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Features of Opioid-Induced Neurotoxicity (OIN)

Features of Opioid-Induced Neurotoxicity (OIN). Severe Sedation Cognitive failure Hallucinations/delirium Myoclonus/grand mal seizures Hyperalgesia/allodynia. O.I.N. Diagnosis. Cognitive Failure Myoclonus Hyperalgesia Tactile hallucinations. History Of:. High opioid dose

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Features of Opioid-Induced Neurotoxicity (OIN)

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  1. Features of Opioid-Induced Neurotoxicity (OIN) Severe Sedation Cognitive failure Hallucinations/delirium Myoclonus/grand mal seizures Hyperalgesia/allodynia Opioid Analgesics 6-02

  2. O.I.N. Diagnosis • Cognitive Failure • Myoclonus • Hyperalgesia • Tactile hallucinations History Of: • High opioid dose • Prolonged time • Borderline cognition • Decreased glomerular filtration Opioid Analgesics 6-02

  3. Rotation for opioid other than methadone Step 1. Calculate total (regular + rescue) daily dose of current opioid Step 2. Calculate daily dose of new opioid using analgesic table Step 3. Reduce new opioid dose by 30-50% (cross-tolerance) Step 4. Prescribe regular daily dose of new opioid Step 5. Order adequate (approximate 10% of daily dose Step 6. Continue frequent assessment Opioid Analgesics 6-02

  4. MORPHINE - HYDROMORPHONE Pereira et al, JPSM 22:2001) Opioid Analgesics 6-02

  5. RELATIONSHIP BETWEEN HYDROMORPHONE & MORPHINE Opioid Analgesics 6-02

  6. OXYCODONE RATIOS Opioid Analgesics 6-02

  7. FENTANYL (4 Studies) 66 – 100 : 1 Opioid Analgesics 6-02

  8. Opioid Analgesics 6-02

  9. Methadone:Potential Advantages • Oral, rectal & IV routes, good bioavailability • No known active metabolites • No significant accumulation in renal failure • Low cost • NMDA Receptor Antagonist- • Neuropathic pain • Opioid Resistance • Extended dosing intervals • Constipation may develop more gradually Opioid Analgesics 6-02

  10. NMDA receptor antagonists • Ketamine • Dextrometorphan • Methadone • Amantadine-Mematine • Magnesium Opioid Analgesics 6-02

  11. Methadone and NMDA • L- and d- methadone interact with NMDA in brain and spine • D- methadone weak opioid • Dose ratio was not different in patients with neuropathic cancer pain (Gagnon) Opioid Analgesics 6-02

  12. WHY DOES METHADONE WORK? • Better  Opioid Agonist • NMDA Receptor Antagonist • Inhibits Reuptake of N.E. & Serotonin Opioid Analgesics 6-02

  13. METHADONE RATIOS Opioid Analgesics 6-02

  14. Relationship Between Previous MEDD and Methadone Dose Bruera et al. Proc 9th World Congress on Pain;2000

  15. Opioid Analgesics 6-02

  16. Figure 1 Opioid Analgesics 6-02

  17. Opioid Analgesics 6-02

  18. RELATIONSHIP BETWEEN HYDROMORPHONE & MORPHINE Opioid Analgesics 6-02

  19. Opioid Analgesics 6-02

  20. Opioid Analgesics 6-02

  21. Watanabe et al, Cancer Treat. Rev.; 1996 Opioid Analgesics 6-02

  22. Methadone custom made suppositories • Daily dose PO/ IV • Powder in hydrogenated oil • 45’ in the fridge • 10% daily dose for BTP Opioid Analgesics 6-02

  23. Methadone custom made suppositories • 79 patients for median of 32 days • Median dose of 60 (20- 600 mg) • Median interval 12 hs (8-24 hs) • Median cost: 8.8% of parenteral methadone Opioid Analgesics 6-02

  24. Equianalgesic Dose Ratios Hydromorphone/Methadone Ripamonti et al. Ann Oncol; 1998 Opioid Analgesics 6-02

  25. Opioid Analgesics 6-02

  26. A Method for Immediate Discontinuation of Morphine and Rotation to Methadone Administered every 4 Hours Opioid Analgesics 6-02

  27. DRUGS THAT AFFECT THE CYP-450 SYSTEM AND CAN POTENTIALLY INTERACT WITH METHADONE 3A4 Isoenzyme Inhibitors (  methadone) Antibiotics Erythromycin and other macrolides Ketoconazole and other imidazoles Ciprofloxacin and other quinolones Antidepressants Selective serotonin reuptake inhibitors (in particular fluvoxamine) Atypic antidepressants (e.g. nefazodone) Diazepam Antiviral drugs Ritonavir, nevirapine 3A4 Isoenzyme Inducers (  methadone) Anticonvulsants Phenytoin, carbamazepine, and phenobarbital Rifampacin Corticosteroids Opioid Analgesics 6-02

  28. OPIOID COSTS Opioid Analgesics 6-02

  29. 108 Pts. – CANCER PAIN • Normal Cognition • Daily Assessment x 7 & weekly x 4 Opioid Analgesics 6-02

  30. METHADONE ROTATION • MEDD  100mg : Methadone 15 mg • MEDD > 100mg : 3 Day Rotation 108 Admitted Patients 103 Completed Rotation Opioid Analgesics 6-02

  31. RESULTS AFTER THE OPIOID ROTATION TO METHADONE Opioid Analgesics 6-02

  32. SYMPTOM MEASUREMENT BEFORE AND AFTER METHDADONE ROTATION Opioid Analgesics 6-02

  33. Opioid Analgesics 6-02

  34. 103 Pts. – CANCER PAIN • No Strong Opioids • Normal Cognition • Daily Assessment x 7 & Weekly x 4 Opioid Analgesics 6-02

  35. RCT Methadone 7.5 mg q 12 h Morphine 15 mg q 12 h Opioid Analgesics 6-02

  36. Baseline Characteristics Methadone n = 49 Morphine n = 54 Median age (range), years 57 (26-84) 60 (32-88) Gender (%) Male Female 16 (33) 33 (67) 21 (39) 33 (61) Primary cancer diagnosis (%) Gastrointestinal Breast Gynecological Genitourinary Lung Skin Other Unknown 8 (16) 9 (18) 8 (16) 4 (8) 5 (10) 4 (8) 8 (16) 3 (6) 13 (24) 10 (18) 10 (18) 7 (13) 7 (13) 2 (4) 4 (8) 1 (2) ) Patient Demographics Opioid Analgesics 6-02

  37. Patient Demographics Baseline Characteristics Methadone Morphine n=49 n=54 Neuropathic pain (%) Present Absent 19 (39) 30 (61) 21 (39) 33 (61 Pain Staging ESSCP(%) Stage 1 Stage 2 Stage 3 Unknown 17 (35) 8 (16) 23 (47) 1 (2) 20 (37) 6 (11) 27 (50) 1 (2) Bowel Movement, 0-3 scale1 (SD) 1.12 (1.0) 1.17 (1.1) 1Categorical Scale: 0=absent, 1=small, 2=moderate, 3=large Opioid Analgesics 6-02

  38. Methadone Registered Evaluable (n=49) (n=42)3 Morphine Registered Evaluable (n=54) (n=50)3 Methadone (n=42)3 Morphine (n=50)3 P value Comparison of changes in symptom scores of methadone and morphine from baseline to day 8 Symptom Baseline mean Score 0-101 (SD)2 Day 8 – baseline mean Score 0-101 (SD)2 Pain 7.7 (2) 7.6 (2) 7.8 (2) 7.8 (2) -4.9 (3) -4.7 (3) 0.80 Sedation 2.0 (3) 2.3 (3) 1.4 (3) 1.2 (2) 2.2 (4) 1.5 (4) 0.35 Nausea 1.9 (3) 2.1 (3) 1.8 (3) 1.6 (3) -0.3 (4) -0.8 (3) 0.45 Confusion 0.5 (2) 0.6 (2) 0.4 (1) 0.3 (1) 0.6 (3) 0.4 (2) 0.68 Constipation 4.6 (4) 4.5 (4) 4.1 (4) 4.0 (4) -1.5 (4) -1.8 (4) 0.75 1Categorical Scale0-10: 0 = best, 10 = worst 2 SD: Standard Deviation 3 Patients who completed the first 7 days of treatment. Opioid Analgesics 6-02

  39. N Treatment Effect Time Effect Treatment* Time Effect Pain 91 0.66 <0.0001 0.25 Sedation 89 0.23 0.36 0.03 Nausea 89 0.26 0.93 0.93 Confusion 88 0.38 0.31 0.01 Constipation 85 0.87 0.05 0.68 Repeated Measures Analyses of Variance Significance Levels: Opioid Analgesics 6-02

  40. Mean Pain Scores for patients receiving methadone and morphine for baseline through day 8 Opioid Analgesics 6-02

  41. Mean Sedation Scores for patients receiving methadone and morphine for baseline through day 8 Opioid Analgesics 6-02

  42. Opioid Analgesics 6-02

  43. Estimated Conversion Ratiosand Mean Dosages Opioid Analgesics 6-02

  44. Linear Regression – ME/IV to MEDD/PO Opioid Analgesics 6-02

  45. Linear Regression – ME/PO to MEDD/PO Opioid Analgesics 6-02

  46. Opioid Analgesics 6-02

  47. OPIOID ROTATION:FUTURE RESEARCH • RCTs vs. Dose Reduction? • Which 2nd Line Opioid? • Opioid Rotation vs. Adjuvant Drugs • Cognitive Function & Survival • Prevention? Rotation? • High Dose • History of O.I.N. • Rapid Escalation • Poor Cognition Opioid Analgesics 6-02

  48. Opioid Analgesics 6-02

  49. Opioid Analgesics 6-02

  50. Baseline Characteristics Methadone n = 48 Morphine n = 54 Median age (range), years 60 (26-84) 60 (32-88) Gender (%) Male Female 15 (31) 33 (69) 21 (39) 33 (61) Primary cancer diagnosis (%) Gastrointestinal Breast Gynecological Genitourinary Lung Skin Other Unknown 8 (17) 9 (19) 8 (17) 4 (8) 4 (8) 4 (8) 8 (17) 3 (6) 13 (24) 10 (18) 10 (18) 7 (13) 7 (13) 2 (4) 4 (8) 1 (2) Neuropathic pain Present Absent 18 (38) 30 (62) 21 (39) 33 (61) Pain Staging ESSCP1 Stage 1 Stage 2 Stage 3 Unknown 17 (35) 8 (17) 22 (46) 1 (2) 20 (37) 6 (11) 27 (50) 1 (2) Pain, 0-10 Scale2 (SD)3 7.65 (2.0) 7.83 (1.8) Sedation, 0-10 Scale2 (SD)3 2.04 (2.9) 1.41 (2.6) Nausea, 0-10 Scale2 (SD)3 1.81 (2.9) 1.83 (3.0) Confusion, 0-10 Scale2 (SD)3 0.50 (1.7) 0.41 (1.1) Constipation, 0-10 Scale2 (SD)3 4.60 (3.9) 4.09 (3.7) Bowel Movement, 0-3 Scale4 (SD) 3 1.12 (1.0) 1.17 (1.1) Opioid Analgesics 6-02

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