buprenorphine and naloxone: clinical pharmacology abuse liability john mendelson md california...
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Buprenorphine and Naloxone: Clinical Pharmacology
Abuse Liability
Buprenorphine and Naloxone: Clinical Pharmacology
Abuse Liability
John Mendelson MDCalifornia Pacific Medical Research Institute
and theUniversity of California at San Francisco
Presentation GoalsPresentation Goals
Review Buprenorphine Pharmacology– Basic Pharmacology– Sublingual pharmacokinetics
Review Rational for Suboxone (Buprenorphine Naloxone combo tablet)– Predicted effects in
Buprenorphine treated patientsMMT patientsUntreated Heroin Addicts
OnwardOnward
Review Buprenorphine Pharmacology– Basic Pharmacology– Sublingual pharmacokinetics
Review Rational for Suboxone (Buprenorphine Naloxone combo tablet)– Predicted effects in
Buprenorphine treated patientsMMT patientsUntreated Heroin Addicts
Buprenorphine PharmacologyBuprenorphine 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 BuprenorphinePharmacotherapy 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
AnalgesiaBuprenorphine vs. MorphineAnalgesiaBuprenorphine 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 PropertiesPharmacological Properties
Partial agonist effects suggested by
– Ceiling on analgesic effects
– Antagonizes fentanyl induced respiratory depression without complete loss of anesthesiaIndicates high affinity for µ-receptor
– Can precipitate opiate withdrawal in highly µ-dependent people
Advantages of BuprenorphineAdvantages 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 BuprenorphineDisadvantages 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 ImplicationsReceptor 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 NaloxoneNaloxone is effective if given
before buprenorphine but not after
Dosing IssuesDosing Issues
Review Buprenorphine Pharmacology– Basic Pharmacology– Sublingual pharmacokinetics
Review Rational for Suboxone (buprenorphine Naloxone combo tablet)– Predicted effects in
Buprenorphine treated patientsMMT patientsUntreated Heroin Addicts
Absorption and Distribution of BuprenorphineAbsorption 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 TabletsBuprenorphine 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 PharmacokineticsBuprenorphine Pharmacokinetics
Absorption
– Poor oral absorption due to extensive first pass metabolismMetabolism in gut wallHigh hepatic extraction
– Adequate sublingual absorption
Bioavailability of Sublingual and Oral Buprenorphine/NaloxoneBioavailability 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 HopeThe Hope
Oral administration would be as good as sublingual administration
Ease of dosing would be improved
MethodsMethods
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 DosesBuprenorphine 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 DosingSublingual 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 MeasuresPharmacokinetic 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 LevelsPlasma Buprenorphine Levels
JJ
JJJJJJJ J
J J J J J J JÉÉ
É
ÉÉÉ
É
É
É
ÉÉ É É É É É É
0
0.5
1
1.5
2
2.5
3
0 6 12 18 24 30 36 42 48Time (hours)
J PO
É SLJJ
JJJJJ J J J J J JÉÉ
É
ÉÉÉÉ
ÉÉ
É É É É0
1
2
3
0 2 4 6 8 10 12
Plasma Buprenorphine LevelsPlasma Buprenorphine Levels
JJ
JJJJJJJ J
J J J J J J JÉÉ
É
ÉÉÉ
É
É
É
ÉÉ É É É É É É
0
0.5
1
1.5
2
2.5
3
0 6 12 18 24 30 36 42 48Time (hours)
J PO
É SLJJ
JJJJJ J J J J J JÉÉ
É
ÉÉÉÉ
ÉÉ
É É É É0
1
2
3
0 2 4 6 8 10 12Sublingual F >> than Oral
Could be due to either gut or hepatic metabolism
Plasma Buprenorphine LevelsPlasma Buprenorphine Levels
H
HHHHH
HH H
HH H H
H H
H
JJJJJ
J J
JJ J
JJ J J J
0.1
1
10
100
0 6 12 18 24 30 36 42 48Time (hours)
H IV
J SL
Plasma Buprenorphine LevelsPlasma Buprenorphine Levels
H
HHHHH
HH H
HH H H
H H
H
JJJJJ
J J
JJ J
JJ J J J
B
BBB
BBBB B
B B B B B B B0.1
1
10
100
0 6 12 18 24 30 36 42 48Time (hours)
H IV
J SL
B PO
Oral vs Sublingual:Absolute and Relative FOral vs Sublingual:Absolute and Relative F
Absolute RelativeOral Buprenorphine 6.4%Sublingual Buprenorphine 14.7%
44%
Oral Naloxone 0%Sublingual Naloxone 3%
SL dosing yields 2.5 times more buprenorphine than PO dosingNo difference in metabolite generation
Plasma Norbuprenorphine LevelsPlasma Norbuprenorphine Levels
J
J
J
JJJJJ J
J J J J J J J J
ÉÉ
É
ÉÉÉÉÉÉ
É É ÉÉ
É É É É
0
0.4
0.8
1.2
1.6
0 6 12 18 24 30 36 42 48Time (hours)
J PO
É SLJJ
JJJ J J J J
J J J J
ÉÉ
ÉÉÉÉ
É É É É É É É0
0.4
0.8
1.2
1.6
0 2 4 6 8 10 12
Plasma Norbuprenorphine LevelsPlasma Norbuprenorphine Levels
J
J
J
JJJJJ J
J J J J J J J J
ÉÉ
É
ÉÉÉÉÉÉ
É É ÉÉ
É É É É
0
0.4
0.8
1.2
1.6
0 6 12 18 24 30 36 42 48Time (hours)
J PO
É SLJJ
JJJ J J J J
J J J J
ÉÉ
ÉÉÉÉ
É É É É É É É0
0.4
0.8
1.2
1.6
0 2 4 6 8 10 12Metabolite levels after PO and SL administration are identical
Suggests a high hepatic extraction
Pharmacology of Oral NaloxonePharmacology 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 levelsPlasma Naloxone levels
J J J
J JJ
J JÉ
É
ÉÉ
É É É
É É0
0.1
0.2
0.3
0.4
0.5
0 0.5 1 1.5 2 2.5 3 3.5 4Time (hours)
J PO
É SL
J J JJ
ÉÉ
É É É
0
0.25
0.5
0 0.5 1
Plasma Naloxone levelsPlasma Naloxone levels
J J J
J JJ
J JÉ
É
ÉÉ
É É É
É É0
0.1
0.2
0.3
0.4
0.5
0 0.5 1 1.5 2 2.5 3 3.5 4Time (hours)
J PO
É SL
J J JJ
ÉÉ
É É É
0
0.25
0.5
0 0.5 1
Subnanogram levels indicate almost no systemic absorption
Naloxone PharmacokineticsNaloxone 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 MeasuresPharmacodynamic 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 ScalesSubject and observer rated
Subjective IntoxicationSubjective Intoxication
B B
BB B
B B B
BB
JJ
J
J
J
JJ
J
J
J
H
H
HH
HH
HH
H
H
0
10
20
30
40
50
60
0 1 2 3 4 5 6Time (hours)
B PO J SL H IV
Respiratory rateRespiratory rate
B B B
B B
B
B B
B B
J
J J
J J
J
J
J
J J
H
H
H H
H H
H H H
H
8
10
12
14
16
0 1 2 3 4 5 6Time (hours)
B PO J SL H IV
No differences inNo differences in
Heart Rate, Blood Pressure Global withdrawal rating VA Bad drug or sickness ratings Opiate agonist and withdrawal scales
ConclusionsConclusions
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?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
ImplicationsImplications
Sublingual dosing is the best method Clinically significant Naloxone
absorption unlikely Better tablets may improve drug
delivery
Liquid-tablet differences in bioavailability 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 kineticsLiquid-tablet kinetics
Parameter Tablet Solution ANOVACMax (ng/ml) 2.9 ± 0.5 7.1 ± 2.8 p< 0.02TMax (hours) 1.2 ±0.3 0.9 ± 0.3 p< 0.05
AUCunexp (h-ng/ml) 13.0 ± 5.9 30.5 ± 11.2 p<0.04
SL Buprenorphine 8 mg for 5 minutes, N=6
Nath et al J. Clin Pharmacol 199;39:619-23
SuboxoneSuboxone
Review Buprenorphine Pharmacology– Basic Pharmacology– Sublingual pharmacokinetics
Review Rational for Suboxone (Buprenorphine Naloxone combo tablet)– Predicted effects in
Buprenorphine treated patientsMMT patientsUntreated Heroin Addicts
The Basic Idea Behind SuboxoneThe 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 SuboxoneRational 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?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 AbusersPopulations 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 µ-opiate dependent people
Evaluation of EfficacyEvaluation 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 SuboxonePeople who might abuse Suboxone
Treated Opiate Addicts
–Buprenorphine treated patients
–Methadone Maintenance PatientsUntreated Opiate AddictsNew Opiate Abusers
Effects of B/N in Buprenorphine Treated PatientsEffects 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
Sublingual Buprenorphine and Naloxone Interactions in Opiate-Dependent Patients Stabilized On BuprenorphineSublingual Buprenorphine and Naloxone Interactions in Opiate-Dependent Patients Stabilized On Buprenorphine
Bup Challenge Doses:A Bup 8mg/ Nal 8mgB Bup 8mg/ Nal 4mgC Bup 8mg/ Nal 0mgIV Bup 4mg/ Nal 4mg
(no Bup given)
MaintenancePhase
Challenge Phase
OutpatientPhase
B
BB
B B B B B B B B B BB B B
BBH
H H H H H H H J J J F
0
10
20
30
40
0
4
8
12
0
10
20
30
40
0
4
8
12
Withdrawal Scale BUP Dose (mg)
Days
B Withdrawal Scale (0-84)
H Bup Maintenance Dose
J Bup/Nal Challenges
F Bup/Nal IV Challenge
8 9762 3 4 5 13 14 15 16 17 1810 11 12-2 -1 1
Bup Maintenance Doses:Day 1 Bup 4mgDays 2-8Bup 8mg
Sublingual Buprenorphine and Naloxone Interactions in Opiate-Dependent Patients Stabilized On BuprenorphineSublingual Buprenorphine and Naloxone Interactions in Opiate-Dependent Patients Stabilized On Buprenorphine
Bup Challenge Doses:A Bup 8mg/ Nal 8mgB Bup 8mg/ Nal 4mgC Bup 8mg/ Nal 0mgIV Bup 4mg/ Nal 4mg
(no Bup given)
MaintenancePhase
Challenge Phase
OutpatientPhase
B
BB
B B B B B B B B B BB B B
BBH
H H H H H H H J J J F
0
10
20
30
40
0
4
8
12
0
10
20
30
40
0
4
8
12
Withdrawal Scale BUP Dose (mg)
Days
B Withdrawal Scale (0-84)
H Bup Maintenance Dose
J Bup/Nal Challenges
F Bup/Nal IV Challenge
8 9762 3 4 5 13 14 15 16 17 1810 11 12-2 -1 1
Bup Maintenance Doses:Day 1 Bup 4mgDays 2-8Bup 8mg
Results - SL Buprenorphine
8 mg SL Buprenorphine rapidly stabilizes withdrawal
Sublingual Buprenorphine and Naloxone Interactions in Opiate-Dependent Patients Stabilized On BuprenorphineSublingual Buprenorphine and Naloxone Interactions in Opiate-Dependent Patients Stabilized On Buprenorphine
Bup Challenge Doses:A Bup 8mg/ Nal 8mgB Bup 8mg/ Nal 4mgC Bup 8mg/ Nal 0mgIV Bup 4mg/ Nal 4mg
(no Bup given)
MaintenancePhase
Challenge Phase
OutpatientPhase
B
BB
B B B B B B B B B BB B B
BBH
H H H H H H H J J J F
0
10
20
30
40
0
4
8
12
0
10
20
30
40
0
4
8
12
Withdrawal Scale BUP Dose (mg)
Days
B Withdrawal Scale (0-84)
H Bup Maintenance Dose
J Bup/Nal Challenges
F Bup/Nal IV Challenge
8 9762 3 4 5 13 14 15 16 17 1810 11 12-2 -1 1
Bup Maintenance Doses:Day 1 Bup 4mgDays 2-8Bup 8mg
Results - SL Naloxone
Withdrawal not increased by addition of sublingual Naloxone 2, 4 or 8mg
Plasma Buprenorphine and Naloxone AUC's
Plasma Buprenorphine and Naloxone AUC's
Columns are mean values, circles are subjects' data points
Plasma Buprenorphine
0
10
20
30
40
50
60
70
AUC ratio (percent)
Plasma Naloxone
0
10
20
30
40
50
60
70
AUC ratio (percent)
Sublingual Buprenorphine and Naloxone Interactions in Opiate-Dependent Patients Stabilized On BuprenorphineSublingual Buprenorphine and Naloxone Interactions in Opiate-Dependent Patients Stabilized On Buprenorphine
Bup Challenge Doses:A Bup 8mg/ Nal 8mgB Bup 8mg/ Nal 4mgC Bup 8mg/ Nal 0mgIV Bup 4mg/ Nal 4mg
(no Bup given)
MaintenancePhase
Challenge Phase
OutpatientPhase
B
BB
B B B B B B B B B BB B B
BBH
H H H H H H H J J J F
0
10
20
30
40
0
4
8
12
0
10
20
30
40
0
4
8
12
Withdrawal Scale BUP Dose (mg)
Days
B Withdrawal Scale (0-84)
H Bup Maintenance Dose
J Bup/Nal Challenges
F Bup/Nal IV Challenge
8 9762 3 4 5 13 14 15 16 17 1810 11 12-2 -1 1
Bup Maintenance Doses:Day 1 Bup 4mgDays 2-8Bup 8mg
Results - IV Bup/Nal
No precipitated withdrawal with slow IV infusion of Buprenorphine 4 mg with Naloxone 4 mg
Sublingual Buprenorphine and Naloxone Interactions in Opiate-Dependent Patients Stabilized On BuprenorphineSublingual Buprenorphine and Naloxone Interactions in Opiate-Dependent Patients Stabilized On Buprenorphine
Bup Challenge Doses:A Bup 8mg/ Nal 8mgB Bup 8mg/ Nal 4mgC Bup 8mg/ Nal 0mgIV Bup 4mg/ Nal 4mg
(no Bup given)
MaintenancePhase
Challenge Phase
OutpatientPhase
B
BB
B B B B B B B B B BB B B
BBH
H H H H H H H J J J F
0
10
20
30
40
0
4
8
12
0
10
20
30
40
0
4
8
12
Withdrawal Scale BUP Dose (mg)
Days
B Withdrawal Scale (0-84)
H Bup Maintenance Dose
J Bup/Nal Challenges
F Bup/Nal IV Challenge
8 9762 3 4 5 13 14 15 16 17 1810 11 12-2 -1 1
Bup Maintenance Doses:Day 1 Bup 4mgDays 2-8Bup 8mg
Buprenorphine Discontinuation
After abrupt discontinuation of SL Buprenorphine resulted in only minimal withdrawal for about 5 days
ConclusionsConclusions
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 ImplicationsClinical 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 AddictsEffects in Treated Addicts
Review Buprenorphine Pharmacology– Basic Pharmacology– Sublingual pharmacokinetics
Review Rational for Suboxone (Buprenorphine Naloxone combo tablet)– Predicted effects in
Buprenorphine treated patientsMMT patientsUntreated Heroin Addicts
Effects in Methadone Patients Effects in Methadone Patients
Highly µ dependent peopleOften withdrawal phobicUsually continue to abuse heroin
and other opiates
Our StudyOur 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
PEAK EFFECTS - MEANS (±SD)
Bad Drug Sickness
0
20
40
60
80
100
0
20
40
60
80
100
A Buprenorphine placebo, Naloxone placeboD Buprenorphine 0.2 mg, Naloxone 0.1 mgC Buprenorphine placebo, Naloxone 0.1 mg
A DCB
B Buprenorphine 0.2 mg, Naloxone placebo
A DCB
Conclusion, Clinical ImplicationsConclusion, 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 AddictsEffects in Street Addicts
Review Buprenorphine Pharmacology– Basic Pharmacology– Sublingual pharmacokinetics
Review Rational for Suboxone (Buprenorphine Naloxone combo tablet)– Predicted effects in
Buprenorphine treated patientsMMT patientsUntreated Heroin Addicts
Effects in Untreated AddictsEffects 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 AddictsEffects 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
Mean Peak AmountWould Pay for Drug
Naloxone 0.00 ± 0.00
Placebo 0.00 ± 0.00
Buprenorphine 11.90 ± 7.00
Bup/Nal $ 1.90 ± 3.70
B
BB B BB
BJ
JJ J J J
J
HHHH H H H
F F F F F F F
0
10
20
30
40
50
0 15 30 45 60Minutes
B BB B B B
JJ J
J J J
H H H H H H
F FF F F F
90 120 180 240
B
BB B B
B B
J J J J J J JH
H
HHH H H
F F F F F F F048
1216202428
0 15 30 45 60
BB
B B B B
J J J J J J
H H
H H H H
F F F F F F90 120 180 240
B Bup/Nal
J Naloxone
H Buprenorphine
F Placebo
Conclusions, Clinical ImplicationsConclusions, 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?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 DosesIntravenous 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
Buprenorphine and Morphine have Opiate Agonist Effects
Opiate Agonist Measures
VAS Good Drug Effect (0-100)
Opiate Agonist (0-64)
Global Intoxication (0-100)
GG
GG
G
G
JJJ
J
J
J HHHH
H
H FFFFFF B
BB
BB
BÉÉÉ
ÉÉ
É
4
10
16
0 15 30 45 60Minutes
VAS Drug Liking (0-100)
GGG
GG
GJ
JJJJ
J
HHHH
HH
FF
FFFF
BBBB
B
BÉ
É
ÉÉÉÉ
15
30
45
GG
GGGG
G JJJJJJJ
HHHHHHHFFFFFFF
BBB
BB
B
BÉÉÉÉÉÉÉ
15
30
GGGG
G
G JJJJJJ
HHHH
HH
FFFFFF
BBB
B
B
B ÉÉÉÉÉÉ
25
50
Buprenorphine Naloxone in 2:1, 4:1 or 8:1 Ratios has little Opiate Agonist Effects
Opiate Agonist Measures
VAS Good Drug Effect (0-100)
Opiate Agonist (0-64)
Global Intoxication (0-100)
GG
GG
G
G
JJJ
J
J
J HHHH
H
H FFFFFF B
BB
BB
BÉÉÉ
ÉÉ
É
4
10
16
0 15 30 45 60Minutes
VAS Drug Liking (0-100)
GGG
GG
GJ
JJJJ
J
HHHH
HH
FF
FFFF
BBBB
B
BÉ
É
ÉÉÉÉ
15
30
45
GG
GGGG
G JJJJJJJ
HHHHHHHFFFFFFF
BBB
BB
B
BÉÉÉÉÉÉÉ
15
30
GGGG
G
G JJJJJJ
HHHH
HH
FFFFFF
BBB
B
B
B ÉÉÉÉÉÉ
25
50
In contrast to Buprenorphine alone or Morphine Buprenorphine and Naloxone in 2:1, 4:1 or 8:1 ratios can be really unpleasant
Opiate Withdrawal (0-84)
Global Withdrawal (0-100)
VAS Sickness (0-100)
Opiate Antagonist Measures
VAS Bad Drug Effect (0-100)
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8
16
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0 15 30 45 60Minutes
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Conclusions - SL BuprenorphineConclusions - 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 BuprenorphineConclusions - 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 SuboxonePredictions 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
AcknowledgementsAcknowledgements
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
