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 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

Onward Review Buprenorphine Pharmacology




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

AnalgesiaBuprenorphine 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 anesthesiaIndicates 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

NaloxoneNaloxone is effective if given

before buprenorphine but not after

Dosing Issues Review Buprenorphine Pharmacology


Review Rational for Suboxone (buprenorphine Naloxone combo tablet)– Predicted effects in


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 metabolismMetabolism in gut wallHigh 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

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0 2 4 6 8 10 12Sublingual F >> than Oral

Could be due to either gut or hepatic metabolism


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Oral 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 Levels

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Plasma Norbuprenorphine Levels

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0 2 4 6 8 10 12Metabolite levels after PO and SL administration are identical

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

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Plasma Naloxone levels

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Subnanogram levels indicate almost no systemic absorption

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 ScalesSubject and observer rated

Subjective Intoxication

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Respiratory rate

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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 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<0.04SL Buprenorphine 8 mg for 5 minutes, N=6

Nath et al J. Clin Pharmacol 199;39:619-23

Suboxone Review Buprenorphine Pharmacology




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 µ-

opiate 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 AddictsNew 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

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

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BBH

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Withdrawal Scale BUP Dose (mg)

Days

B Withdrawal Scale (0-84)H Bup Maintenance DoseJ 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



(no Bup given)

MaintenancePhase

Challenge Phase

OutpatientPhase

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BBH


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Days



8 9762 3 4 5 13 14 15 16 17 1810 11 12-2 -1 1


Results - SL Buprenorphine

8 mg SL Buprenorphine rapidly stabilizes withdrawal



(no Bup given)

MaintenancePhase

Challenge Phase

OutpatientPhase

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BBH


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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

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40

50

60

70

AUC ratio (percent)

Plasma Naloxone

0

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AUC ratio (percent)



(no Bup given)

MaintenancePhase

Challenge Phase

OutpatientPhase

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BBH


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8 9762 3 4 5 13 14 15 16 17 1810 11 12-2 -1 1


Results - IV Bup/Nal

No precipitated withdrawal with slow IV infusion of Buprenorphine 4 mg with Naloxone 4 mg



(no Bup given)

MaintenancePhase

Challenge Phase

OutpatientPhase

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BBH


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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




Effects in Methadone Patients

Highly µ dependent peopleOften withdrawal phobicUsually 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

PEAK EFFECTS - MEANS (±SD)

Bad Drug Sickness

0

20

40

60

80

100

0

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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 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




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

Mean Peak AmountWould Pay for Drug

Naloxone 0.00 ± 0.00

Placebo 0.00 ± 0.00Buprenorphine 11.90 ± 7.00

Bup/Nal $ 1.90 ± 3.70

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B Bup/NalJ NaloxoneH BuprenorphineF Placebo

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

Buprenorphine and Morphine have Opiate Agonist Effects

Opiate Agonist Measures

VAS Good Drug Effect (0-100)

Opiate Agonist (0-64)

Global Intoxication (0-100)

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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)

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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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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

buprenorphine and naloxone: clinical pharmacology abuse liability

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