opioids in organ failure
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OPIOIDS IN ORGAN FAILURE
MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH
2
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
END STAGE LIVER DISEASE
3
HIGH VS. LOW EXTRACTION RATIO
FIRST PASS CLEARANCE SHUNTING
ALBUMIN VS. ALPHA1 ACID GLYCOPROTEIN
BINDING
TYPE I VS. TYPE II METABOLISM
FACTORS INFLUENCING DRUG KINETICS IN LIVER DISEASE
4
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
FENTANYL
5
METABOLIZED BY CYP3A4
SINGLE DOSE T ½ IS DUE TO REDISTRIBUTION
STEADY STATE CLEARANCE LIMITED BY CYP3A4
ALBUMIN BOUND
FENTANYL
6
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
FENTANYL IN RENAL DISEASE
7
CLINICAL IMPORTANCE
DO NOT START WITH A TRANSDERMAL PATCH
TRANSDERMAL ABSORPTION MAY BE ALTERED
DIALYSIS DOES NOT REMOVE FENTANYL
FENTANYL IN RENAL DISEASE
8
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
FENTANYL IN LIVER DISEASE
9
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
HYDROMORPHONE
10
ACCUMULATION OF HYDROMORPHONE-3-
GLUCURONIDE
INCREASES POTENTIAL FOR NEUROTOXICITY
CLINICAL IMPORTANCE
BETTER TOLERATED THAN MORPHINE IN RENAL FAILURE
NEUROTOXICITY
SUBJECT TO DIALYSIS
HYDROMORPHONE IN RENAL DISEASE
11
HYDROMORPHONE AND RENAL CLEARANCE
GFR ml/min AUC relative to normal
>60 1
40-60 2
<30 4
12
GREATER BIOAVAILABILITY DUE TO SHUNTING
MINOR INFLUENCE ON PHARMACOKINETICS
RELATIVE SPARING OF GLUCURONIDATION
ALBUMIN LEVELS HAVE LITTLE INFLUENCE ON UNBOUND
DRUG
HYDROMORPHONE IN LIVER DISEASE
13
CLINICAL IMPORTANCE
INCREASED ORAL BIOAVAILABILITY
RELATIVELY SPARED T ½
START WITH LOWER THAN NORMAL DOSES, MAINTAIN
INTERVALS
AVOID SUSTAINED RELEASE HYDROMORPHONE
HYDROMORPHONE IN LIVER DISEASE
14
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
MORPHINE
15
ACCUMULATION OF MORPHINE TO GLUCURONIDE
DELAYED OPIOID TOXICITY
ACCUMULATION OF MORPHINE 3 GLUCURONIDE
DELAYED NEUROTOXICITY
HEMODIALYSIS BUT NOT PERITONEAL DIALYSIS
REMOVES GLUCURONIDE METABOLITES
MORPHINE IN RENAL FAILURE
16
CLINICAL IMPORTANCE:
DOSE REDUCTION
EXTEND INTERVALS
AVOID SUSTAINED RELEASE
PRN SCHEDULE AS INITIAL DOSING STRATEGY
HEMODIALYSIS RELATED CHANGES IN ANALGESIA
MORPHINE IN RENAL FAILURE
17
DOSE REDUCTION FOR GFR
GFR (ml/min) Morphine (%) Methadone (%)
20-50 75 100
10-20 50 100
<10 25 50
18
MORPHINE T ½ IS PROLONGED WITH:
ALTERED CLOTTING TIMES
PRESENCE OF ASCITES
HISTORY OF ENCEPHALOPATHY
MORPHINE CLEARANCE IN LIVER DISEASE
19
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
MORPHINE IN LIVER DISEASE
20
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.
OXYCODONE
21
↑ 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
OXYCODONE IN RENAL DISEASE
22
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
OXYCODONE IN LIVER DISEASE
23
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
METHADONE
24
INACTIVE METABOLITE
FECAL EXCRETION
MULTIPLE CYTOCHROME METABOLISM
CLINICAL IMPORTANCE:
RELATIVELY SAFE IN RENAL FAILURE
METHADONE IN RENAL DISEASE
25
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
METHADONE IN LIVER DISEASE
26
MORPHINE
HYDROMORPHONE
? LEVORPHANOL
? BUPRENORPHINE
SUMMARY
OPIOIDS USED IN LIVER FAILURE / CIRRHOSIS
27
METHADONE
? FENTANYL
BUPRENORPHINE
HYDROMORPHONE > MORPHINE
SUMMARY
OPIOIDS USED IN RENAL FAILURE
28
29
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
30
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
31
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
32
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
33
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
34
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
35
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.
REFERENCES
36
ADJUVANT ANALGESICS
37
38
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
ADJUVANT ANALGESICS
39
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
ADJUVANT ANALGESIC
40
OPIOIDS VS. ADJUVANTS
LACK OF END ORGAN DAMAGE
LACK OF “CEILING” DOSE
VERSATILITY (MULTIPLE ADMINISTRATION ROUTES)
POTENTIAL FOR END ORGAN DAMAGE
“CEILING” DOSE
LIMITED VERSATILITY (FOR MOST)
ADJUVANTSOPIOIDS
41
OPIOIDS VS. ADJUVANTS
OPIOIDS
NO “THERAPEUTIC” LEVEL
ANALGESIC TOLERANCE
WIDE DIFFERENCES IN EQUIANALGESIA BETWEEN INDIVIDUALS DUE TO PHARMACOGENOMICS
THERAPEUTIC PLASMA LEVELS
LACK OF ANALGESIC TOLERANCE
CONSISTENT EQUIANALGESIA
ADJUVANTS
42
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
OPIOIDS VS. ADJUVANTS
OPIOIDS
43
OPIOIDS
WITHDRAWAL SYNDROME WITH CHRONIC USE
RESPONSES BETWEEN OPIOIDS DIFFER (NON-CROSS 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
OPIOIDS VS. ADJUVANTS
44
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
ADJUVANT ANALGESIC STRATEGY
45
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
ADJUVANT ANALGESIC STRATEGY
46
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)
ADJUVANT ANALGESIC STRATEGY
47
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)
ADJUVANT SELECTION
48
FEW EVIDENCE BASED STUDIES IN CANCER
BASED ON EXPERIENCE IN NON-MALIGNANT PAIN
ADJUVANT ANALGESICS
49
GABAPENTIN
CANNABINOIDS
ZICONOTIDE
CALCIUM CHANNEL BLOCKERS
50
CARBAMAZEPINE
PHENYTOIN/PHENOBARBITAL
TRICYCLIC ANTI-DEPRESSANTS
MEXILITINE
LIDOCAINE
LAMOTRIGINE
SODIUM CHANNEL BLOCKERS
51
TRICYCLIC ANTI-DEPRESSANTS
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
ATYPICAL ANTI-DEPRESSANTS – VENLAFAXINE,
MIRTAZAPINE, DULOXETINE
MONOAMINE REUPTAKE INHIBITORS
52
CLONAZAPINE
VALPROIC ACID
GABA AGONISTS
53
KETAMINE
AMANTADINE
MEMANTINE
LEVORPHANOL
METHADONE
DEXTROMETHORPHAN
MAGNESIUM
NMDA INHIBITORS
54
CANNABINOIDS
CLONAZEPAM
PSYCHOSTIMULANTS
EMLA
CAPSAICIN
MISCELLANEOUS
55
ADJUVANTS POTENTIATE OPIOID ANALGESIA
OPIOID “SPARING”
OPIOID DOSING AND SCHEDULE SHOULD BE
OPTIMIZED BEFORE ADDING AN ADJUVANT
ANALGESIC
SUMMARY
56
CHOICE OF AN ADJUVANT BASED UPON
TYPE AND SEVERITY OF PAIN
SYMPTOMS OTHER THAN PAIN
THERAPEUTIC INDEX
DRUG INTERACTIONS
EFFICACY AND COST
SUMMARY
57
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
58
OPIOID ROTATION
59
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
OPIOIDS
60
ARRAY OF G PROTEINS ACTIVATION
DIFFERENT OPIOID RECEPTORS
INTRINSIC EFFICACY
RECEPTOR DESENSITIZATION AND TRAFFICKING
TYPE OF MU RECEPTOR SUBTYPES
DIFFERENT OPIOIDS
61
CYTOCHROMES: CYP1A2, CYP2D6, CYP3A4
CONJUGASES: UGT1A3, UGT1A1, UGT2B7
CYP2D6 ACTIVATES CODEINE AND TRAMADOL
UGT2B7: MORPHINE TO M-6G
DIFFERENT METABOLIC PATHWAY
62
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
OPIOID EFFICACY
63
FENTANYL
METHADONE
SUFENTANIL
HIGH INTRINSIC EFFICACY OPIOIDS
64
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
OPIOID ROTATION
65
39% COGNITIVE FAILURE
24% HALLUCINATIONS
16% UNCONTROLLED PAIN
11% MYOCLONUS
9% NAUSEA
1% LOCAL IRRITATION
INDICATION FOR OPIOID ROTATION
66
MORPHINE ROUTE CHANGE:
ALTERS METABOLISM
REDUCES NEUROTOXIC METABOLITES
REDUCES MYOCLONUS 3-FOLD
ALTERNATIVE: SWITCHING ROUTES
67
ROUTE CONVERSION (STEADY STATE)
ORAL PARENTERAL
MORPHINE 3 1
HYDROMORPHONE 2 1
METHADONE 2 1
OXYCODONE 2 1
68
SUBLINGUAL OPIOIDS: ROUTE CONVERSION
FENTANYL ?
METHADONE 1:2 (1:3)
BUPRENORPHINE 1:2
69
TRANSDERMAL OPIOIDS: ROTATION
MORPHINE EQUIVALENT
FENTANYL 100:1
BUPRENORPHINE 110:1
70
PREDOMINATELY FOR PAIN
USE 100% EQUIVALENTS
PREDOMINANTLY FOR SIDE EFFECTS
USE 50-70% EQUIVALENTS
OPIOID ROTATION
71
OPIOID ROTATION EQUIVALENTS
OPIOID EQUIVALENTS
MORPHINE 1:1
HYDROMORPHONE 1:5
OXYCODONE 1:1 (1:1.5)
FENTANYL 1:100 (TD/IV)
METHADONE
<90 1:4
>90 <300 1:8
>300 <1000 1:12
>1000 1:20
72
OPIOID ROTATION EQUIVALENTS
OPIOID OPIOIDEQUIVALEN
T
HYDROMORPHINE (IV) METHADONE (PD) 1.14:11
FENTANYL (TD) METHADONE (PD) 1:17-20
FENTANYL (TD) BUPRENORPHINE (TD) 1:1.1
1 DOSE DEPENDENT
73
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
OPIOID ROTATION PITFALLS
74
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
OPIOID ROTATION PITFALLS
75
OPIOID ROTATION TO RE-ESTABLISH PAIN
CONTROL
RESOLVE SIDE EFFECTS IN THE MAJORITY
NON-CROSS TOLERANCE
EQUIVALENT TABLES ARE GUIDELINES
SUMMARY
76
DOSES ADJUSTED BASED ON CLINICAL CONTEXT
50-70% EQUIVALENCE FOR SIDE EFFECTS
ADJUSTMENT ANALGESICS CAN BE “OPIOID
SPARING”
ALLOW DOSE REDUCTION AND RESOLVE TOXICITY
SUMMARY
77
METHADONE ROTATIONS ARE UNIQUE; SHOULD
BE DONE BY EXPERIENCED CLINICIAN
ROUTE CHANGES ALTERNATIVE TO ROTATION
BASED LARGELY ON ORAL BIOAVAILABILITY
SUMMARY
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