1. Buprenorphine and Naloxone: Clinical Pharmacology Abuse Liability
dr shabeel pn

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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)

14. Buprenorphine Pharmacokinetics
Absorption
Poor oral absorption due to extensive first pass metabolism
Metabolism in gut wall
High hepatic extraction
Adequate sublingual absorption

15. 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

16. The Hope
Oral administration would be as good as sublingual administration
Ease of dosing would be improved

17. 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

18. 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

19. 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

20. 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

21. Plasma Buprenorphine Levels

22. Plasma Buprenorphine Levels
Sublingual F >> than Oral
Could be due to either gut or hepatic metabolism

23. Plasma Buprenorphine Levels

24. Plasma Buprenorphine Levels

25. Oral vs Sublingual: Absolute and Relative F
SL dosing yields 2.5 times more buprenorphine than PO dosing
No difference in metabolite generation

26. Plasma Norbuprenorphine Levels

27. Plasma Norbuprenorphine Levels
Metabolite levels after PO and SL administration are identical
Suggests a high hepatic extraction

28. 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

29. Plasma Naloxone levels

30. Plasma Naloxone levels
Subnanogram levels indicate almost no systemic absorption

31. 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

32. 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

33. Subjective Intoxication

34. Respiratory rate

35. No differences in Heart Rate, Blood Pressure Global withdrawal rating
VA Bad drug or sickness ratings
Opiate agonist and withdrawal scales

36. 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

37. 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

38. Implications Sublingual dosing is the best method
Clinically significant Naloxone absorption unlikely
Better tablets may improve drug delivery

39. 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

40. Liquid-tablet kinetics
SL Buprenorphine 8 mg for 5 minutes, N=6
Nath et al J. Clin Pharmacol 199;39:619-23

41. 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

42. 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

43. 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

44. 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

45. 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

46. Evaluation of Efficacy
For Suboxone to work there should be:
an aversive reaction with parenteral administration
no aversive reaction with sublingual administration

47. People who might abuse Suboxone
Treated Opiate Addicts
Buprenorphine treated patients
Methadone Maintenance Patients
Untreated Opiate Addicts
New Opiate Abusers

48. 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

50. Results - SL Buprenorphine
8 mg SL Buprenorphine rapidly stabilizes withdrawal

51. Results - SL Naloxone
Withdrawal not increased by addition of sublingual Naloxone 2, 4 or 8mg

53. Results - IV Bup/Nal
No precipitated withdrawal with slow IV infusion of Buprenorphine 4 mg with Naloxone 4 mg

54. Buprenorphine Discontinuation
After abrupt discontinuation of SL Buprenorphine resulted in only minimal withdrawal for about 5 days

55. 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

56. 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

57. 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

58. Effects in Methadone Patients
Highly µ dependent people
Often withdrawal phobic
Usually continue to abuse heroin and other opiates

59. 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

61. 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

62. 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

63. 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

64. 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

66. 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

67. 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

68. 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

69. Buprenorphine and Morphine have Opiate Agonist Effects

70. Buprenorphine Naloxone in 2:1, 4:1 or 8:1 Ratios has little Opiate Agonist Effects

71. In contrast to Buprenorphine alone or Morphine Buprenorphine and Naloxone in 2:1, 4:1 or 8:1 ratios can be really unpleasant

72. 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

73. 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

74. 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

75. 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