J J J J JF FJ
60 90 120
180
240
J
B
F
10 JFH F F
B
0 HH H
0 15
F
F
H
30
H
45
B
B
Bup/Nal
J
Naloxone
H
Buprenorphine
F
Placebo
Mean Peak Amount
Would Pay for Drug
J
J
B
B B
20
H
J
J
J JF JF
B
F F
F
F B
F B
B B B B
H
H
H H H H H
60 90 120
180
240
Minutes
Bup/Nal
Naloxone
Buprenorphine
Placebo
$ 1.90 ± 3.70
0.00 ± 0.00
11.90 ± 7.00
0.00 ± 0.00
Conclusions, Clinical Implications
 Buprenorphine produces pleasurable
effects and would be purchased by
these illicit users
 Naloxone attenuates Buprenorphine
effects
 Suboxone should decrease abuse
liability in untreated addicts
Is the 4:1 Dose Ratio Effective in
Untreated Addicts?
 Our Study
– 12 daily heroin injectors (dependence
confirmed with a Naloxone challenge)
– Admitted to GCRC and stabilized on
IM MS 60 mg Q 6 hours for 16 days
Intravenous Challenge Doses
 Buprenorphine 2 mg
 Buprenorphine 2 mg with
– Naloxone 1 mg (2:1 ratio)
– Naloxone 0.5 mg (4:1 ratio)
– Naloxone 0.25 mg (8:1 ratio)
 Morphine Sulfate 15 mg (positive
control)
 No Naloxone alone
Opiate Agonis t M e as ur e s
30
Buprenorphine
and Morphine
have Opiate
Agonist Effects
Global Intoxi cation (0-100)
B
G
15
B
F
H
JG
É
H
F
É
J
B
B
G
G
H
F
É
J
H
F
É
J
G
B
G
B
H
F
É
J
H
F
É
J
B
G
H
F
É
J
VAS Good Drug Effect (0-100)
50
B
G
25
É
F
JG
B
H
45
B
G
H
F
É
J
H
F
É
J
B
G
G
B
30
15
F
JÉ
G
B
H
F
H
É
J
H
F
É
J
B
G
B
B
G
B
G
H
F
J
É
H
F
J
É
G
B
H
F
J
É
VAS Drug Li king (0-100)
B
B
G
G
H
F
J
É
H
F
É
J
16
B
G
H
F
É
J
Opiate Agoni st (0-64)
É
G
H
10 B
JF
F
É
G
É
F
H
J
H
J
4
0
15
G
B
F
É
H
J
30
Minutes
B
G
F
É
H
J
45
F
H
G
B
É
J
60
Opiate Agonis t M e as ur e s
30
Global Intoxi cation (0-100)
B
G
15
B
F
H
JG
É
B
G
G
H
F
É
J
H
F
É
J
G
B
G
B
H
F
É
J
H
F
É
J
B
G
H
F
É
J
VAS Good Drug Effect (0-100)
50
B
G
25
É
F
JG
B
H
Buprenorphine
Naloxone in
2:1, 4:1 or 8:1
Ratios has little
Opiate Agonist
Effects
H
F
É
J
B
45
B
G
H
F
É
J
H
F
É
J
B
G
G
B
30
15
F
JÉ
G
B
H
F
H
É
J
H
F
É
J
B
G
B
B
G
B
G
H
F
J
É
H
F
J
É
G
B
H
F
J
É
VAS Drug Li king (0-100)
B
B
G
G
H
F
J
É
H
F
É
J
16
B
G
H
F
É
J
Opiate Agoni st (0-64)
É
G
H
10 B
JF
F
É
G
É
F
H
J
H
J
4
0
15
G
B
F
É
H
J
30
Minutes
B
G
F
É
H
J
45
F
H
G
B
É
J
60
Opiate Antagonis t Me as ure s
60
Global Withdrawal (0-100)
J
40
In contrast to
Buprenorphine
alone or
Morphine
Buprenorphine
and Naloxone in
2:1, 4:1 or 8:1
ratios can be
really unpleasant
H
F
20
G
É
B
J
H
F
B
É
G
J
H
F
É
G
B
J
J
H
F
É
G
B
H
J
40
F
20
É
JG
F
H
B
VAS Bad Drug Effect (0-100)
J
60
J
É
F
G
H
B
F
É
H
G
B
H
J
J
É
JG
H
F
B
50
B
G
É
F
B
G
É
F
H
B
É
G
H
F
B
G
É
J
H
25
F
É
G
F
J
H
B
24
B
É
G
J
G
H
F
B
É
VAS Sickness (0-100)
J
H
B
F
G
É
J
H
F
É
B
G
É
J
G
H
F
B
É
JG
F
B
H
Opiate Withdrawal (0-84)
J
16
H
F
8
0
É
G
B
H
F
J
0
É
B
G
J
H
F
É
G
B
J
H
F
É
G
B
JÉ
F
H
G
B
15
30
45
Minutes
J
É
F
G
H
B
60
Conclusions - SL Buprenorphine
 Adequately absorbed
 Has opiate agonist effects
 Most likely to be abused by untreated
heroin addicts
 Has less but some abuse potential in
Methadone patients
 Probably has minimal abuse liability in
Buprenorphine treated patients
Conclusions - Adding Naloxone
to Buprenorphine
 Has no effect on treatment with SL
Buprenorphine but
 Attenuates opiate agonist effects in
– Methadone patients
– Untreated Addicts
 Probably has little effect on IV
Buprenorphine abuse in Suboxone
treated patients
Predictions About Suboxone
 Will deter abuse and diversion in µ
dependent addicts
 Should be safe even in highly
dependent addicts
 Can and will have abuse potential in
new initiates to opiate abuse but
– Should have a lower risk of overdose
– Will not be as rewarding as heroin
Acknowledgements
 The scientists and staffs of the UCSF
– Drug Dependence Research Center
– The General Clinical Research
Center
 The NIDA medications development
team
 Our patient and hard working research
participants