1. OPIOIDS IN ORGAN FAILURE MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH

2. 2  SICK CELL THEORY REDUCED HEPATOCYTE FUNCTION, SPARED BLOOD FLOW  INTACT HEPATOCYTE THEORY WELL FUNCTIONING RESIDUAL HEPATOCYTES, REDUCED NUMBERS  IMPAIRED DRUG UPTAKE THEORY LOSS OF FENESTRATION IN SINUSOIDAL ENDOTHELIUM, DEVELOPMENT OF BASAL LAMINA IN SPACE OF DISSE BLOCK IN DIFFUSION END STAGE LIVER DISEASE

3. 3  HIGH VS. LOW EXTRACTION RATIO  FIRST PASS CLEARANCE SHUNTING  ALBUMIN VS. ALPHA1 ACID GLYCOPROTEIN BINDING  TYPE I VS. TYPE II METABOLISM FACTORS INFLUENCING DRUG KINETICS IN LIVER DISEASE

4. 4  LOW ORAL BIOAVAILABILITY, HIGH FIRST PASS CLEARANCE  LIPOPHILIC WITH RAPID CNS PENETRATION  SUBJECT TO: PULMONARY SEQUESTRATION PRIOR TO CNS EFFLUX PUMPS  LARGE VOLUME OF DISTRIBUTION SEQUESTRATION IN MUSCLE FAT FENTANYL

5. 5  METABOLIZED BY CYP3A4  SINGLE DOSE T ½ IS DUE TO REDISTRIBUTION  STEADY STATE CLEARANCE LIMITED BY CYP3A4  ALBUMIN BOUND FENTANYL

6. 6  REDUCED CLEARANCE LATE UREMIA INHIBITS CYP3A4 REDUCED ALBUMIN IN NEPHROTIC SYNDROME ? LARGER VOLUME OF DISTRIBUTION  T ½ = 0.693 VD/CL  Vd  CL VIA CYP3A4 FENTANYL IN RENAL DISEASE

7. 7  CLINICAL IMPORTANCE DO NOT START WITH A TRANSDERMAL PATCH TRANSDERMAL ABSORPTION MAY BE ALTERED DIALYSIS DOES NOT REMOVE FENTANYL FENTANYL IN RENAL DISEASE

8. 8  REDUCED CLEARANCE IN LIVER DISEASE REDUCED ALBUMIN REDUCED CYP3A4 REDUCED HEPATIC BLOOD FLOW  CLINICAL IMPORTANCE DO NOT USE PATCH IN ADVANCED LIVER DISEASE LOW DOSES, WATCH FOR DELAYED TOXICITY FENTANYL IN LIVER DISEASE

9. 9  MODERATE BIOAVAILABILITY (50-60%)  LOW BINDING TO ALBUMIN (≤ 40%)  CROSSES THE CNS SIMILAR TO MORPHINE  GLUCURONIDATED TO HYDROM-3 GLUCURONIDE NEUROTOXIN  GLUCURONIDE METABOLITE RENALLY CLEARED HYDROMORPHONE

10. 10  ACCUMULATION OF HYDROMORPHONE-3- GLUCURONIDE INCREASES POTENTIAL FOR NEUROTOXICITY  CLINICAL IMPORTANCE BETTER TOLERATED THAN MORPHINE IN RENAL FAILURE NEUROTOXICITY SUBJECT TO DIALYSIS HYDROMORPHONE IN RENAL DISEASE

11. 11 HYDROMORPHONE AND RENAL CLEARANCE GFR ml/minAUC relative to normal >601 40-602 <304

12. 12  GREATER BIOAVAILABILITY DUE TO SHUNTING  MINOR INFLUENCE ON PHARMACOKINETICS RELATIVE SPARING OF GLUCURONIDATION ALBUMIN LEVELS HAVE LITTLE INFLUENCE ON UNBOUND DRUG HYDROMORPHONE IN LIVER DISEASE

13. 13  CLINICAL IMPORTANCE INCREASED ORAL BIOAVAILABILITY RELATIVELY SPARED T ½ START WITH LOWER THAN NORMAL DOSES, MAINTAIN INTERVALS AVOID SUSTAINED RELEASE HYDROMORPHONE HYDROMORPHONE IN LIVER DISEASE

14. 14  ORAL BIOAVAILABILITY OF 30% (15-50%)  1/3 ALBUMIN BOUND  SUBJECT TO EFFLUX PROTEINS  METABOLIZED GLUCURONYL TRANSFERASES UGT B > UGT 1A1, UGT 1A3  ENTEROHEPATIC RECIRCULATION  GLUCURONIDES CLEARED BY KIDNEYS MORPHINE

15. 15  ACCUMULATION OF MORPHINE TO GLUCURONIDE DELAYED OPIOID TOXICITY  ACCUMULATION OF MORPHINE 3 GLUCURONIDE DELAYED NEUROTOXICITY  HEMODIALYSIS BUT NOT PERITONEAL DIALYSIS REMOVES GLUCURONIDE METABOLITES MORPHINE IN RENAL FAILURE

16. 16  CLINICAL IMPORTANCE: DOSE REDUCTION EXTEND INTERVALS AVOID SUSTAINED RELEASE PRN SCHEDULE AS INITIAL DOSING STRATEGY HEMODIALYSIS RELATED CHANGES IN ANALGESIA MORPHINE IN RENAL FAILURE

17. 17 DOSE REDUCTION FOR GFR GFR (ml/min)Morphine (%)Methadone (%) 20-5075100 10-2050100 <102550

18. 18  MORPHINE T ½ IS PROLONGED WITH: ALTERED CLOTTING TIMES PRESENCE OF ASCITES HISTORY OF ENCEPHALOPATHY MORPHINE CLEARANCE IN LIVER DISEASE

19. 19  INCREASED BIOAVAILABILITY  RELATIVELY SPARED T ½  LITTLE INFLUENCE OF HYPOALBUMINEMIA  CLINICAL IMPORTANCE START AT LOWER THAN USUAL DOSES MAINTAIN INTERVALS AVOID SUSTAINED RELEASE IN ADVANCED CIRRHOSIS MORPHINE IN LIVER DISEASE

20. 20  ORAL BIOAVAILABILITY 60%  ALBUMIN BOUND 40%  ACTIVELY TRANSPORTED INTO CNS PLASMA/BRAIN RATIO 3  METABOLIZED BY CYP2D6, CYP3A4 OXYMORPHONE NOROXYCODONE  METABOLITES ± OXYCODONE CLEARED BY KID. OXYCODONE

21. 21  ↑ NOROXYCODONE & OXYMORPHONE  HALF-LIFE OF OXYCODONE IS LENGTHENED  CNS TOXICITY AT NORMAL DOSES  CLINICAL IMPORTANCE START AT REDUCED DOSES DO NOT USE SUSTAINED RELEASE OXYCODONE USE PRN TO FIND CORRECT INDIVIDUAL DOSING INTERVAL OXYCODONE IN RENAL DISEASE

22. 22  MAXIMUM CONCENTRATION INCREASES 40%, AUC 90%  IMMEDIATE RELEASE T ½ GOES FROM 3.4 TO 14 HOURS (4.6-24)  HYPOALBUMINEMIA PLAYS A MINOR ROLE  CLINICAL IMPORTANCE DO NOT USE SUSTAINED RELEASE OXYCODONE LENGTHEN INTERVALS BETWEEN DOSES USE A PRN TO FIND INDIVIDUAL INTERVALS OXYCODONE IN LIVER DISEASE

23. 23  ORAL BIOAVAILABILITY 80%  LOW FIRST PASS CLEARANCE  BINDS TO ALPHA1 ACID GLYCOPROTEIN  CROSSES THE BBB (EFFLUX PROTEINS)  METABOLIZED BY MULTIPLE CYTOCHROMES CYP3A4, CYP3A5, CYP2B6, CYP2D6, CYP1A2 INACTIVE METABOLITE METHADONE

24. 24  INACTIVE METABOLITE  FECAL EXCRETION  MULTIPLE CYTOCHROME METABOLISM  CLINICAL IMPORTANCE: RELATIVELY SAFE IN RENAL FAILURE METHADONE IN RENAL DISEASE

25. 25  BOTH METHADONE AND METABOLITES ARE EXCRETED IN FECES VS. URINE  T ½ IS PROLONGED IN SEVERE LIVER DISEASE (20 HRS TO 32 HRS)  HEPATITIS C STIMULATES CYP3A4 COMPENSATE FOR REDUCED CYTOCHROMES METHADONE IN LIVER DISEASE

26. 26  MORPHINE  HYDROMORPHONE  ? LEVORPHANOL  ? BUPRENORPHINE SUMMARY OPIOIDS USED IN LIVER FAILURE / CIRRHOSIS

27. 27  METHADONE  ? FENTANYL  BUPRENORPHINE  HYDROMORPHONE > MORPHINE SUMMARY OPIOIDS USED IN RENAL FAILURE

28. 28

29. 29 Case History 1 42 year old male with hepatitis C with hepatocellular carcinoma and abdominal pain from hepatic capsular invasion Physical Examination: no ascites, mild palm erythema, no asterixis Laboratory: albumin 3.0 mg /dl, PT INR 1.3

30. 30 Case History 1 Treatment Acetaminophen 1000 mg 4 times daily Naproxen 5000 mg 3 times daily Oxycodone 5 mg every 4 hours ATC Morphine 5 mg every 4 hours ATC Transhepatic arterial embolization Celiac block

31. 31 Case History 1 He sustains a portal vein thrombosis and develops ascites His pain escalates to a 7(NRS) unrelieved by oxycodone 5 mg every 4 hours Laboratory: Bilirubin 2mg /dl, Albumin 2.8, PT-INR 1.6, Creatinine 1 mg /dl

32. 32 Case History 1 Treatment Fentanyl Transdermal at 50 mcg /h Oxycodone Sustained Release 20 mg twice daily and 5 mg of immediate release every 2 hours as needed Morphine 1 mg /h IV continuous with 1 mg q2 hours as needed Methadone 5 mg every 3 hours as needed Titrate the immediate release oxycodone and avoid the sustained release Trans-hepatic embolization

33. 33 Case History 1 He is on morphine 1 mg/h continuous infusion, but has developed asterixis, visual hallucinations and tactile hallucinations Pain is 5 by NRS Laboratory: Bilirubin 3mg /dl, PT-INR 2, Creatinine 2.2mg/dl

34. 34 Case History 1 Treatment Reduced morphine to 0.5 mg /h and add naproxen Switch to methadone Switch to buprenorphine Switch to continuous fentanyl at 25 mcg /h Celiac block Oxycodone 5 mg every 4 hours by mouth

35. 35  Davis M. Cholestasis and Endogenous Opioids. Clin Pharmacokinet 2007 46:825-850.  Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of Opioids in Liver Disease. Clin Pharmacokinet 1999; 37:17-40.  Volles D, McGory R. Perspectives in Pain Management. Critical Care Clinics 1999;15.  Rhee C, Broadbent AM. Palliation and Liver Failure: Palliative Medications Dosage Guidelines. J Pall Med 2007;10:677-685. REFERENCES

36. 36 ADJUVANT ANALGESICS

37. 37

38. 38  ANY DRUG WITH A PRIMARY INDICATION OTHER THAN PAIN BUT WITH ANALGESIC PROPERTIES IN SOME PAINFUL CONDITIONS  CO-ADMINISTSERED WITH CLASSICAL ANALGESICS (ACETAMINOPHEN, NSAIDS, OPIOIDS)  CO-ANALGESIC ARE SOMETIMES USED SYNONYMOUSLY FOR ADJUVANT ANALGESIC ADJUVANT ANALGESICS

39. 39  ARE ADDED TO OPIOIDS TO: ENHANCE ANALGESIA ALLOW OPIOID DOSE REDUCTION  FIRST LINE DRUGS FOR NON MALIGNANT PAIN  MISNOMER IF DRUG USED AS FIRST LINE ADJUVANT ANALGESIC

40. 40 OPIOIDS VS. ADJUVANTS  LACK OF END ORGAN DAMAGE  LACK OF “CEILING” DOSE  VERSATILITY (MULTIPLE ADMINISTRATION ROUTES)  POTENTIAL FOR END ORGAN DAMAGE  “CEILING” DOSE  LIMITED VERSATILITY (FOR MOST) ADJUVANTSOPIOIDS

41. 41 OPIOIDS VS. ADJUVANTS OPIOIDS  NO “THERAPEUTIC” LEVEL  ANALGESIC TOLERANCE  WIDE DIFFERENCES IN EQUIANALGESIA BETWEEN INDIVIDUALS DUE TO PHARMACOGENOMICS  THERAPEUTIC PLASMA LEVELS  LACK OF ANALGESIC TOLERANCE  CONSISTENT EQUIANALGESIA ADJUVANTS

42. 42  PSYCHOLOGIC DEPENDENCY RISK  CHANGE IN THERAPEUTIC INDEX WITH CONVERSION (ROUTE CHANGE)  EFFICACY UNRELATED TO TYPE OF PAIN  PRESCRIPTION RESTRICTIONS (LEGAL) ADJUVANTS  RELATIVE LACK OF PSYCHOLOGIC DEPENDENCE  LACK OF BENEFIT TO ROUTE CHANGE, THERAPEUTIC INDEX REMAINS UNCHANGED  EFFICACY GENERALLY LIMITED TO EITHER NOCICEPTIVE OR NEUROPATHIC PAIN  RELATIVELY FREE OF LEGAL RESTRICTION OPIOIDS VS. ADJUVANTS OPIOIDS

43. 43 OPIOIDS  WITHDRAWAL SYNDROME WITH CHRONIC USE  RESPONSES BETWEEN OPIOIDS DIFFER (NON- CROSS TOLERANCE)  PERIPHERAL AND CENTRAL ACTION  DOSES LIMITED BY SIDE EFFECTS ADJUVANTS  WITHDRAWAL SYNDROME DEPENDS UPON ADJUVANT  NON-CROSS TOLERANCE BETWEEN CLASSES (NSAIDs, ANTI-SEIZURE MEDICATIONS)  PERIPHERAL AND CENTRAL ACTION  DOSES LIMITED BY LACK OF RESPONSE AT THERAPEUTIC LEVELS AND END-ORGAN FAILURE OPIOIDS VS. ADJUVANTS

44. 44  OPTIMIZE OPIOID DOSING AND SCHEDULE BEFORE ADDING AN ADJUVANT  CONSIDER OTHER TECHNIQUES FOR PAIN CONTROL OPIOID ROTATION OPIOID CONVERSION ROUTE TREATMENT OF SIDE EFFECTS FROM OPIOIDS NON-PHARMACOLOGIC APPROACHES ADJUVANT ANALGESIC STRATEGY

45. 45  SELECT ADJUVANTS BASED UPON PAIN MECHANISM AND PATIENT CO-MORBIDITY  PRESCRIBE AN ADJUVANT BASED UPON PHARMACOLOGICAL CHARACTERISTICS, INDICATIONS (APPROVED AND UNAPPROVED) SIDE EFFECT PROFILE, DRUG INTERACTIONS, VERSATILITY AND COST ADJUVANT ANALGESIC STRATEGY

46. 46  USE THE ADJUVANT WITH THE BEST BENEFIT TO RISK PROFILE  DO NOT INITIATE SEVERAL ADJUVANTS AT ONCE  START LOW AND TITRATE TO RESPONSE  REASSESS RESPONSE AND TAPER TO EFFECT  CONSIDER COMBINING ADJUVANTS IN DIFFICULT PAIN (COMPLIMENTARY ACTIONS) ADJUVANT ANALGESIC STRATEGY

47. 47  CHOICES ARE NOT BASED UPON EVIDENCE OF DIFFERENTIAL EFFICACY BUT: TYPE OF PAIN SEVERITY OF PAIN (PAIN INTERFERENCE) ADDITIONAL SYMPTOMS (DEPRESSION, ANOREXIA) CO-MORBIDITY (HEART FAILURE, DEMENTIA, RENAL DYSFUNCTION) ADJUVANT SELECTION

48. 48  FEW EVIDENCE BASED STUDIES IN CANCER  BASED ON EXPERIENCE IN NON-MALIGNANT PAIN ADJUVANT ANALGESICS

49. 49  GABAPENTIN  CANNABINOIDS  ZICONOTIDE CALCIUM CHANNEL BLOCKERS

50. 50  CARBAMAZEPINE  PHENYTOIN/PHENOBARBITAL  TRICYCLIC ANTI-DEPRESSANTS  MEXILITINE  LIDOCAINE  LAMOTRIGINE SODIUM CHANNEL BLOCKERS

51. 51  TRICYCLIC ANTI-DEPRESSANTS  SELECTIVE SEROTONIN REUPTAKE INHIBITORS  ATYPICAL ANTI-DEPRESSANTS – VENLAFAXINE, MIRTAZAPINE, DULOXETINE MONOAMINE REUPTAKE INHIBITORS

52. 52  CLONAZAPINE  VALPROIC ACID GABA AGONISTS

53. 53  KETAMINE  AMANTADINE  MEMANTINE  LEVORPHANOL  METHADONE  DEXTROMETHORPHAN  MAGNESIUM NMDA INHIBITORS

54. 54  CANNABINOIDS  CLONAZEPAM  PSYCHOSTIMULANTS  EMLA  CAPSAICIN MISCELLANEOUS

55. 55  ADJUVANTS POTENTIATE OPIOID ANALGESIA  OPIOID “SPARING”  OPIOID DOSING AND SCHEDULE SHOULD BE OPTIMIZED BEFORE ADDING AN ADJUVANT ANALGESIC SUMMARY

56. 56  CHOICE OF AN ADJUVANT BASED UPON TYPE AND SEVERITY OF PAIN SYMPTOMS OTHER THAN PAIN THERAPEUTIC INDEX DRUG INTERACTIONS EFFICACY AND COST SUMMARY

57. 57 Case History 1 42 year old male with hepatitis C with hepatocellular carcinoma and abdominal pain from hepatic capsular invasion Physical Examination: no ascites, mild palm erythema, no asterixis Laboratory: albumin 3.0 mg /dl, PT INR 1.3

58. 58 OPIOID ROTATION

59. 59  A MINORITY OF INDIVIDUALS DEVELOP UNCONTROLLED AND RATE-LIMITING SIDE EFFECTS DURING TITRATION WITH MORPHINE  AGGRESSIVE ATTEMPTS TO PREVENT AND TREAT ADVERSE EFFECTS SHOULD BE MADE BEFORE ROTATION IS CONSIDERED OPIOIDS

60. 60  ARRAY OF G PROTEINS ACTIVATION  DIFFERENT OPIOID RECEPTORS  INTRINSIC EFFICACY  RECEPTOR DESENSITIZATION AND TRAFFICKING  TYPE OF MU RECEPTOR SUBTYPES DIFFERENT OPIOIDS

61. 61  CYTOCHROMES: CYP1A2, CYP2D6, CYP3A4  CONJUGASES: UGT1A3, UGT1A1, UGT2B7  CYP2D6 ACTIVATES CODEINE AND TRAMADOL  UGT2B7: MORPHINE TO M-6G DIFFERENT METABOLIC PATHWAY

62. 62  FRACTIONAL RECEPTOR OCCUPANCY TO PRODUCE RELIEF  RELATED TO ABILITY TO ACTIVATE RECEPTOR  LEADS TO CHANGES IN EQUIVALENTS WITH PAIN SEVERITY AND AT HIGH DOSES  LESS SHIFT IN DOSE RESPONSE CURVES WITH HIGH INTRINSIC EFFICACY OPIOIDS OPIOID EFFICACY

63. 63  FENTANYL  METHADONE  SUFENTANIL HIGH INTRINSIC EFFICACY OPIOIDS

64. 64  OPIOID RESPONSIVENESS IS HIGHLY VARIABLE BETWEEN INDIVIDUALS  OPIOID RESPONSIVENESS NOT TO BE JUDGED ON ANALGESIC RESPONSE TO ONE OPIOID  INADEQUATE PAIN RELIEF AND DOSE LIMITING SIDE EFFECTS OPIOID ROTATION

65. 65  39% COGNITIVE FAILURE  24% HALLUCINATIONS  16% UNCONTROLLED PAIN  11% MYOCLONUS  9% NAUSEA  1% LOCAL IRRITATION INDICATION FOR OPIOID ROTATION

66. 66 MORPHINE ROUTE CHANGE:  ALTERS METABOLISM  REDUCES NEUROTOXIC METABOLITES  REDUCES MYOCLONUS 3-FOLD ALTERNATIVE: SWITCHING ROUTES

67. 67 ROUTE CONVERSION (STEADY STATE) ORALPARENTERAL MORPHINE31 HYDROMORPHONE21 METHADONE21 OXYCODONE21

68. 68 SUBLINGUAL OPIOIDS: ROUTE CONVERSION FENTANYL? METHADONE1:2 (1:3) BUPRENORPHINE1:2

69. 69 TRANSDERMAL OPIOIDS: ROTATION MORPHINE EQUIVALENT FENTANYL100:1 BUPRENORPHINE110:1

70. 70  PREDOMINATELY FOR PAIN USE 100% EQUIVALENTS  PREDOMINANTLY FOR SIDE EFFECTS USE 50-70% EQUIVALENTS OPIOID ROTATION

71. 71 OPIOID ROTATION EQUIVALENTS OPIOIDEQUIVALENTS MORPHINE1:1 HYDROMORPHONE1:5 OXYCODONE1:1 (1:1.5) FENTANYL1:100 (TD/IV) METHADONE <90 1:4 >90 <300 1:8 >300 <1000 1:12 >1000 1:20

72. 72 OPIOID ROTATION EQUIVALENTS OPIOID EQUIVALEN T HYDROMORPHINE (IV)METHADONE (PD)1.14:1 1 FENTANYL (TD)METHADONE (PD)1:17-20 FENTANYL (TD)BUPRENORPHINE (TD)1:1.1 1 DOSE DEPENDENT

73. 73  OTHER CAUSES OF COGNITIVE FAILURE, HALLUCINATIONS, MYOCLONUS AND NAUSEA  DELAYS IN SIDE EFFECT RESOLUTION WHICH MAY BE ATTRIBUTED TO THE SECOND OPIOID  ORGAN FAILURE WILL CHANGE EQUIVALENTS  DRUG INTERACTION WILL CHANGE EQUIVALENTS OPIOID ROTATION PITFALLS

74. 74  BI-DIRECTIONAL DIFFERENCES IN EQUIVALENTS WITH ROUTE CONVERSION AND ROTATION METHADONE ORAL TO IV: 1:2 METHADONE IV TO ORAL: 1:1 HYDROMORPHONE TO MORPHINE: 1:3.7 MORPHINE TO HYDROMORPHONE: 5:1 OPIOID ROTATION PITFALLS

75. 75  OPIOID ROTATION TO RE-ESTABLISH PAIN CONTROL  RESOLVE SIDE EFFECTS IN THE MAJORITY  NON-CROSS TOLERANCE  EQUIVALENT TABLES ARE GUIDELINES SUMMARY

76. 76  DOSES ADJUSTED BASED ON CLINICAL CONTEXT  50-70% EQUIVALENCE FOR SIDE EFFECTS  ADJUSTMENT ANALGESICS CAN BE “OPIOID SPARING” ALLOW DOSE REDUCTION AND RESOLVE TOXICITY SUMMARY

77. 77  METHADONE ROTATIONS ARE UNIQUE; SHOULD BE DONE BY EXPERIENCED CLINICIAN  ROUTE CHANGES ALTERNATIVE TO ROTATION BASED LARGELY ON ORAL BIOAVAILABILITY SUMMARY