1. Buprenorphine and Naloxone: Clinical Pharmacology Abuse Liability John Mendelson MD California Pacific Medical Research Institute and the University of California at San Francisco

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 H 2 O

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. Sublingual F >> than Oral Could be due to either gut or hepatic metabolism

23. 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. 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. 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