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OPIOID TOXICITY

OPIOID TOXICITY. MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH. MANIFESTATIONS. MILD SEDATION NAUSEA VOMITING CONSTIPATION / DRY MOUTH / URINE RETENTION VISUAL / TACTILE HALLUCINATIONS. MANIFESTATIONS. CONFUSION / DELIRIUM / DIZZINESS HYPERALGESIA / TOLERANCE DRUG SEEKING BEHAVIOR

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OPIOID TOXICITY

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  1. OPIOID TOXICITY MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH

  2. MANIFESTATIONS • MILD SEDATION • NAUSEA • VOMITING • CONSTIPATION / DRY MOUTH / URINE RETENTION • VISUAL / TACTILE HALLUCINATIONS 2

  3. MANIFESTATIONS • CONFUSION / DELIRIUM / DIZZINESS • HYPERALGESIA / TOLERANCE • DRUG SEEKING BEHAVIOR • IMPOTENCE, MENOPAUSAL SYMPTOMS • PRURITUS 3

  4. CNS OPIOID RECEPTORS • STRIATAL MYOCLONUS • LIMBIC/CINGULATE GYRUS HALLUCUCINATIONS • PITUITARY ↓ LIBIDO / ↓ GONADOTROPIN • NUCLEUS ACCUMBENS ADDICTION • NUCLEUS TRACTUS SOLITARIUS N/V 4

  5. Symptom n (%) Decreased libido 40 (95) Dry mouth 38 (90) Sedation 29 (69) Myoclonus 27 (64) Depression 24 (57) Constipation 25 (60) Flushing 20 (48) Weakness 17 (40) 5

  6. Symptom n (%) Sweating 16 (38) Urinary hesitancy16(38) Anorexia 15 (36) Anxiety 15 (36) Dizziness 15 (36) Dysphoria 15 (36) Difficulty sleeping13(31) Voice change 13 (31) 6

  7. OPIOID BOWEL SYNDROME 7

  8. OPIOID BOWEL SYNDROME (OBS) • HARD STOOL • STRAINING AT STOOL • INCOMPLETE EVACUATION • BLOATING • DISTENSION • GASTROESOPHAGEAL REFLUX • ANOREXIA • EARLY SATIETY 8

  9. COMPLICATIONS • FECAL IMPACTION • TENESMUS • PARADOXICAL DIARRHEA • PSEUDO-OBSTRUCTION • OBSTRUCTION 9

  10. COMPLICATIONS • SECONDARY ANOREXIA • REDUCED COMPLIANCE • MALABSORPTION • URINARY RETENTION 10

  11. PRECIPITATING FACTORS • DEHYDRATION • GI METASTASES • HYPERCALCEMIA • LACK OF PRIVACY • LACK OF BOWEL REGIMEN • RECENT SURGERY OR BARIUM STUDIES • SEDENTARY LIFESTYLE 11

  12. PRECIPITATING FACTORS • MEDICATION INTERACTION WITH: • CALCIUM CHANNEL BLOCKERS • SSRI, ANTICHOLINERGICS • THALIDOMIDE • TRICYCLIC ANTIDEPRESSANTS • VINCA ALKALOIDS 12

  13. 13

  14. DECREASED BOWEL SOUNDS, EARLY SATIETY, BLOATING, POOR DEFECATION • EARLY SATIETY, COLIC, INCOMPLETE EVACUATION • DRY HARD STOOL PHYSIOLOGYCLINICAL • BLOCKS LONGITUDINAL MUSCLE CONTRACTION • INCREASES CIRCULAR MUSCLE CONTRACTION • INHIBITS SECRETIONS AND INCREASES ABSORPTION 14

  15. TREATMENT: NON-PHARMACOLOGIC • INCREASE FLUIDS • EXERCISE/AMBULATE • PROMOTE REGULAR BOWEL HABIT • ASSURE PRIVACY 15

  16. BULK AGENTS • NOT TARGET SPECIFIC • PERISTALSIS REFLEX BLOCKED BY OPIOIDS • DO NOT PREVENT ABSORPTION • REQUIRES 200-300 ML OF EXTRA FLUID DAILY • LIMITED TOLERABILITY 16

  17. OSMOTIC LAXATIVES SALTS - MAGNESIUM • WORKS THROUGHOUT BOWEL • BY OSMOSIS • INTERFERES WITH MEDS AND NUTRIENTS 17

  18. OSMOTIC LAXATIVES CARBOHYDRATES - LACTULOSE, SORBITOL • WORKS AND IS FERMENTED IN COLON • BY OSMOSIS • SWEET – MAY NOT BE TOLERATED AT REQUIRED DOSE 18

  19. OSMOTIC LAXATIVES POLYETHYLENE GLYCOL – MIRALAX • WORKS THROUGHOUT BOWEL • BY OSMOSIS • REQUIRES LARGE VOLUME 19

  20. ANTHRAQUINONES: MECHANISM DANTHRON/SENNA/CASCARA • STIMULATES PERISTALSIS • INHIBITS ATPASE NA+, K+ • SENNA: DEGRADED IN COLON TO AGLYCONE 20

  21. ANTHRAQUINONES: LIMITATION • LAXATIVE PROPERTIES LIMITED TO COLON • MYENTERIC DAMAGES LONG TERM • COLONIC MELANOSIS • CRAMPS 21

  22. DIPHENYLMETHANES • BISACODYL • PHENOLPHTHALEIN 22

  23. CLEVELAND CLINIC PROTOCOL • DOCUSATE 100MG THREE TIMES DAILY • MILK OF MAGNESIA 30ML AS NEEDED • BISACODYL 10MG SUPPOSITORY AS NEEDED 23

  24. OPIOID ANTAGONIST • POORLY ABSORBED OPIOID RECEPTOR ANTAGONISTS • PERIPHERALLY RESTRICTED OPIOID (QUATERNARY) RECEPTOR ANTAGONISTS 24

  25. NALOXONE • 2% BIOAVAILABLITY (FIRST PASS CLEARANCE) • INITIAL DOSE 5 MG • TITRATE TO 10-20% OF TOTAL DAILY OPIOID • WATCH FOR WITHDRAWAL, UNCONTROLLED PAIN 25

  26. METHYLNALTREXONE • CANNOT BE DEMETHYLATED BY HUMANS • LAXATION WITHIN HOURS • ORAL ABSORPTION < 1% • SINGLE PARENTERAL DOSES 0.35 – 0.45 MG/KG 26

  27. 100 80 60 40 20 0 DAY 1 DAY 3 DAY 5 % LAXATION WITHIN 4 HOURS 1 5 12.5 20 METHYLNALTREXONE DOSE (MG) 27

  28. METHYLNALTREXONE TOXICITY • HIGH PARENTERAL DOSES (0.64-1.25MG/KG) BLOCKS NICOTINIC GANGLIONIC AND CARDIAC MUSCARINIC RECEPTORS • ORTHOSTATIC HYPOTENSION • 19.2MG/KG ORAL: WELL TOLERATED • ABDOMINAL CRAMPS IN A FEW 28

  29. ALVIMOPAN • LARGE MOLECULAR WEIGHT (461KDA) • ZWITTERIONIC:POLARITY LIMITS CNS ACCESS • LARGE SUBSTITUTED N GROUP INCREASES MU RECEPTOR ANTAGONISM NEARY, P. 2005 29

  30. ALVIMOPAN IN OBS • STOOL WITHIN 8 HOURS: 29% PLACEBO 43% (38-48%) – 0.5 MG/DAY 54% (48-61%) – 1 MG/DAY • MEDIAN TIME TO STOOL: 21 HOURS – PLACEBO 7 HOURS – 0.5 MG/DAY 3 HOURS – 1 MG/DAY 30

  31. Follow-up Treatment AVERAGE WEEKLY SBM FREQUENCY SBM / week (CI) Week LOCF TREATMENT vs. PLACEBO (P < 0.01) 31

  32. SUMMARY • OBS OCCURS ESPECIALLY IN THOSE NOT ON PROPHYLACTIC LAXATIVES • GUIDELINES ARE EXPERT OPINION • OPIOID ROTATION MAY REDUCE OBS • POORLY ABSORBED OR PERIPHERALLY RESTRICTED OPIOID RECEPTOR ANTAGONIST ARE TARGET SPECIFIC AND REVERSE OBS RAPIDLY 32

  33. NAUSEA & VOMITING IMPOTENCE & AMENORRHEA PRURITIS 33

  34. NAUSEA & VOMITING: MECHANISM • MEDULLARY CENTRAL PATTERN GENERATOR • GASTRIC STASIS • VESTIBULAR SENSITIVITY 34

  35. NAUSEA & VOMITING: TREATMENT • CYCLIZINE • HALOPERIDOL • ONDANSETRON • DROPERIDOL • METOCLOPRAMIDE • METHYLNALTREXONE • RISPERIDONE • OPIOID ROTATION OR ROUTE CONVERSION 35

  36. IMPOTENCE AND AMENORRHEA MECHANISM • HYPOGONADOTROPIN HYPOGONADISM • HORMONE REPLACEMENT TREATMENT 36

  37. CUTANEOUS PRURITIS: MECHANISM • HISTAMINE RELEASE FROM MAST CELLS • DISINHIBITION OF ITCH SPECIFIC NEURONS • CENTRAL SEROTONIN RELEASE 37

  38. CUTANEOUS PRURITIS: TREATMENT • ANTIHISTAMINE • ONDANSETRON • PROPOFOL • OPIOID ROTATION • PAROXETINE • SWITCH TO HYDROMORPHONE 38

  39. RESPIRATORY DEPRESSION 39

  40. RESPIRATORY DEPRESSION • OPIOIDS TREAT ACUTE AND CHRONIC PAIN • S/E CAN BE LIFE THREATENING • RESPIRATORY DEPRESSION • CARDIAC ARRHYTHMIA (METHADONE) • FREQUENCY OF SERIOUS RESPIRATORY EVENTS POORLY STUDIED 40

  41. RESPIRATORY DEPRESSION • RESPIRATORY COMPLICATIONS ERRONEOUSLY MISTAKEN FOR PROGRESSIVE DISEASE • RESPIRATORY DEPRESSION 0.3-17% OF POSTOPERATIVE PATIENTS 41

  42. RESPIRATORY DEPRESSION • BUPRENORPHINE • PARTIAL MU AGONIST • KAPPA PARTIAL AGONIST • ORL-1 AGONIST • RESPIRATORY DEPRESSION CEILING WITHOUT ANALGESIC CEILING • COPD, SLEEP APNEA, ELDERLY 42

  43. TREATMENT • NALOXONE – T ½ 30 MINUTES • CONTINUOUS INFUSION • HIGH POTENCY OPIOID- FENTANYL • HIGH AFFINITY/LONG RECEPTOR DWELL TIME OPIOID – BUPRENORPHINE • LONG ACTING OPIOID – METHADONE • DILUTE 0.4 MG IN 10ML; GIVE 1CC(40 MCG) EVERY 3 MINS UNTIL RESPIRATORY RATE ≥ 10 • RESPONSE: IMPROVED SEDATION,RR>10 • CONTINUOUS INFUSION 43

  44. RESPIRATORY FUNCTION DURING PARENTERAL OPIOID TITRATION • MEAN ET-CO2 (p = ns) • DAY 1 33.3 ± 5 MM HG (RANGE 26-44) • LAST DAY 34.7 ± 5.7 MM HG (RANGE 22-47) ET-CO2 (mmHg) First study day Last study day ESTFAN PM 2007 44

  45. CONCLUSION • RESPIRATORY DEPRESSION MINIMIZED BY PROPER TITRATION • RESPIRATORY DEPRESSION IS GREATEST • AT NIGHT • IMPROPER DOSING STRATEGIES • “TITRATE TO COMFORT” ORDERS • CLINICAL CIRCUMSTANCES LEADING TO DELAYED OPIOID CLEARANCE OR PHARMACODYNAMICS DRUG INTERACTIONS • VULNERABLE POPULATIONS 45

  46. MORPHINE INDUCED NEUROTOXICITY 46

  47. 47

  48. MECHANISMS OF M3G NEUROTOXICITY • M3G LOW AFFINITY FOR OPIOID RECEPTOR • PRESYNAPTIC RELEASE OF EXCITATORY NEUROTRANSMITTERS • NOCICEPTIN (ORL) • CHOLECYSTOKINEN (CCICB) • SUBSTANCE P • GLUTAMATE 48

  49. OPIOID NEUROTOXICITY • NOT PARTICULAR TO MORPHINE • HYDROMORPHONE 3 GLUCURONIDE TOXICITY 2.5 FOLD GREATER • ALLODYNIA • MYOCLONUS • SEIZURES Smith MT 2000 Wright AW 2001 49

  50. 3-GLUCURONIDE NEUROTOXICITY RATIONALE FOR ROTATION TO DISSIMILAR OPIOID • METHADONE • FENTANYL 50

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