OPIOIDS IN ORGAN FAILURE

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

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


• 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


• 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

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

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

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


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


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)


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

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OPIOID ROTATION

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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

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ARRAY OF G PROTEINS ACTIVATION

DIFFERENT OPIOID RECEPTORS

INTRINSIC EFFICACY

RECEPTOR DESENSITIZATION AND TRAFFICKING

TYPE OF MU RECEPTOR SUBTYPES

DIFFERENT OPIOIDS

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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

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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

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TRANSDERMAL OPIOIDS: ROTATION

MORPHINE EQUIVALENT

FENTANYL 100:1

BUPRENORPHINE 110:1

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PREDOMINATELY FOR PAIN

USE 100% EQUIVALENTS

PREDOMINANTLY FOR SIDE EFFECTS

USE 50-70% EQUIVALENTS

OPIOID ROTATION

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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

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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

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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

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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

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OPIOID ROTATION TO RE-ESTABLISH PAIN

CONTROL

RESOLVE SIDE EFFECTS IN THE MAJORITY

NON-CROSS TOLERANCE

EQUIVALENT TABLES ARE GUIDELINES

SUMMARY

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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

OPIOIDS IN ORGAN FAILURE

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