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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
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MANIFESTATIONS
 CONFUSION / DELIRIUM / DIZZINESS
 HYPERALGESIA / TOLERANCE
 DRUG SEEKING BEHAVIOR
 IMPOTENCE, MENOPAUSAL SYMPTOMS
 PRURITUS
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CNS OPIOID RECEPTORS
 STRIATAL
MYOCLONUS
 LIMBIC/CINGULATE GYRUS
 PITUITARY
HALLUCUCINATIONS
↓ LIBIDO / ↓ GONADOTROPIN
 NUCLEUS ACCUMBENS
ADDICTION
 NUCLEUS TRACTUS SOLITARIUS
N/V
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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)
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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)
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OPIOID BOWEL SYNDROME
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OPIOID BOWEL SYNDROME (OBS)
 HARD STOOL
 STRAINING AT STOOL
 INCOMPLETE EVACUATION
 BLOATING
 DISTENSION
 GASTROESOPHAGEAL REFLUX
 ANOREXIA
 EARLY SATIETY
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COMPLICATIONS
 FECAL IMPACTION
 TENESMUS
 PARADOXICAL DIARRHEA
 PSEUDO-OBSTRUCTION
 OBSTRUCTION
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COMPLICATIONS
 SECONDARY ANOREXIA
 REDUCED COMPLIANCE
 MALABSORPTION
 URINARY RETENTION
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PRECIPITATING FACTORS
 DEHYDRATION
 GI METASTASES
 HYPERCALCEMIA
 LACK OF PRIVACY
 LACK OF BOWEL REGIMEN
 RECENT SURGERY OR BARIUM STUDIES
 SEDENTARY LIFESTYLE
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PRECIPITATING FACTORS
 MEDICATION INTERACTION WITH:
 CALCIUM CHANNEL BLOCKERS
 SSRI, ANTICHOLINERGICS
 THALIDOMIDE
 TRICYCLIC ANTIDEPRESSANTS
 VINCA ALKALOIDS
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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
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TREATMENT: NON-PHARMACOLOGIC
 INCREASE FLUIDS
 EXERCISE/AMBULATE
 PROMOTE REGULAR BOWEL HABIT
 ASSURE PRIVACY
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BULK AGENTS
 NOT TARGET SPECIFIC
 PERISTALSIS REFLEX BLOCKED BY OPIOIDS
 DO NOT PREVENT ABSORPTION
 REQUIRES 200-300 ML OF EXTRA FLUID DAILY
 LIMITED TOLERABILITY
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OSMOTIC LAXATIVES
SALTS - MAGNESIUM
 WORKS THROUGHOUT BOWEL
 BY OSMOSIS
 INTERFERES WITH MEDS AND NUTRIENTS
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OSMOTIC LAXATIVES
CARBOHYDRATES - LACTULOSE, SORBITOL
 WORKS AND IS FERMENTED IN COLON
 BY OSMOSIS
 SWEET – MAY NOT BE TOLERATED AT REQUIRED
DOSE
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OSMOTIC LAXATIVES
POLYETHYLENE GLYCOL – MIRALAX
 WORKS THROUGHOUT BOWEL
 BY OSMOSIS
 REQUIRES LARGE VOLUME
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ANTHRAQUINONES: MECHANISM
DANTHRON/SENNA/CASCARA
 STIMULATES PERISTALSIS
 INHIBITS ATPASE NA+, K+
 SENNA: DEGRADED IN COLON TO AGLYCONE
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ANTHRAQUINONES: LIMITATION
 LAXATIVE PROPERTIES LIMITED TO COLON
 MYENTERIC DAMAGES LONG TERM
 COLONIC MELANOSIS
 CRAMPS
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DIPHENYLMETHANES
 BISACODYL
 PHENOLPHTHALEIN
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CLEVELAND CLINIC PROTOCOL
 DOCUSATE 100MG THREE TIMES DAILY
 MILK OF MAGNESIA 30ML AS NEEDED
 BISACODYL 10MG SUPPOSITORY AS NEEDED
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OPIOID ANTAGONIST
 POORLY ABSORBED OPIOID RECEPTOR
ANTAGONISTS
 PERIPHERALLY RESTRICTED OPIOID
(QUATERNARY) RECEPTOR ANTAGONISTS
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NALOXONE
 2% BIOAVAILABLITY (FIRST PASS CLEARANCE)
 INITIAL DOSE 5 MG
 TITRATE TO 10-20% OF TOTAL DAILY OPIOID
 WATCH FOR WITHDRAWAL, UNCONTROLLED PAIN
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METHYLNALTREXONE
 CANNOT BE DEMETHYLATED BY HUMANS
 LAXATION WITHIN HOURS
 ORAL ABSORPTION < 1%
 SINGLE PARENTERAL DOSES 0.35 – 0.45 MG/KG
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% LAXATION WITHIN 4 HOURS
100
DAY 1
80
DAY 3
DAY 5
60
40
20
0
1
5
12.5
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METHYLNALTREXONE DOSE (MG)
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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
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ALVIMOPAN
 LARGE MOLECULAR WEIGHT (461KDA)
 ZWITTERIONIC:POLARITY LIMITS CNS ACCESS
 LARGE SUBSTITUTED N GROUP INCREASES MU
RECEPTOR ANTAGONISM
NEARY, P. 2005
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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
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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)
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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
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NAUSEA & VOMITING
IMPOTENCE & AMENORRHEA
PRURITIS
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NAUSEA & VOMITING: MECHANISM

MEDULLARY CENTRAL PATTERN GENERATOR
 GASTRIC STASIS

VESTIBULAR SENSITIVITY
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NAUSEA & VOMITING: TREATMENT
 CYCLIZINE
 HALOPERIDOL
 ONDANSETRON
 DROPERIDOL
 METOCLOPRAMIDE
 METHYLNALTREXONE
 RISPERIDONE
 OPIOID ROTATION OR ROUTE CONVERSION
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IMPOTENCE AND AMENORRHEA
MECHANISM

HYPOGONADOTROPIN HYPOGONADISM
TREATMENT
 HORMONE REPLACEMENT
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CUTANEOUS PRURITIS: MECHANISM
 HISTAMINE RELEASE FROM MAST CELLS
 DISINHIBITION OF ITCH SPECIFIC NEURONS
 CENTRAL SEROTONIN RELEASE
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CUTANEOUS PRURITIS: TREATMENT
 ANTIHISTAMINE
 ONDANSETRON
 PROPOFOL
 OPIOID ROTATION
 PAROXETINE
 SWITCH TO HYDROMORPHONE
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RESPIRATORY DEPRESSION
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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
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RESPIRATORY DEPRESSION
 RESPIRATORY COMPLICATIONS ERRONEOUSLY
MISTAKEN FOR PROGRESSIVE DISEASE
 RESPIRATORY DEPRESSION 0.3-17% OF
POSTOPERATIVE PATIENTS
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RESPIRATORY DEPRESSION
 BUPRENORPHINE
 PARTIAL MU AGONIST
 KAPPA PARTIAL AGONIST
 ORL-1 AGONIST
 RESPIRATORY DEPRESSION CEILING WITHOUT
ANALGESIC CEILING
 COPD, SLEEP APNEA, ELDERLY
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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
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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
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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
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MORPHINE INDUCED
NEUROTOXICITY
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MECHANISMS OF M3G NEUROTOXICITY
 M3G LOW AFFINITY FOR OPIOID RECEPTOR
 PRESYNAPTIC RELEASE OF EXCITATORY
NEUROTRANSMITTERS
 NOCICEPTIN (ORL)
 CHOLECYSTOKINEN (CCICB)
 SUBSTANCE P
 GLUTAMATE
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OPIOID NEUROTOXICITY
 NOT PARTICULAR TO MORPHINE
 HYDROMORPHONE 3 GLUCURONIDE TOXICITY 2.5
FOLD GREATER
 ALLODYNIA
 MYOCLONUS
 SEIZURES
Smith MT 2000
Wright AW 2001
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3-GLUCURONIDE NEUROTOXICITY
RATIONALE FOR ROTATION TO
DISSIMILAR OPIOID
 METHADONE
 FENTANYL
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MYOCLONUS:MECHANISM
 ANTIGLYCINERGIC EFFECT
 DOPAMINERGIC UPREGULATION
 PRESYNAPTIC RELEASE OF GLUTAMATE BY
NEUROACTIVE METABOLITES
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MYOCLONUS:TREATMENT
 OPIOID DOSE REDUCTION / ROTATION
 CLONAZEPAM
 DIAZEPAM
 VALPROIC ACID
 BACLOFEN
 DANTROLENE
 PHENOBARBITAL
 GABAPENTIN
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SEDATION
MECHANISM
MECHANISM
 INHIBITION OF CHOLINERGIC TRANSMISSIONS
TREATMENT
TREATMENT





DEXTROAMPHETAMINES
METHYLPHENIDATE
DONEPEZIL
OPIOID SWITCH
ROUTE CONVERSION TO EPIDURAL OPIOID
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DELIRIUM
MECHANISM
 INHIBITION OF CHOLINERGIC
TRANSMISSIONS
TREATMENT





OPIOID DOSE REDUCTION
ROUTE CONVERSION / OPIOID ROTATION
HALOPERIDOL
CHLORPROMAZINE
ADD BENZODIAZEPINE TO HALOPERIDOL
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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
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OPIOID-INDUCED HYPERALGESIA
TREATMENT
TREATMENT
 OPIOID DOSE REDUCTION WITH ADDITION OF
AN ADJUVANT ANALGESIC
 OPIOID ROTATION
 NMDA RECEPTOR ANTAGONIST (KETAMINE)
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TOLERANCE TO OPIOIDS
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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)
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MECHANISM
 PHARMACODYNAMIC
 GENETICALLY DETERMINED
 SPINAL (NMDA RECEPTOR ACTIVATION)
 SUPRASPINAL (RVM FACILITATION)
 ? TOLERANCE IS A MILD FORM OF OPIOID
HYPERALGESIA BALANCED BY ANALGESIA
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TOLERANCE
 DOSE ESCALATION AND TIME DEPENDENT
REDUCTIONS IN THERAPEUTIC INDEX ARE
REVERSED BY
 CHANGE IN ROUTE
 CHANGE IN DRUG
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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
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Response
Toxicity
E50
Dose
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Response
Toxicity
E50
Dose
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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
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OPIOID INSENSITIVITY
 BLADDER AND RECTAL TENESMUS
 CUTANEOUS PAIN
 DELERIUM
 DEPRESSION
 SOMATIZED EXISTENTIAL PAIN
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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
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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
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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
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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
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CASES
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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
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CASE 1
 FLUMAZENIL TO REVERSE THE BENZODIAZEPINE
 METHYLPHENIDATE
 NALOXONE 40MCG EVERY 3 MINUTES TO RR > 10
 NALOXONE INFUSION
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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
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CASE HISTORY 2
 PHYSICAL EXAMINATION
 ALLODYNIA WHICH IS IN BOTH LOWER EXTREMITIES
 NO NEW FINDINGS
 MRI (WITHOUT CONTRAST)
 BONE METASTASES
 NO CORD COMPRESSION
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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
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QUESTIONS
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