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OPIOID TOXICITY MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH MANIFESTATIONS MILD SEDATION NAUSEA VOMITING CONSTIPATION / DRY MOUTH / URINE RETENTION VISUAL / TACTILE HALLUCINATIONS 2 MANIFESTATIONS CONFUSION / DELIRIUM / DIZZINESS HYPERALGESIA / TOLERANCE DRUG SEEKING BEHAVIOR IMPOTENCE, MENOPAUSAL SYMPTOMS PRURITUS 3 CNS OPIOID RECEPTORS STRIATAL MYOCLONUS LIMBIC/CINGULATE GYRUS PITUITARY HALLUCUCINATIONS ↓ LIBIDO / ↓ GONADOTROPIN NUCLEUS ACCUMBENS ADDICTION NUCLEUS TRACTUS SOLITARIUS N/V 4 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 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 OPIOID BOWEL SYNDROME 7 OPIOID BOWEL SYNDROME (OBS) HARD STOOL STRAINING AT STOOL INCOMPLETE EVACUATION BLOATING DISTENSION GASTROESOPHAGEAL REFLUX ANOREXIA EARLY SATIETY 8 COMPLICATIONS FECAL IMPACTION TENESMUS PARADOXICAL DIARRHEA PSEUDO-OBSTRUCTION OBSTRUCTION 9 COMPLICATIONS SECONDARY ANOREXIA REDUCED COMPLIANCE MALABSORPTION URINARY RETENTION 10 PRECIPITATING FACTORS DEHYDRATION GI METASTASES HYPERCALCEMIA LACK OF PRIVACY LACK OF BOWEL REGIMEN RECENT SURGERY OR BARIUM STUDIES SEDENTARY LIFESTYLE 11 PRECIPITATING FACTORS MEDICATION INTERACTION WITH: CALCIUM CHANNEL BLOCKERS SSRI, ANTICHOLINERGICS THALIDOMIDE TRICYCLIC ANTIDEPRESSANTS VINCA ALKALOIDS 12 13 PHYSIOLOGY BLOCKS LONGITUDINAL MUSCLE CONTRACTION INCREASES CIRCULAR MUSCLE CONTRACTION INHIBITS SECRETIONS CLINICAL DECREASED BOWEL SOUNDS, EARLY SATIETY, BLOATING, POOR DEFECATION EARLY SATIETY, COLIC, INCOMPLETE EVACUATION DRY HARD STOOL AND INCREASES ABSORPTION 14 TREATMENT: NON-PHARMACOLOGIC INCREASE FLUIDS EXERCISE/AMBULATE PROMOTE REGULAR BOWEL HABIT ASSURE PRIVACY 15 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 OSMOTIC LAXATIVES SALTS - MAGNESIUM WORKS THROUGHOUT BOWEL BY OSMOSIS INTERFERES WITH MEDS AND NUTRIENTS 17 OSMOTIC LAXATIVES CARBOHYDRATES - LACTULOSE, SORBITOL WORKS AND IS FERMENTED IN COLON BY OSMOSIS SWEET – MAY NOT BE TOLERATED AT REQUIRED DOSE 18 OSMOTIC LAXATIVES POLYETHYLENE GLYCOL – MIRALAX WORKS THROUGHOUT BOWEL BY OSMOSIS REQUIRES LARGE VOLUME 19 ANTHRAQUINONES: MECHANISM DANTHRON/SENNA/CASCARA STIMULATES PERISTALSIS INHIBITS ATPASE NA+, K+ SENNA: DEGRADED IN COLON TO AGLYCONE 20 ANTHRAQUINONES: LIMITATION LAXATIVE PROPERTIES LIMITED TO COLON MYENTERIC DAMAGES LONG TERM COLONIC MELANOSIS CRAMPS 21 DIPHENYLMETHANES BISACODYL PHENOLPHTHALEIN 22 CLEVELAND CLINIC PROTOCOL DOCUSATE 100MG THREE TIMES DAILY MILK OF MAGNESIA 30ML AS NEEDED BISACODYL 10MG SUPPOSITORY AS NEEDED 23 OPIOID ANTAGONIST POORLY ABSORBED OPIOID RECEPTOR ANTAGONISTS PERIPHERALLY RESTRICTED OPIOID (QUATERNARY) RECEPTOR ANTAGONISTS 24 NALOXONE 2% BIOAVAILABLITY (FIRST PASS CLEARANCE) INITIAL DOSE 5 MG TITRATE TO 10-20% OF TOTAL DAILY OPIOID WATCH FOR WITHDRAWAL, UNCONTROLLED PAIN 25 METHYLNALTREXONE CANNOT BE DEMETHYLATED BY HUMANS LAXATION WITHIN HOURS ORAL ABSORPTION < 1% SINGLE PARENTERAL DOSES 0.35 – 0.45 MG/KG 26 % LAXATION WITHIN 4 HOURS 100 DAY 1 80 DAY 3 DAY 5 60 40 20 0 1 5 12.5 20 METHYLNALTREXONE DOSE (MG) 27 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 ALVIMOPAN LARGE MOLECULAR WEIGHT (461KDA) ZWITTERIONIC:POLARITY LIMITS CNS ACCESS LARGE SUBSTITUTED N GROUP INCREASES MU RECEPTOR ANTAGONISM NEARY, P. 2005 29 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 AVERAGE WEEKLY SBM FREQUENCY Follow-up Treatment SBM / week (CI) 6 Placebo (n=129) 5 Alvimopan 0.5mg BID (n=130) Alvimopan 1mg QD (n=133) Alvimopan 1mg BID (n=130) 4 3 2 1 0 0 LOCF 1 2 3 4 5 6 7 8 Week TREATMENT vs. PLACEBO (P < 0.01) 31 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 NAUSEA & VOMITING IMPOTENCE & AMENORRHEA PRURITIS 33 NAUSEA & VOMITING: MECHANISM MEDULLARY CENTRAL PATTERN GENERATOR GASTRIC STASIS VESTIBULAR SENSITIVITY 34 NAUSEA & VOMITING: TREATMENT CYCLIZINE HALOPERIDOL ONDANSETRON DROPERIDOL METOCLOPRAMIDE METHYLNALTREXONE RISPERIDONE OPIOID ROTATION OR ROUTE CONVERSION 35 IMPOTENCE AND AMENORRHEA MECHANISM HYPOGONADOTROPIN HYPOGONADISM TREATMENT HORMONE REPLACEMENT 36 CUTANEOUS PRURITIS: MECHANISM HISTAMINE RELEASE FROM MAST CELLS DISINHIBITION OF ITCH SPECIFIC NEURONS CENTRAL SEROTONIN RELEASE 37 CUTANEOUS PRURITIS: TREATMENT ANTIHISTAMINE ONDANSETRON PROPOFOL OPIOID ROTATION PAROXETINE SWITCH TO HYDROMORPHONE 38 RESPIRATORY DEPRESSION 39 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 RESPIRATORY DEPRESSION RESPIRATORY COMPLICATIONS ERRONEOUSLY MISTAKEN FOR PROGRESSIVE DISEASE RESPIRATORY DEPRESSION 0.3-17% OF POSTOPERATIVE PATIENTS 41 RESPIRATORY DEPRESSION BUPRENORPHINE PARTIAL MU AGONIST KAPPA PARTIAL AGONIST ORL-1 AGONIST RESPIRATORY DEPRESSION CEILING WITHOUT ANALGESIC CEILING COPD, SLEEP APNEA, ELDERLY 42 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 RESPIRATORY FUNCTION DURING PARENTERAL OPIOID TITRATION MEAN ET-CO2 (p = ns) DAY 1 33.3 ± 5 MM HG (RANGE 26-44) ET-CO2 (mmHg) LAST DAY 34.7 ± 5.7 MM HG (RANGE 22-47) First study day Last study day ESTFAN PM 2007 44 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 MORPHINE INDUCED NEUROTOXICITY 46 47 MECHANISMS OF M3G NEUROTOXICITY M3G LOW AFFINITY FOR OPIOID RECEPTOR PRESYNAPTIC RELEASE OF EXCITATORY NEUROTRANSMITTERS NOCICEPTIN (ORL) CHOLECYSTOKINEN (CCICB) SUBSTANCE P GLUTAMATE 48 OPIOID NEUROTOXICITY NOT PARTICULAR TO MORPHINE HYDROMORPHONE 3 GLUCURONIDE TOXICITY 2.5 FOLD GREATER ALLODYNIA MYOCLONUS SEIZURES Smith MT 2000 Wright AW 2001 49 3-GLUCURONIDE NEUROTOXICITY RATIONALE FOR ROTATION TO DISSIMILAR OPIOID METHADONE FENTANYL 50 MYOCLONUS:MECHANISM ANTIGLYCINERGIC EFFECT DOPAMINERGIC UPREGULATION PRESYNAPTIC RELEASE OF GLUTAMATE BY NEUROACTIVE METABOLITES 51 MYOCLONUS:TREATMENT OPIOID DOSE REDUCTION / ROTATION CLONAZEPAM DIAZEPAM VALPROIC ACID BACLOFEN DANTROLENE PHENOBARBITAL GABAPENTIN 52 SEDATION MECHANISM MECHANISM INHIBITION OF CHOLINERGIC TRANSMISSIONS TREATMENT TREATMENT DEXTROAMPHETAMINES METHYLPHENIDATE DONEPEZIL OPIOID SWITCH ROUTE CONVERSION TO EPIDURAL OPIOID 53 DELIRIUM MECHANISM INHIBITION OF CHOLINERGIC TRANSMISSIONS TREATMENT OPIOID DOSE REDUCTION ROUTE CONVERSION / OPIOID ROTATION HALOPERIDOL CHLORPROMAZINE ADD BENZODIAZEPINE TO HALOPERIDOL 54 OPIOID-INDUCED HYPERALGESIA LOW DOSE GS PROTEINS WHICH DEPOLARIZE NEURONS OPIOIDS HAVE BIMODAL RESPONSE MAINTENANCE DOSE/WITHDRAWAL – OPIOID RECEPTOR ACTIVATION/KINASE ACTIVATION AND COLD HYPERSENSITIVITY ESCALATING DOSE/HIGH DOSE/SPINAL OPIOIDS – STRYCHNINE EFFECT ON GLYCINE INHIBITION, NMDA ACTIVATION AND ALLODYNIA 55 OPIOID-INDUCED HYPERALGESIA TREATMENT TREATMENT OPIOID DOSE REDUCTION WITH ADDITION OF AN ADJUVANT ANALGESIC OPIOID ROTATION NMDA RECEPTOR ANTAGONIST (KETAMINE) 56 TOLERANCE TO OPIOIDS 57 TOLERANCE DIFFERENTIATE FROM PROGRESSIVE DISEASE TOLERANCE IS WELL DOCUMENTED (HOUDE RW) OPIOID-INDUCED HYPERALGESIA / WITHDRAWAL AND PAIN IF ABRUPTLY STOPPED HYPERSENSITIVITY IS MORE COMMON IN THOSE WITHOUT PAIN (METHADONE MAINTENANCE) 58 MECHANISM PHARMACODYNAMIC GENETICALLY DETERMINED SPINAL (NMDA RECEPTOR ACTIVATION) SUPRASPINAL (RVM FACILITATION) ? TOLERANCE IS A MILD FORM OF OPIOID HYPERALGESIA BALANCED BY ANALGESIA 59 TOLERANCE DOSE ESCALATION AND TIME DEPENDENT REDUCTIONS IN THERAPEUTIC INDEX ARE REVERSED BY CHANGE IN ROUTE CHANGE IN DRUG 60 TOLERANCE DIFFERENT DOSE-RESPONSE AND DOSEADVERSE EFFECT CURVES SLOPES EXPLOITABLE DIFFERENCES RELATED TO: DIFFERENT INTRINSIC EFFICACY “DOWNSTREAM” EVENTS AFTER RECEPTOR ACTIVATION SHIFT LEFT DOSE RESPONSE CURVES FOR ANALGESIA OR SHIFT RIGHT TOXICITY CURVES 61 Response Toxicity E50 Dose 62 Response Toxicity E50 Dose 63 OPIOID INSENSITIVITY PAIN WHICH DOES NOT RESPOND TO INCREASING OPIOID DOSES NEUROPATHIC PAIN – NEUROPLASTICITY WHICH RESEMBLES OPIOID TOLERANCE DOSE RESPONSE CURVES SHIFT RIGHT AND APPROXIMATE DOSE ADVERSE EFFECT CURVES THRESHOLD FOR CHANGES IN ROUTE, DRUG OR ADDING AN ADJUVANT IS LOWER WITH NEUROPATHIC PAIN 64 OPIOID INSENSITIVITY BLADDER AND RECTAL TENESMUS CUTANEOUS PAIN DELERIUM DEPRESSION SOMATIZED EXISTENTIAL PAIN 65 CHANGING DRUG OR ROUTE? THOSE WHO CAN CHANGE ROUTE WHEN ORAL MORPHINE NO LONGER WORKS, CHANGE ROUTE THOSE WHO CANNOT CHANGE ROUTE, CHANGE DRUG EVIDENCE OF BEST APPROACH (ROUTE CONVERSION VS SWITCH) IS SPARSE 66 SUMMARY MORPHINE OPIOID OF CHOICE (NON-INFERIORITY) TOLERANCE IN MOST, CLINICALLY RELEVANT IN SOME HYPERSENSITIVITY TO OPIOIDS RELATED TO PAIN TYPE AND INDIVIDUAL PHARMACOGENTICS OPIOID RECEPTOR SUBTYPES BETA-ARRESTIN (TRAFFICKING) STAT6 (RECEPTOR EXPRESSION) MERITS OF ROUTE OR DRUG CHANGE FOR INSENSITIVE PAIN IS UNKNOWN 67 SUMMARY OPIOID TOXICITY IS RELATED TO OPIOID RECEPTORS IN NON-NOCICEPTIVE PATHWAYS AND COUNTER-OPIOID RESPONSES DETERMINED BY GENETICS, ORGAN FUNCTION, MEDICATION INTERACTIONS STRATEGIES INCLUDE PROACTIVE MANAGEMENT OF CONSTIPATION, NAUSEA AND SLOW TITRATION FOR SIDE EFFECT TOLERANCE RATE LIMITING SIDE EFFECTS ARE MANAGED BY ADJUVANTS, OPIOID CONVERSION AND ROTATION 68 SUMMARY OPIOID TOXICITY IS RELATED TO OPIOID RECEPTORS IN NON-NOCICEPTIVE PATHWAYS AND COUNTER-OPIOID RESPONSES DETERMINED BY GENETICS, ORGAN FUNCTION, CO-MEDICATIONS STRATEGIES INCLUDE PROACTIVE MANAGEMENT OF CONSTIPATION, NAUSEA AND SLOW TITRATION FOR SIDE EFFECT TOLERANCE RATE LIMITING SIDE EFFECTS ARE MANAGED BY ADJUVANTS, OPIOID CONVERSION AND ROTATION 69 CASES 70 CASE HISTORY 1 48 YEAR OLD MALE WITH MULTIPLE MYELOMA LUMBAR PAIN MORPHINE INDUCED COGNITIVE FAILURE SWITCHED TO METHADONE SINGLE FRACTION RADIATION 48 HOURS LATER OBTUNDATION RESPIRATORY RATE OF 4 71 CASE 1 FLUMAZENIL TO REVERSE THE BENZODIAZEPINE METHYLPHENIDATE NALOXONE 40MCG EVERY 3 MINUTES TO RR > 10 NALOXONE INFUSION 72 CASE HISTORY 2 35 YEAR OLD FEMALE BREAST CANCER, SEVERE BONE PAIN AND SCIATICA MORPHINE CI 17MG/H PAIN FROM 10 TO 7 NRS ADDING RESCUE DOSES & ↑ THE RATE BY 30% BASAL RATE OF 35 MG/H 48 HOURS LATER INCREASING PAIN ASSOCIATED WITH ALLODYNIA IN R LEG 73 CASE HISTORY 2 PHYSICAL EXAMINATION ALLODYNIA WHICH IS IN BOTH LOWER EXTREMITIES NO NEW FINDINGS MRI (WITHOUT CONTRAST) BONE METASTASES NO CORD COMPRESSION 74 CASE 2 CONSULT RADIOTHERAPIST TO RADIATE BACK ADD GABAPENTIN AND TITRATE THE MORPHINE SWITCH TO SPINAL MORPHINE ↓ MORPHINE DOSE ↓ MORPHINE DOSE, ADD KETOROLAC ↓ MORPHINE DOSE, ADD KETAMINE 75 QUESTIONS 76