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OPIOIDS IN ORGAN FAILURE
MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH
END STAGE LIVER DISEASE
 SICK CELL THEORY
 REDUCED HEPATOCYTE FUNCTION, SPARED BLOOD FLOW
 INTACT HEPATOCYTE THEORY
 WELL FUNCTIONING RESIDUAL HEPATOCYTES, REDUCED
NUMBERS
 IMPAIRED DRUG UPTAKE THEORY
 LOSS OF FENESTRATION IN SINUSOIDAL ENDOTHELIUM,
DEVELOPMENT OF BASAL LAMINA IN SPACE OF DISSE
 BLOCK IN DIFFUSION
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FACTORS INFLUENCING DRUG
KINETICS IN LIVER DISEASE
 HIGH VS. LOW EXTRACTION RATIO
 FIRST PASS CLEARANCE SHUNTING
 ALBUMIN VS. ALPHA1 ACID GLYCOPROTEIN
BINDING
 TYPE I VS. TYPE II METABOLISM
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FENTANYL
 LOW ORAL BIOAVAILABILITY, HIGH FIRST PASS
CLEARANCE
 LIPOPHILIC WITH RAPID CNS PENETRATION
 SUBJECT TO:
 PULMONARY SEQUESTRATION PRIOR TO CNS
 EFFLUX PUMPS
 LARGE VOLUME OF DISTRIBUTION
 SEQUESTRATION IN MUSCLE FAT
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FENTANYL
 METABOLIZED BY CYP3A4
 SINGLE DOSE T ½ IS DUE TO REDISTRIBUTION
 STEADY STATE CLEARANCE LIMITED BY CYP3A4
 ALBUMIN BOUND
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FENTANYL IN RENAL DISEASE
 REDUCED CLEARANCE LATE
 UREMIA INHIBITS CYP3A4
 REDUCED ALBUMIN IN NEPHROTIC SYNDROME
 ? LARGER VOLUME OF DISTRIBUTION
 T ½ = 0.693 VD/CL
  Vd
  CL VIA CYP3A4
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FENTANYL IN RENAL DISEASE
 CLINICAL IMPORTANCE
 DO NOT START WITH A TRANSDERMAL PATCH
 TRANSDERMAL ABSORPTION MAY BE ALTERED
 DIALYSIS DOES NOT REMOVE FENTANYL
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FENTANYL IN LIVER DISEASE
 REDUCED CLEARANCE IN LIVER DISEASE
 REDUCED ALBUMIN
 REDUCED CYP3A4
 REDUCED HEPATIC BLOOD FLOW
 CLINICAL IMPORTANCE
 DO NOT USE PATCH IN ADVANCED LIVER DISEASE
 LOW DOSES, WATCH FOR DELAYED TOXICITY
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HYDROMORPHONE
 MODERATE BIOAVAILABILITY (50-60%)
 LOW BINDING TO ALBUMIN (≤ 40%)
 CROSSES THE CNS SIMILAR TO MORPHINE
 GLUCURONIDATED TO HYDROM-3 GLUCURONIDE
 NEUROTOXIN
 GLUCURONIDE METABOLITE RENALLY CLEARED
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HYDROMORPHONE IN RENAL DISEASE
 ACCUMULATION OF HYDROMORPHONE-3GLUCURONIDE
 INCREASES POTENTIAL FOR NEUROTOXICITY
 CLINICAL IMPORTANCE
 BETTER TOLERATED THAN MORPHINE IN RENAL FAILURE
 NEUROTOXICITY
 SUBJECT TO DIALYSIS
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HYDROMORPHONE AND RENAL
CLEARANCE
GFR ml/min
AUC relative to normal
>60
1
40-60
2
<30
4
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HYDROMORPHONE IN LIVER DISEASE
 GREATER BIOAVAILABILITY DUE TO SHUNTING
 MINOR INFLUENCE ON PHARMACOKINETICS
 RELATIVE SPARING OF GLUCURONIDATION
 ALBUMIN LEVELS HAVE LITTLE INFLUENCE ON UNBOUND
DRUG
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HYDROMORPHONE IN LIVER DISEASE
 CLINICAL IMPORTANCE
 INCREASED ORAL BIOAVAILABILITY
 RELATIVELY SPARED T ½
 START WITH LOWER THAN NORMAL DOSES, MAINTAIN
INTERVALS
 AVOID SUSTAINED RELEASE HYDROMORPHONE
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MORPHINE
 ORAL BIOAVAILABILITY OF 30% (15-50%)
 1/3 ALBUMIN BOUND
 SUBJECT TO EFFLUX PROTEINS
 METABOLIZED GLUCURONYL TRANSFERASES
 UGT B > UGT 1A1, UGT 1A3
 ENTEROHEPATIC RECIRCULATION
 GLUCURONIDES CLEARED BY KIDNEYS
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MORPHINE IN RENAL FAILURE
 ACCUMULATION OF MORPHINE TO GLUCURONIDE
 DELAYED OPIOID TOXICITY
 ACCUMULATION OF MORPHINE 3 GLUCURONIDE
 DELAYED NEUROTOXICITY
 HEMODIALYSIS BUT NOT PERITONEAL DIALYSIS
REMOVES GLUCURONIDE METABOLITES
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MORPHINE IN RENAL FAILURE
 CLINICAL IMPORTANCE:
 DOSE REDUCTION
 EXTEND INTERVALS
 AVOID SUSTAINED RELEASE
 PRN SCHEDULE AS INITIAL DOSING STRATEGY
 HEMODIALYSIS RELATED CHANGES IN ANALGESIA
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DOSE REDUCTION FOR GFR
GFR (ml/min)
Morphine (%)
Methadone (%)
20-50
75
100
10-20
50
100
<10
25
50
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MORPHINE CLEARANCE IN LIVER
DISEASE
 MORPHINE T ½ IS PROLONGED WITH:
 ALTERED CLOTTING TIMES
 PRESENCE OF ASCITES
 HISTORY OF ENCEPHALOPATHY
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MORPHINE IN LIVER DISEASE
 INCREASED BIOAVAILABILITY
 RELATIVELY SPARED T ½
 LITTLE INFLUENCE OF HYPOALBUMINEMIA
 CLINICAL IMPORTANCE
 START AT LOWER THAN USUAL DOSES
 MAINTAIN INTERVALS
 AVOID SUSTAINED RELEASE IN ADVANCED CIRRHOSIS
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OXYCODONE
 ORAL BIOAVAILABILITY 60%
 ALBUMIN BOUND 40%
 ACTIVELY TRANSPORTED INTO CNS
 PLASMA/BRAIN RATIO 3
 METABOLIZED BY CYP2D6, CYP3A4
 OXYMORPHONE
 NOROXYCODONE
 METABOLITES ± OXYCODONE CLEARED BY KID.
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OXYCODONE IN RENAL DISEASE
 ↑ NOROXYCODONE & OXYMORPHONE
 HALF-LIFE OF OXYCODONE IS LENGTHENED
 CNS TOXICITY AT NORMAL DOSES
 CLINICAL IMPORTANCE
 START AT REDUCED DOSES
 DO NOT USE SUSTAINED RELEASE OXYCODONE
 USE PRN TO FIND CORRECT INDIVIDUAL DOSING INTERVAL
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OXYCODONE IN LIVER DISEASE
 MAXIMUM CONCENTRATION INCREASES 40%,
AUC 90%
 IMMEDIATE RELEASE T ½ GOES FROM 3.4 TO 14
HOURS (4.6-24)
 HYPOALBUMINEMIA PLAYS A MINOR ROLE
 CLINICAL IMPORTANCE
 DO NOT USE SUSTAINED RELEASE OXYCODONE
 LENGTHEN INTERVALS BETWEEN DOSES
 USE A PRN TO FIND INDIVIDUAL INTERVALS
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METHADONE
 ORAL BIOAVAILABILITY 80%
 LOW FIRST PASS CLEARANCE
 BINDS TO ALPHA1 ACID GLYCOPROTEIN
 CROSSES THE BBB (EFFLUX PROTEINS)
 METABOLIZED BY MULTIPLE CYTOCHROMES
 CYP3A4, CYP3A5, CYP2B6, CYP2D6, CYP1A2
 INACTIVE METABOLITE
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METHADONE IN RENAL DISEASE
 INACTIVE METABOLITE
 FECAL EXCRETION
 MULTIPLE CYTOCHROME METABOLISM
 CLINICAL IMPORTANCE:
 RELATIVELY SAFE IN RENAL FAILURE
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METHADONE IN LIVER DISEASE
 BOTH METHADONE AND METABOLITES ARE
EXCRETED IN FECES VS. URINE
 T ½ IS PROLONGED IN SEVERE LIVER DISEASE (20
HRS TO 32 HRS)
 HEPATITIS C STIMULATES CYP3A4
 COMPENSATE FOR REDUCED CYTOCHROMES
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SUMMARY
OPIOIDS USED IN LIVER FAILURE / CIRRHOSIS
 MORPHINE
 HYDROMORPHONE
 ? LEVORPHANOL
 ? BUPRENORPHINE
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SUMMARY
OPIOIDS USED IN RENAL FAILURE
 METHADONE
 ? FENTANYL
 BUPRENORPHINE
 HYDROMORPHONE > MORPHINE
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Case History 1
• 42 year old male with hepatitis C with hepatocellular
carcinoma and abdominal pain from hepatic capsular
invasion
• Physical Examination: no ascites, mild palm erythema,
no asterixis
• Laboratory: albumin 3.0 mg /dl, PT INR 1.3
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Case History 1 Treatment
• Acetaminophen 1000 mg 4 times daily
• Naproxen 5000 mg 3 times daily
• Oxycodone 5 mg every 4 hours ATC
• Morphine 5 mg every 4 hours ATC
• Transhepatic arterial embolization
• Celiac block
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Case History 1
• He sustains a portal vein thrombosis and develops
ascites
• His pain escalates to a 7(NRS) unrelieved by
oxycodone 5 mg every 4 hours
• Laboratory: Bilirubin 2mg /dl, Albumin 2.8, PT-INR 1.6,
Creatinine 1 mg /dl
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Case History 1 Treatment
• Fentanyl Transdermal at 50 mcg /h
• Oxycodone Sustained Release 20 mg twice daily and
5 mg of immediate release every 2 hours as needed
• Morphine 1 mg /h IV continuous with 1 mg q2 hours
as needed
• Methadone 5 mg every 3 hours as needed
• Titrate the immediate release oxycodone and avoid the
sustained release
• Trans-hepatic embolization
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Case History 1
• He is on morphine 1 mg/h continuous infusion, but has
developed asterixis, visual hallucinations and tactile
hallucinations
• Pain is 5 by NRS
• Laboratory: Bilirubin 3mg /dl, PT-INR 2, Creatinine
2.2mg/dl
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Case History 1 Treatment
• Reduced morphine to 0.5 mg /h and add naproxen
• Switch to methadone
• Switch to buprenorphine
• Switch to continuous fentanyl at 25 mcg /h
• Celiac block
• Oxycodone 5 mg every 4 hours by mouth
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REFERENCES

Davis M. Cholestasis and Endogenous Opioids. Clin Pharmacokinet 2007
46:825-850.

Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of Opioids in Liver
Disease. Clin Pharmacokinet 1999; 37:17-40.

Volles D, McGory R. Perspectives in Pain Management. Critical Care Clinics
1999;15.

Rhee C, Broadbent AM. Palliation and Liver Failure: Palliative Medications
Dosage Guidelines. J Pall Med 2007;10:677-685.
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ADJUVANT ANALGESICS
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ADJUVANT ANALGESICS
 ANY DRUG WITH A PRIMARY INDICATION OTHER
THAN PAIN BUT WITH ANALGESIC PROPERTIES IN
SOME PAINFUL CONDITIONS
 CO-ADMINISTSERED WITH CLASSICAL
ANALGESICS (ACETAMINOPHEN, NSAIDS,
OPIOIDS)
 CO-ANALGESIC ARE SOMETIMES USED
SYNONYMOUSLY FOR ADJUVANT ANALGESIC
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ADJUVANT ANALGESIC
 ARE ADDED TO OPIOIDS TO:
 ENHANCE ANALGESIA
 ALLOW OPIOID DOSE REDUCTION
 FIRST LINE DRUGS FOR NON MALIGNANT PAIN
 MISNOMER IF DRUG USED AS FIRST LINE
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OPIOIDS VS. ADJUVANTS
OPIOIDS
 LACK OF END ORGAN
DAMAGE
 LACK OF “CEILING” DOSE
 VERSATILITY (MULTIPLE
ADMINISTRATION ROUTES)
ADJUVANTS
 POTENTIAL FOR END ORGAN
DAMAGE
 “CEILING” DOSE
 LIMITED VERSATILITY (FOR
MOST)
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OPIOIDS VS. ADJUVANTS
OPIOIDS
 NO “THERAPEUTIC”
LEVEL
 ANALGESIC
TOLERANCE
 WIDE DIFFERENCES IN
EQUIANALGESIA
BETWEEN INDIVIDUALS
DUE TO
PHARMACOGENOMICS
ADJUVANTS
 THERAPEUTIC PLASMA
LEVELS
 LACK OF ANALGESIC
TOLERANCE
 CONSISTENT
EQUIANALGESIA
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OPIOIDS VS. ADJUVANTS
OPIOIDS
 PSYCHOLOGIC
DEPENDENCY RISK
 CHANGE IN THERAPEUTIC
INDEX WITH CONVERSION
(ROUTE CHANGE)
 EFFICACY UNRELATED TO
TYPE OF PAIN
 PRESCRIPTION
RESTRICTIONS (LEGAL)
ADJUVANTS
 RELATIVE LACK OF
PSYCHOLOGIC DEPENDENCE
 LACK OF BENEFIT TO ROUTE
CHANGE, THERAPEUTIC
INDEX REMAINS UNCHANGED
 EFFICACY GENERALLY
LIMITED TO EITHER
NOCICEPTIVE OR
NEUROPATHIC PAIN
 RELATIVELY FREE OF LEGAL
RESTRICTION
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OPIOIDS VS. ADJUVANTS
OPIOIDS
 WITHDRAWAL SYNDROME
WITH CHRONIC USE
 RESPONSES BETWEEN
OPIOIDS DIFFER (NONCROSS TOLERANCE)
 PERIPHERAL AND CENTRAL
ACTION
 DOSES LIMITED BY SIDE
EFFECTS
ADJUVANTS
 WITHDRAWAL SYNDROME
DEPENDS UPON ADJUVANT
 NON-CROSS TOLERANCE
BETWEEN CLASSES (NSAIDs,
ANTI-SEIZURE MEDICATIONS)
 PERIPHERAL AND CENTRAL
ACTION
 DOSES LIMITED BY LACK OF
RESPONSE AT THERAPEUTIC
LEVELS AND END-ORGAN
FAILURE
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ADJUVANT ANALGESIC STRATEGY
 OPTIMIZE OPIOID DOSING AND SCHEDULE
BEFORE ADDING AN ADJUVANT
 CONSIDER OTHER TECHNIQUES FOR PAIN
CONTROL
 OPIOID ROTATION
 OPIOID CONVERSION ROUTE
 TREATMENT OF SIDE EFFECTS FROM OPIOIDS
 NON-PHARMACOLOGIC APPROACHES
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ADJUVANT ANALGESIC STRATEGY
 SELECT ADJUVANTS BASED UPON PAIN
MECHANISM AND PATIENT CO-MORBIDITY
 PRESCRIBE AN ADJUVANT BASED UPON
PHARMACOLOGICAL CHARACTERISTICS,
INDICATIONS (APPROVED AND UNAPPROVED)
SIDE EFFECT PROFILE, DRUG INTERACTIONS,
VERSATILITY AND COST
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ADJUVANT ANALGESIC STRATEGY
 USE THE ADJUVANT WITH THE BEST BENEFIT TO
RISK PROFILE
 DO NOT INITIATE SEVERAL ADJUVANTS AT ONCE
 START LOW AND TITRATE TO RESPONSE
 REASSESS RESPONSE AND TAPER TO EFFECT
 CONSIDER COMBINING ADJUVANTS IN DIFFICULT
PAIN (COMPLIMENTARY ACTIONS)
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ADJUVANT SELECTION
 CHOICES ARE NOT BASED UPON EVIDENCE OF
DIFFERENTIAL EFFICACY BUT:
 TYPE OF PAIN
 SEVERITY OF PAIN (PAIN INTERFERENCE)
 ADDITIONAL SYMPTOMS (DEPRESSION, ANOREXIA)
 CO-MORBIDITY (HEART FAILURE, DEMENTIA, RENAL
DYSFUNCTION)
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ADJUVANT ANALGESICS
 FEW EVIDENCE BASED STUDIES IN CANCER
 BASED ON EXPERIENCE IN NON-MALIGNANT PAIN
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CALCIUM CHANNEL BLOCKERS
 GABAPENTIN
 CANNABINOIDS
 ZICONOTIDE
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SODIUM CHANNEL BLOCKERS
 CARBAMAZEPINE
 PHENYTOIN/PHENOBARBITAL
 TRICYCLIC ANTI-DEPRESSANTS
 MEXILITINE
 LIDOCAINE
 LAMOTRIGINE
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MONOAMINE REUPTAKE INHIBITORS
 TRICYCLIC ANTI-DEPRESSANTS
 SELECTIVE SEROTONIN REUPTAKE INHIBITORS
 ATYPICAL ANTI-DEPRESSANTS – VENLAFAXINE,
MIRTAZAPINE, DULOXETINE
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GABA AGONISTS
 CLONAZAPINE
 VALPROIC ACID
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NMDA INHIBITORS
 KETAMINE
 AMANTADINE
 MEMANTINE
 LEVORPHANOL
 METHADONE
 DEXTROMETHORPHAN
 MAGNESIUM
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MISCELLANEOUS
 CANNABINOIDS
 CLONAZEPAM
 PSYCHOSTIMULANTS
 EMLA
 CAPSAICIN
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SUMMARY
 ADJUVANTS POTENTIATE OPIOID ANALGESIA
 OPIOID “SPARING”
 OPIOID DOSING AND SCHEDULE SHOULD BE
OPTIMIZED BEFORE ADDING AN ADJUVANT
ANALGESIC
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SUMMARY
 CHOICE OF AN ADJUVANT BASED UPON
 TYPE AND SEVERITY OF PAIN
 SYMPTOMS OTHER THAN PAIN
 THERAPEUTIC INDEX
 DRUG INTERACTIONS
 EFFICACY AND COST
56
Case History 1
• 42 year old male with hepatitis C with hepatocellular
carcinoma and abdominal pain from hepatic capsular
invasion
• Physical Examination: no ascites, mild palm erythema,
no asterixis
• Laboratory: albumin 3.0 mg /dl, PT INR 1.3
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OPIOID ROTATION
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OPIOIDS
 A MINORITY OF INDIVIDUALS DEVELOP
UNCONTROLLED AND RATE-LIMITING SIDE
EFFECTS DURING TITRATION WITH MORPHINE
 AGGRESSIVE ATTEMPTS TO PREVENT AND TREAT
ADVERSE EFFECTS SHOULD BE MADE BEFORE
ROTATION IS CONSIDERED
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DIFFERENT OPIOIDS
 ARRAY OF G PROTEINS ACTIVATION
 DIFFERENT OPIOID RECEPTORS
 INTRINSIC EFFICACY
 RECEPTOR DESENSITIZATION AND TRAFFICKING
 TYPE OF MU RECEPTOR SUBTYPES
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DIFFERENT METABOLIC PATHWAY
 CYTOCHROMES: CYP1A2, CYP2D6, CYP3A4
 CONJUGASES: UGT1A3, UGT1A1, UGT2B7
 CYP2D6 ACTIVATES CODEINE AND TRAMADOL
 UGT2B7: MORPHINE TO M-6G
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OPIOID EFFICACY
 FRACTIONAL RECEPTOR OCCUPANCY TO
PRODUCE RELIEF
 RELATED TO ABILITY TO ACTIVATE RECEPTOR
 LEADS TO CHANGES IN EQUIVALENTS WITH PAIN
SEVERITY AND AT HIGH DOSES
 LESS SHIFT IN DOSE RESPONSE CURVES WITH
HIGH INTRINSIC EFFICACY OPIOIDS
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HIGH INTRINSIC EFFICACY OPIOIDS
 FENTANYL
 METHADONE
 SUFENTANIL
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OPIOID ROTATION
 OPIOID RESPONSIVENESS IS HIGHLY VARIABLE
BETWEEN INDIVIDUALS

OPIOID RESPONSIVENESS NOT TO BE JUDGED
ON ANALGESIC RESPONSE TO ONE OPIOID
 INADEQUATE PAIN RELIEF AND DOSE LIMITING
SIDE EFFECTS
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INDICATION FOR OPIOID ROTATION
 39% COGNITIVE FAILURE
 24% HALLUCINATIONS
 16% UNCONTROLLED PAIN
 11% MYOCLONUS
 9% NAUSEA
 1% LOCAL IRRITATION
65
ALTERNATIVE: SWITCHING ROUTES
MORPHINE ROUTE CHANGE:
 ALTERS METABOLISM
 REDUCES NEUROTOXIC METABOLITES
 REDUCES MYOCLONUS 3-FOLD
66
ROUTE CONVERSION (STEADY STATE)
ORAL
PARENTERAL
MORPHINE
3
1
HYDROMORPHONE
2
1
METHADONE
2
1
OXYCODONE
2
1
67
SUBLINGUAL OPIOIDS: ROUTE
CONVERSION
FENTANYL
METHADONE
BUPRENORPHINE
?
1:2 (1:3)
1:2
68
TRANSDERMAL OPIOIDS: ROTATION
MORPHINE EQUIVALENT
FENTANYL
100:1
BUPRENORPHINE
110:1
69
OPIOID ROTATION
 PREDOMINATELY FOR PAIN
 USE 100% EQUIVALENTS
 PREDOMINANTLY FOR SIDE EFFECTS
 USE 50-70% EQUIVALENTS
70
OPIOID ROTATION EQUIVALENTS
OPIOID
EQUIVALENTS
MORPHINE
1:1
HYDROMORPHONE
1:5
OXYCODONE
1:1 (1:1.5)
FENTANYL
METHADONE
1:100 (TD/IV)
<90
1:4
>90 <300
1:8
>300 <1000
1:12
>1000
1:20
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OPIOID ROTATION EQUIVALENTS
1
OPIOID
OPIOID
EQUIVALEN
T
HYDROMORPHINE (IV)
METHADONE (PD)
1.14:11
FENTANYL (TD)
METHADONE (PD)
1:17-20
FENTANYL (TD)
BUPRENORPHINE (TD)
1:1.1
DOSE DEPENDENT
72
OPIOID ROTATION PITFALLS
 OTHER CAUSES OF COGNITIVE FAILURE,
HALLUCINATIONS, MYOCLONUS AND NAUSEA
 DELAYS IN SIDE EFFECT RESOLUTION WHICH
MAY BE ATTRIBUTED TO THE SECOND OPIOID
 ORGAN FAILURE WILL CHANGE EQUIVALENTS
 DRUG INTERACTION WILL CHANGE EQUIVALENTS
73
OPIOID ROTATION PITFALLS
 BI-DIRECTIONAL DIFFERENCES IN EQUIVALENTS
WITH ROUTE CONVERSION AND ROTATION
 METHADONE ORAL TO IV: 1:2
 METHADONE IV TO ORAL: 1:1
 HYDROMORPHONE TO MORPHINE: 1:3.7
 MORPHINE TO HYDROMORPHONE: 5:1
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SUMMARY
 OPIOID ROTATION TO RE-ESTABLISH PAIN
CONTROL
 RESOLVE SIDE EFFECTS IN THE MAJORITY
 NON-CROSS TOLERANCE
 EQUIVALENT TABLES ARE GUIDELINES
75
SUMMARY
 DOSES ADJUSTED BASED ON CLINICAL CONTEXT
 50-70% EQUIVALENCE FOR SIDE EFFECTS
 ADJUSTMENT ANALGESICS CAN BE “OPIOID
SPARING”
 ALLOW DOSE REDUCTION AND RESOLVE TOXICITY
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SUMMARY
 METHADONE ROTATIONS ARE UNIQUE; SHOULD
BE DONE BY EXPERIENCED CLINICIAN
 ROUTE CHANGES ALTERNATIVE TO ROTATION
 BASED LARGELY ON ORAL BIOAVAILABILITY
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