OPIOID TOXICITY

MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH

2

MILD SEDATION

NAUSEA

VOMITING

CONSTIPATION / DRY MOUTH / URINE RETENTION

VISUAL / TACTILE HALLUCINATIONS

MANIFESTATIONS

3

CONFUSION / DELIRIUM / DIZZINESS

HYPERALGESIA / TOLERANCE

DRUG SEEKING BEHAVIOR

IMPOTENCE, MENOPAUSAL SYMPTOMS

PRURITUS

MANIFESTATIONS

4

STRIATAL MYOCLONUS

LIMBIC/CINGULATE GYRUS HALLUCUCINATIONS

PITUITARY ↓ LIBIDO / ↓ GONADOTROPIN

NUCLEUS ACCUMBENS ADDICTION

NUCLEUS TRACTUS SOLITARIUS N/V

CNS OPIOID RECEPTORS

5

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)

6

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)

7

OPIOID BOWEL SYNDROME

8

HARD STOOL

STRAINING AT STOOL

INCOMPLETE EVACUATION

BLOATING

DISTENSION

GASTROESOPHAGEAL REFLUX

ANOREXIA

EARLY SATIETY

OPIOID BOWEL SYNDROME (OBS)

9

FECAL IMPACTION

TENESMUS

PARADOXICAL DIARRHEA

PSEUDO-OBSTRUCTION

OBSTRUCTION

COMPLICATIONS

10

SECONDARY ANOREXIA

REDUCED COMPLIANCE

MALABSORPTION

URINARY RETENTION

COMPLICATIONS

11

DEHYDRATION

GI METASTASES

HYPERCALCEMIA

LACK OF PRIVACY

LACK OF BOWEL REGIMEN

RECENT SURGERY OR BARIUM STUDIES

SEDENTARY LIFESTYLE

PRECIPITATING FACTORS

12

MEDICATION INTERACTION WITH:

CALCIUM CHANNEL BLOCKERS

SSRI, ANTICHOLINERGICS

THALIDOMIDE

TRICYCLIC ANTIDEPRESSANTS

VINCA ALKALOIDS

PRECIPITATING FACTORS

13

14

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

15

INCREASE FLUIDS

EXERCISE/AMBULATE

PROMOTE REGULAR BOWEL HABIT

ASSURE PRIVACY

TREATMENT: NON-PHARMACOLOGIC

16

NOT TARGET SPECIFIC

PERISTALSIS REFLEX BLOCKED BY OPIOIDS

DO NOT PREVENT ABSORPTION

REQUIRES 200-300 ML OF EXTRA FLUID DAILY

LIMITED TOLERABILITY

BULK AGENTS

17

SALTS - MAGNESIUM

WORKS THROUGHOUT BOWEL

BY OSMOSIS

INTERFERES WITH MEDS AND NUTRIENTS

OSMOTIC LAXATIVES

18

CARBOHYDRATES - LACTULOSE, SORBITOL

WORKS AND IS FERMENTED IN COLON

BY OSMOSIS

SWEET – MAY NOT BE TOLERATED AT REQUIRED

DOSE

OSMOTIC LAXATIVES

19

POLYETHYLENE GLYCOL – MIRALAX

WORKS THROUGHOUT BOWEL

BY OSMOSIS

REQUIRES LARGE VOLUME

OSMOTIC LAXATIVES

20

DANTHRON/SENNA/CASCARA

STIMULATES PERISTALSIS

INHIBITS ATPASE NA+, K+

SENNA: DEGRADED IN COLON TO AGLYCONE

ANTHRAQUINONES: MECHANISM

21

LAXATIVE PROPERTIES LIMITED TO COLON

MYENTERIC DAMAGES LONG TERM

COLONIC MELANOSIS

CRAMPS

ANTHRAQUINONES: LIMITATION

22

BISACODYL

PHENOLPHTHALEIN

DIPHENYLMETHANES

23

DOCUSATE 100MG THREE TIMES DAILY

MILK OF MAGNESIA 30ML AS NEEDED

BISACODYL 10MG SUPPOSITORY AS NEEDED

CLEVELAND CLINIC PROTOCOL

24

POORLY ABSORBED OPIOID RECEPTOR

ANTAGONISTS

PERIPHERALLY RESTRICTED OPIOID

(QUATERNARY) RECEPTOR ANTAGONISTS

OPIOID ANTAGONIST

25

2% BIOAVAILABLITY (FIRST PASS CLEARANCE)

INITIAL DOSE 5 MG

TITRATE TO 10-20% OF TOTAL DAILY OPIOID

WATCH FOR WITHDRAWAL, UNCONTROLLED PAIN

NALOXONE

26

CANNOT BE DEMETHYLATED BY HUMANS

LAXATION WITHIN HOURS

ORAL ABSORPTION < 1%

SINGLE PARENTERAL DOSES 0.35 – 0.45 MG/KG

METHYLNALTREXONE

27

100

80

60

40

20

01 5 12.5 20

DAY 1

DAY 3DAY 5

METHYLNALTREXONE DOSE (MG)

% L

AX

AT

ION

WIT

HIN

4 H

OU

RS

28

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

29

LARGE MOLECULAR WEIGHT (461KDA)

ZWITTERIONIC:POLARITY LIMITS CNS ACCESS

LARGE SUBSTITUTED N GROUP INCREASES MU

RECEPTOR ANTAGONISM

NEARY, P. 2005

ALVIMOPAN

30

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

31

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)

32

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

33

NAUSEA & VOMITING

IMPOTENCE & AMENORRHEA

PRURITIS

34

MEDULLARY CENTRAL PATTERN GENERATOR

GASTRIC STASIS

VESTIBULAR SENSITIVITY

NAUSEA & VOMITING: MECHANISM

35

CYCLIZINE

HALOPERIDOL

ONDANSETRON

DROPERIDOL

METOCLOPRAMIDE

METHYLNALTREXONE

RISPERIDONE

OPIOID ROTATION OR ROUTE CONVERSION

NAUSEA & VOMITING: TREATMENT

36

HYPOGONADOTROPIN HYPOGONADISM

HORMONE REPLACEMENT

IMPOTENCE AND AMENORRHEA

MECHANISM

TREATMENT

37

HISTAMINE RELEASE FROM MAST CELLS

DISINHIBITION OF ITCH SPECIFIC NEURONS

CENTRAL SEROTONIN RELEASE

CUTANEOUS PRURITIS: MECHANISM

38

ANTIHISTAMINE

ONDANSETRON

PROPOFOL

OPIOID ROTATION

PAROXETINE

SWITCH TO HYDROMORPHONE

CUTANEOUS PRURITIS: TREATMENT

39

RESPIRATORY DEPRESSION

40

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

41

RESPIRATORY COMPLICATIONS ERRONEOUSLY

MISTAKEN FOR PROGRESSIVE DISEASE

RESPIRATORY DEPRESSION 0.3-17% OF

POSTOPERATIVE PATIENTS

RESPIRATORY DEPRESSION

42

BUPRENORPHINE

PARTIAL MU AGONIST

KAPPA PARTIAL AGONIST

ORL-1 AGONIST

RESPIRATORY DEPRESSION CEILING WITHOUT

ANALGESIC CEILING

COPD, SLEEP APNEA, ELDERLY

RESPIRATORY DEPRESSION

43

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

44

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

45

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

46

MORPHINE INDUCED

NEUROTOXICITY

47

48

M3G LOW AFFINITY FOR OPIOID RECEPTOR

PRESYNAPTIC RELEASE OF EXCITATORY

NEUROTRANSMITTERS

NOCICEPTIN (ORL)

CHOLECYSTOKINEN (CCICB)

SUBSTANCE P

GLUTAMATE

MECHANISMS OF M3G NEUROTOXICITY

49

NOT PARTICULAR TO MORPHINE

HYDROMORPHONE 3 GLUCURONIDE TOXICITY 2.5

FOLD GREATER

ALLODYNIA

MYOCLONUS

SEIZURES

OPIOID NEUROTOXICITY

Smith MT 2000Wright AW 2001

50

METHADONE

FENTANYL

3-GLUCURONIDE NEUROTOXICITY RATIONALE FOR ROTATION TO DISSIMILAR OPIOID

51

MYOCLONUS:MECHANISM

ANTIGLYCINERGIC EFFECT

DOPAMINERGIC UPREGULATION

PRESYNAPTIC RELEASE OF GLUTAMATE BY

NEUROACTIVE METABOLITES

52

OPIOID DOSE REDUCTION / ROTATION

CLONAZEPAM

DIAZEPAM

VALPROIC ACID

BACLOFEN

DANTROLENE

PHENOBARBITAL

GABAPENTIN

MYOCLONUS:TREATMENT

53

SEDATION

MECHANISM

INHIBITION OF CHOLINERGIC TRANSMISSIONS

TREATMENT

DEXTROAMPHETAMINES

METHYLPHENIDATE

DONEPEZIL

OPIOID SWITCH

ROUTE CONVERSION TO EPIDURAL OPIOID

MECHANISM

TREATMENT

54

DELIRIUM

INHIBITION OF CHOLINERGIC TRANSMISSIONS

OPIOID DOSE REDUCTION

ROUTE CONVERSION / OPIOID ROTATION

HALOPERIDOL

CHLORPROMAZINE

ADD BENZODIAZEPINE TO HALOPERIDOL

MECHANISM

TREATMENT

55

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

56

TREATMENT

OPIOID DOSE REDUCTION WITH ADDITION OF

AN ADJUVANT ANALGESIC

OPIOID ROTATION

NMDA RECEPTOR ANTAGONIST (KETAMINE)

OPIOID-INDUCED HYPERALGESIA

TREATMENT

57

TOLERANCE TO OPIOIDS

58

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

59

PHARMACODYNAMIC

GENETICALLY DETERMINED

SPINAL (NMDA RECEPTOR ACTIVATION)

SUPRASPINAL (RVM FACILITATION)

? TOLERANCE IS A MILD FORM OF OPIOID

HYPERALGESIA BALANCED BY ANALGESIA

MECHANISM

60

DOSE ESCALATION AND TIME DEPENDENT

REDUCTIONS IN THERAPEUTIC INDEX ARE

REVERSED BY

CHANGE IN ROUTE

CHANGE IN DRUG

TOLERANCE

61

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

62

E50

Response Toxicity

Dose

63

ResponseToxicity

E50

Dose

64

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

65

OPIOID INSENSITIVITY

BLADDER AND RECTAL TENESMUS

CUTANEOUS PAIN

DELERIUM

DEPRESSION

SOMATIZED EXISTENTIAL PAIN

66

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

67

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

68

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

69

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

70

CASES

71

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

72

CASE 1

FLUMAZENIL TO REVERSE THE BENZODIAZEPINE

METHYLPHENIDATE

NALOXONE 40MCG EVERY 3 MINUTES TO RR > 10

NALOXONE INFUSION

73

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

74

CASE HISTORY 2

PHYSICAL EXAMINATION

ALLODYNIA WHICH IS IN BOTH LOWER EXTREMITIES

NO NEW FINDINGS

MRI (WITHOUT CONTRAST)

BONE METASTASES

NO CORD COMPRESSION

75

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

76

QUESTIONS