OPIOID TOXICITY
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Transcript of OPIOID TOXICITY
OPIOID TOXICITY
MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH
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MILD SEDATION
NAUSEA
VOMITING
CONSTIPATION / DRY MOUTH / URINE RETENTION
VISUAL / TACTILE HALLUCINATIONS
MANIFESTATIONS
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CONFUSION / DELIRIUM / DIZZINESS
HYPERALGESIA / TOLERANCE
DRUG SEEKING BEHAVIOR
IMPOTENCE, MENOPAUSAL SYMPTOMS
PRURITUS
MANIFESTATIONS
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STRIATAL MYOCLONUS
LIMBIC/CINGULATE GYRUS HALLUCUCINATIONS
PITUITARY ↓ LIBIDO / ↓ GONADOTROPIN
NUCLEUS ACCUMBENS ADDICTION
NUCLEUS TRACTUS SOLITARIUS N/V
CNS OPIOID RECEPTORS
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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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HARD STOOL
STRAINING AT STOOL
INCOMPLETE EVACUATION
BLOATING
DISTENSION
GASTROESOPHAGEAL REFLUX
ANOREXIA
EARLY SATIETY
OPIOID BOWEL SYNDROME (OBS)
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FECAL IMPACTION
TENESMUS
PARADOXICAL DIARRHEA
PSEUDO-OBSTRUCTION
OBSTRUCTION
COMPLICATIONS
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SECONDARY ANOREXIA
REDUCED COMPLIANCE
MALABSORPTION
URINARY RETENTION
COMPLICATIONS
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DEHYDRATION
GI METASTASES
HYPERCALCEMIA
LACK OF PRIVACY
LACK OF BOWEL REGIMEN
RECENT SURGERY OR BARIUM STUDIES
SEDENTARY LIFESTYLE
PRECIPITATING FACTORS
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MEDICATION INTERACTION WITH:
CALCIUM CHANNEL BLOCKERS
SSRI, ANTICHOLINERGICS
THALIDOMIDE
TRICYCLIC ANTIDEPRESSANTS
VINCA ALKALOIDS
PRECIPITATING FACTORS
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BLOCKS LONGITUDINAL MUSCLE CONTRACTION
INCREASES CIRCULAR MUSCLE CONTRACTION
INHIBITS SECRETIONS AND INCREASES ABSORPTION
PHYSIOLOGY CLINICAL
DECREASED BOWEL SOUNDS, EARLY SATIETY, BLOATING, POOR DEFECATION
EARLY SATIETY, COLIC, INCOMPLETE EVACUATION
DRY HARD STOOL
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INCREASE FLUIDS
EXERCISE/AMBULATE
PROMOTE REGULAR BOWEL HABIT
ASSURE PRIVACY
TREATMENT: NON-PHARMACOLOGIC
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NOT TARGET SPECIFIC
PERISTALSIS REFLEX BLOCKED BY OPIOIDS
DO NOT PREVENT ABSORPTION
REQUIRES 200-300 ML OF EXTRA FLUID DAILY
LIMITED TOLERABILITY
BULK AGENTS
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SALTS - MAGNESIUM
WORKS THROUGHOUT BOWEL
BY OSMOSIS
INTERFERES WITH MEDS AND NUTRIENTS
OSMOTIC LAXATIVES
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CARBOHYDRATES - LACTULOSE, SORBITOL
WORKS AND IS FERMENTED IN COLON
BY OSMOSIS
SWEET – MAY NOT BE TOLERATED AT REQUIRED
DOSE
OSMOTIC LAXATIVES
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POLYETHYLENE GLYCOL – MIRALAX
WORKS THROUGHOUT BOWEL
BY OSMOSIS
REQUIRES LARGE VOLUME
OSMOTIC LAXATIVES
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DANTHRON/SENNA/CASCARA
STIMULATES PERISTALSIS
INHIBITS ATPASE NA+, K+
SENNA: DEGRADED IN COLON TO AGLYCONE
ANTHRAQUINONES: MECHANISM
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LAXATIVE PROPERTIES LIMITED TO COLON
MYENTERIC DAMAGES LONG TERM
COLONIC MELANOSIS
CRAMPS
ANTHRAQUINONES: LIMITATION
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BISACODYL
PHENOLPHTHALEIN
DIPHENYLMETHANES
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DOCUSATE 100MG THREE TIMES DAILY
MILK OF MAGNESIA 30ML AS NEEDED
BISACODYL 10MG SUPPOSITORY AS NEEDED
CLEVELAND CLINIC PROTOCOL
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POORLY ABSORBED OPIOID RECEPTOR
ANTAGONISTS
PERIPHERALLY RESTRICTED OPIOID
(QUATERNARY) RECEPTOR ANTAGONISTS
OPIOID ANTAGONIST
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2% BIOAVAILABLITY (FIRST PASS CLEARANCE)
INITIAL DOSE 5 MG
TITRATE TO 10-20% OF TOTAL DAILY OPIOID
WATCH FOR WITHDRAWAL, UNCONTROLLED PAIN
NALOXONE
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CANNOT BE DEMETHYLATED BY HUMANS
LAXATION WITHIN HOURS
ORAL ABSORPTION < 1%
SINGLE PARENTERAL DOSES 0.35 – 0.45 MG/KG
METHYLNALTREXONE
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100
80
60
40
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01 5 12.5 20
DAY 1
DAY 3DAY 5
METHYLNALTREXONE DOSE (MG)
% L
AX
AT
ION
WIT
HIN
4 H
OU
RS
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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
METHYLNALTREXONE TOXICITY
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LARGE MOLECULAR WEIGHT (461KDA)
ZWITTERIONIC:POLARITY LIMITS CNS ACCESS
LARGE SUBSTITUTED N GROUP INCREASES MU
RECEPTOR ANTAGONISM
NEARY, P. 2005
ALVIMOPAN
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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
ALVIMOPAN IN OBS
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AVERAGE WEEKLY SBM FREQUENCYS
BM
/ w
eek
SB
M /
week
(CI)
(CI)
WeekWeek
Treatment Follow-up
LOCF LOCF
TREATMENT vs. PLACEBO TREATMENT vs. PLACEBO (P (P < < 0.01)0.01)
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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
SUMMARY
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NAUSEA & VOMITING
IMPOTENCE & AMENORRHEA
PRURITIS
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MEDULLARY CENTRAL PATTERN GENERATOR
GASTRIC STASIS
VESTIBULAR SENSITIVITY
NAUSEA & VOMITING: MECHANISM
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CYCLIZINE
HALOPERIDOL
ONDANSETRON
DROPERIDOL
METOCLOPRAMIDE
METHYLNALTREXONE
RISPERIDONE
OPIOID ROTATION OR ROUTE CONVERSION
NAUSEA & VOMITING: TREATMENT
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HYPOGONADOTROPIN HYPOGONADISM
HORMONE REPLACEMENT
IMPOTENCE AND AMENORRHEA
MECHANISM
TREATMENT
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HISTAMINE RELEASE FROM MAST CELLS
DISINHIBITION OF ITCH SPECIFIC NEURONS
CENTRAL SEROTONIN RELEASE
CUTANEOUS PRURITIS: MECHANISM
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ANTIHISTAMINE
ONDANSETRON
PROPOFOL
OPIOID ROTATION
PAROXETINE
SWITCH TO HYDROMORPHONE
CUTANEOUS PRURITIS: TREATMENT
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RESPIRATORY DEPRESSION
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OPIOIDS TREAT ACUTE AND CHRONIC PAIN
S/E CAN BE LIFE THREATENING
RESPIRATORY DEPRESSION
CARDIAC ARRHYTHMIA (METHADONE)
FREQUENCY OF SERIOUS RESPIRATORY EVENTS
POORLY STUDIED
RESPIRATORY DEPRESSION
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RESPIRATORY COMPLICATIONS ERRONEOUSLY
MISTAKEN FOR PROGRESSIVE DISEASE
RESPIRATORY DEPRESSION 0.3-17% OF
POSTOPERATIVE PATIENTS
RESPIRATORY DEPRESSION
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BUPRENORPHINE
PARTIAL MU AGONIST
KAPPA PARTIAL AGONIST
ORL-1 AGONIST
RESPIRATORY DEPRESSION CEILING WITHOUT
ANALGESIC CEILING
COPD, SLEEP APNEA, ELDERLY
RESPIRATORY DEPRESSION
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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
TREATMENT
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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)
RESPIRATORY FUNCTION DURING PARENTERAL OPIOID TITRATION
First study day Last study day
ET
-CO
2 (m
mH
g)
ESTFAN PM 2007
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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
CONCLUSION
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MORPHINE INDUCED
NEUROTOXICITY
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M3G LOW AFFINITY FOR OPIOID RECEPTOR
PRESYNAPTIC RELEASE OF EXCITATORY
NEUROTRANSMITTERS
NOCICEPTIN (ORL)
CHOLECYSTOKINEN (CCICB)
SUBSTANCE P
GLUTAMATE
MECHANISMS OF M3G NEUROTOXICITY
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NOT PARTICULAR TO MORPHINE
HYDROMORPHONE 3 GLUCURONIDE TOXICITY 2.5
FOLD GREATER
ALLODYNIA
MYOCLONUS
SEIZURES
OPIOID NEUROTOXICITY
Smith MT 2000Wright AW 2001
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METHADONE
FENTANYL
3-GLUCURONIDE NEUROTOXICITY RATIONALE FOR ROTATION TO DISSIMILAR OPIOID
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MYOCLONUS:MECHANISM
ANTIGLYCINERGIC EFFECT
DOPAMINERGIC UPREGULATION
PRESYNAPTIC RELEASE OF GLUTAMATE BY
NEUROACTIVE METABOLITES
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OPIOID DOSE REDUCTION / ROTATION
CLONAZEPAM
DIAZEPAM
VALPROIC ACID
BACLOFEN
DANTROLENE
PHENOBARBITAL
GABAPENTIN
MYOCLONUS:TREATMENT
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SEDATION
MECHANISM
INHIBITION OF CHOLINERGIC TRANSMISSIONS
TREATMENT
DEXTROAMPHETAMINES
METHYLPHENIDATE
DONEPEZIL
OPIOID SWITCH
ROUTE CONVERSION TO EPIDURAL OPIOID
MECHANISM
TREATMENT
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DELIRIUM
INHIBITION OF CHOLINERGIC TRANSMISSIONS
OPIOID DOSE REDUCTION
ROUTE CONVERSION / OPIOID ROTATION
HALOPERIDOL
CHLORPROMAZINE
ADD BENZODIAZEPINE TO HALOPERIDOL
MECHANISM
TREATMENT
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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
OPIOID-INDUCED HYPERALGESIA
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TREATMENT
OPIOID DOSE REDUCTION WITH ADDITION OF
AN ADJUVANT ANALGESIC
OPIOID ROTATION
NMDA RECEPTOR ANTAGONIST (KETAMINE)
OPIOID-INDUCED HYPERALGESIA
TREATMENT
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TOLERANCE TO OPIOIDS
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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)
TOLERANCE
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PHARMACODYNAMIC
GENETICALLY DETERMINED
SPINAL (NMDA RECEPTOR ACTIVATION)
SUPRASPINAL (RVM FACILITATION)
? TOLERANCE IS A MILD FORM OF OPIOID
HYPERALGESIA BALANCED BY ANALGESIA
MECHANISM
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DOSE ESCALATION AND TIME DEPENDENT
REDUCTIONS IN THERAPEUTIC INDEX ARE
REVERSED BY
CHANGE IN ROUTE
CHANGE IN DRUG
TOLERANCE
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DIFFERENT DOSE-RESPONSE AND DOSE-
ADVERSE 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
TOLERANCE
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E50
Response Toxicity
Dose
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ResponseToxicity
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