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OPIOIDS IN ORGAN FAILURE

OPIOIDS IN ORGAN FAILURE. MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH. END STAGE LIVER DISEASE. SICK CELL THEORY REDUCED HEPATOCYTE FUNCTION, SPARED BLOOD FLOW INTACT HEPATOCYTE THEORY WELL FUNCTIONING RESIDUAL HEPATOCYTES, REDUCED NUMBERS IMPAIRED DRUG UPTAKE THEORY

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OPIOIDS IN ORGAN FAILURE

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

  2. END STAGE LIVER DISEASE • 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 2

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

  4. FENTANYL • 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 4

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

  6. FENTANYL IN RENAL DISEASE • 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 6

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

  8. FENTANYL IN LIVER DISEASE • 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 8

  9. HYDROMORPHONE • 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 9

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

  11. HYDROMORPHONE AND RENAL CLEARANCE 11

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

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

  14. MORPHINE • 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 14

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

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

  17. DOSE REDUCTION FOR GFR 17

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

  19. MORPHINE IN LIVER DISEASE • 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 19

  20. OXYCODONE • 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. 20

  21. OXYCODONE IN RENAL DISEASE • ↑ 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 21

  22. OXYCODONE IN LIVER DISEASE • 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 22

  23. METHADONE • 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 23

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

  25. METHADONE IN LIVER DISEASE • 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 25

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

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

  28. 28

  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 29

  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 30

  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 31

  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 32

  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 33

  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 34

  35. REFERENCES • 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. 35

  36. ADJUVANT ANALGESICS 36

  37. 37

  38. ADJUVANT ANALGESICS • 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 38

  39. ADJUVANT ANALGESIC • 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 39

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

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

  42. PSYCHOLOGIC DEPENDENCY RISK CHANGE IN THERAPEUTIC INDEX WITH CONVERSION (ROUTE CHANGE) EFFICACY UNRELATED TO TYPE OF PAIN PRESCRIPTION RESTRICTIONS (LEGAL) OPIOIDS VS. ADJUVANTS OPIOIDS 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 42

  43. OPIOIDS WITHDRAWAL SYNDROME WITH CHRONIC USE RESPONSES BETWEEN OPIOIDS DIFFER (NON-CROSS TOLERANCE) PERIPHERAL AND CENTRAL ACTION DOSES LIMITED BY SIDE EFFECTS OPIOIDS VS. ADJUVANTS 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 43

  44. ADJUVANT ANALGESIC STRATEGY • 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 44

  45. ADJUVANT ANALGESIC STRATEGY • 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 45

  46. ADJUVANT ANALGESIC STRATEGY • 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) 46

  47. ADJUVANT SELECTION • 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) 47

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

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

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

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