OPIOID TOXICITY

MELLAR DAVIS, WAEL LASHEEN, DECLAN WALSH

MANIFESTATIONS

 MILD SEDATION

 NAUSEA

 VOMITING

 CONSTIPATION / DRY MOUTH / URINE RETENTION

 VISUAL / TACTILE HALLUCINATIONS

2
MANIFESTATIONS

 CONFUSION / DELIRIUM / DIZZINESS

 HYPERALGESIA / TOLERANCE

 DRUG SEEKING BEHAVIOR

 IMPOTENCE, MENOPAUSAL SYMPTOMS

 PRURITUS

3
CNS OPIOID RECEPTORS

 STRIATAL MYOCLONUS

 LIMBIC/CINGULATE GYRUS HALLUCUCINATIONS

 PITUITARY ↓ LIBIDO / ↓ GONADOTROPIN

 NUCLEUS ACCUMBENS ADDICTION

 NUCLEUS TRACTUS SOLITARIUS N/V

4
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)

5
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)

6
OPIOID BOWEL SYNDROME

7
OPIOID BOWEL SYNDROME (OBS)
 HARD STOOL
 STRAINING AT STOOL
 INCOMPLETE EVACUATION
 BLOATING
 DISTENSION
 GASTROESOPHAGEAL REFLUX
 ANOREXIA
 EARLY SATIETY

8
COMPLICATIONS

 FECAL IMPACTION

 TENESMUS

 PARADOXICAL DIARRHEA

 PSEUDO-OBSTRUCTION

 OBSTRUCTION

9
COMPLICATIONS

 SECONDARY ANOREXIA

 REDUCED COMPLIANCE

 MALABSORPTION

 URINARY RETENTION

10
PRECIPITATING FACTORS
 DEHYDRATION
 GI METASTASES
 HYPERCALCEMIA
 LACK OF PRIVACY
 LACK OF BOWEL REGIMEN
 RECENT SURGERY OR BARIUM STUDIES
 SEDENTARY LIFESTYLE

11
PRECIPITATING FACTORS

 MEDICATION INTERACTION WITH:

 CALCIUM CHANNEL BLOCKERS

 SSRI, ANTICHOLINERGICS

 THALIDOMIDE

 TRICYCLIC ANTIDEPRESSANTS

 VINCA ALKALOIDS

12
13
PHYSIOLOGY CLINICAL
 BLOCKS  DECREASED BOWEL
LONGITUDINAL SOUNDS, EARLY
MUSCLE CONTRACTION SATIETY, BLOATING,
POOR DEFECATION
 INCREASES CIRCULAR
MUSCLE CONTRACTION  EARLY SATIETY, COLIC,
INCOMPLETE
 INHIBITS SECRETIONS
EVACUATION
AND INCREASES
ABSORPTION  DRY HARD STOOL

14
TREATMENT: NON-PHARMACOLOGIC

 INCREASE FLUIDS

 EXERCISE/AMBULATE

 PROMOTE REGULAR BOWEL HABIT

 ASSURE PRIVACY

15
BULK AGENTS

 NOT TARGET SPECIFIC

 PERISTALSIS REFLEX BLOCKED BY OPIOIDS

 DO NOT PREVENT ABSORPTION

 REQUIRES 200-300 ML OF EXTRA FLUID DAILY

 LIMITED TOLERABILITY

16
OSMOTIC LAXATIVES

SALTS - MAGNESIUM

 WORKS THROUGHOUT BOWEL

 BY OSMOSIS

 INTERFERES WITH MEDS AND NUTRIENTS

17
OSMOTIC LAXATIVES

CARBOHYDRATES - LACTULOSE, SORBITOL

 WORKS AND IS FERMENTED IN COLON

 BY OSMOSIS

 SWEET – MAY NOT BE TOLERATED AT REQUIRED

DOSE

18
OSMOTIC LAXATIVES
POLYETHYLENE GLYCOL – MIRALAX

 WORKS THROUGHOUT BOWEL

 BY OSMOSIS

 REQUIRES LARGE VOLUME

19
ANTHRAQUINONES: MECHANISM

DANTHRON/SENNA/CASCARA

 STIMULATES PERISTALSIS

 INHIBITS ATPASE NA+, K+

 SENNA: DEGRADED IN COLON TO AGLYCONE

20
ANTHRAQUINONES: LIMITATION

 LAXATIVE PROPERTIES LIMITED TO COLON

 MYENTERIC DAMAGES LONG TERM

 COLONIC MELANOSIS

 CRAMPS

21
DIPHENYLMETHANES

 BISACODYL

 PHENOLPHTHALEIN

22
CLEVELAND CLINIC PROTOCOL

 DOCUSATE 100MG THREE TIMES DAILY

 MILK OF MAGNESIA 30ML AS NEEDED

 BISACODYL 10MG SUPPOSITORY AS NEEDED

23
OPIOID ANTAGONIST

 POORLY ABSORBED OPIOID RECEPTOR

ANTAGONISTS

 PERIPHERALLY RESTRICTED OPIOID

(QUATERNARY) RECEPTOR ANTAGONISTS

24
NALOXONE

 2% BIOAVAILABLITY (FIRST PASS CLEARANCE)

 INITIAL DOSE 5 MG

 TITRATE TO 10-20% OF TOTAL DAILY OPIOID

 WATCH FOR WITHDRAWAL, UNCONTROLLED PAIN

25
METHYLNALTREXONE

 CANNOT BE DEMETHYLATED BY HUMANS

 LAXATION WITHIN HOURS

 ORAL ABSORPTION < 1%

 SINGLE PARENTERAL DOSES 0.35 – 0.45 MG/KG

26
 100
% LAXATION WITHIN 4 HOURS
DAY 1
DAY 3
80 DAY 5

60

40

20

0
1 5 12.5 20
METHYLNALTREXONE DOSE (MG)
27
METHYLNALTREXONE TOXICITY

 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

28
ALVIMOPAN

 LARGE MOLECULAR WEIGHT (461KDA)

 ZWITTERIONIC:POLARITY LIMITS CNS ACCESS

 LARGE SUBSTITUTED N GROUP INCREASES MU

RECEPTOR ANTAGONISM
NEARY, P. 2005

29
ALVIMOPAN IN OBS

 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

30
AVERAGE WEEKLY SBM FREQUENCY
Treatment Follow-up
SBM / week
(CI)

Week
LOCF
TREATMENT vs. PLACEBO (P < 0.01)

31
SUMMARY
 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

32
 NAUSEA & VOMITING
IMPOTENCE & AMENORRHEA
PRURITIS

33
NAUSEA & VOMITING: MECHANISM

 MEDULLARY CENTRAL PATTERN GENERATOR

 GASTRIC STASIS

 VESTIBULAR SENSITIVITY

34
NAUSEA & VOMITING: TREATMENT
 CYCLIZINE
 HALOPERIDOL
 ONDANSETRON
 DROPERIDOL
 METOCLOPRAMIDE
 METHYLNALTREXONE
 RISPERIDONE
 OPIOID ROTATION OR ROUTE CONVERSION

35
IMPOTENCE AND AMENORRHEA

MECHANISM
 HYPOGONADOTROPIN HYPOGONADISM

TREATMENT
 HORMONE REPLACEMENT

36
CUTANEOUS PRURITIS: MECHANISM

 HISTAMINE RELEASE FROM MAST CELLS

 DISINHIBITION OF ITCH SPECIFIC NEURONS

 CENTRAL SEROTONIN RELEASE

37
CUTANEOUS PRURITIS: TREATMENT

 ANTIHISTAMINE

 ONDANSETRON

 PROPOFOL

 OPIOID ROTATION

 PAROXETINE

 SWITCH TO HYDROMORPHONE

38
RESPIRATORY DEPRESSION

39
RESPIRATORY DEPRESSION

 OPIOIDS TREAT ACUTE AND CHRONIC PAIN

 S/E CAN BE LIFE THREATENING

 RESPIRATORY DEPRESSION

 CARDIAC ARRHYTHMIA (METHADONE)

 FREQUENCY OF SERIOUS RESPIRATORY EVENTS

POORLY STUDIED

40
RESPIRATORY DEPRESSION

 RESPIRATORY COMPLICATIONS ERRONEOUSLY

MISTAKEN FOR PROGRESSIVE DISEASE

 RESPIRATORY DEPRESSION 0.3-17% OF

POSTOPERATIVE PATIENTS

41
RESPIRATORY DEPRESSION

 BUPRENORPHINE
 PARTIAL MU AGONIST

 KAPPA PARTIAL AGONIST

 ORL-1 AGONIST

 RESPIRATORY DEPRESSION CEILING WITHOUT

ANALGESIC CEILING

 COPD, SLEEP APNEA, ELDERLY

42
TREATMENT
 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

43
RESPIRATORY FUNCTION DURING
PARENTERAL OPIOID TITRATION
 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)
ET-CO2 (mmHg)

First study day Last study day ESTFAN PM 2007

44
CONCLUSION
 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

45
MORPHINE INDUCED
NEUROTOXICITY

46
47
MECHANISMS OF M3G NEUROTOXICITY

 M3G LOW AFFINITY FOR OPIOID RECEPTOR

 PRESYNAPTIC RELEASE OF EXCITATORY

NEUROTRANSMITTERS
 NOCICEPTIN (ORL)
 CHOLECYSTOKINEN (CCICB)
 SUBSTANCE P
 GLUTAMATE

48
OPIOID NEUROTOXICITY

 NOT PARTICULAR TO MORPHINE

 HYDROMORPHONE 3 GLUCURONIDE TOXICITY 2.5

FOLD GREATER

 ALLODYNIA

 MYOCLONUS

 SEIZURES
Smith MT 2000
Wright AW 2001

49
3-GLUCURONIDE NEUROTOXICITY
RATIONALE FOR ROTATION TO
DISSIMILAR OPIOID

 METHADONE

 FENTANYL

50
MYOCLONUS:MECHANISM

 ANTIGLYCINERGIC EFFECT

 DOPAMINERGIC UPREGULATION

 PRESYNAPTIC RELEASE OF GLUTAMATE BY

NEUROACTIVE METABOLITES

51
MYOCLONUS:TREATMENT
 OPIOID DOSE REDUCTION / ROTATION
 CLONAZEPAM
 DIAZEPAM
 VALPROIC ACID
 BACLOFEN
 DANTROLENE
 PHENOBARBITAL
 GABAPENTIN

52
SEDATION
MECHANISM
MECHANISM
 INHIBITION OF CHOLINERGIC TRANSMISSIONS

TREATMENT
TREATMENT
 DEXTROAMPHETAMINES
 METHYLPHENIDATE
 DONEPEZIL
 OPIOID SWITCH
 ROUTE CONVERSION TO EPIDURAL OPIOID
53
DELIRIUM
MECHANISM
 INHIBITION OF CHOLINERGIC
TRANSMISSIONS
TREATMENT
 OPIOID DOSE REDUCTION
 ROUTE CONVERSION / OPIOID ROTATION
 HALOPERIDOL
 CHLORPROMAZINE
 ADD BENZODIAZEPINE TO HALOPERIDOL
54
OPIOID-INDUCED HYPERALGESIA
 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

55
OPIOID-INDUCED HYPERALGESIA

TREATMENT
TREATMENT

 OPIOID DOSE REDUCTION WITH ADDITION OF

AN ADJUVANT ANALGESIC

 OPIOID ROTATION

 NMDA RECEPTOR ANTAGONIST (KETAMINE)

56
TOLERANCE TO OPIOIDS

57
TOLERANCE

 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)

58
MECHANISM

 PHARMACODYNAMIC

 GENETICALLY DETERMINED

 SPINAL (NMDA RECEPTOR ACTIVATION)

 SUPRASPINAL (RVM FACILITATION)

 ? TOLERANCE IS A MILD FORM OF OPIOID

HYPERALGESIA BALANCED BY ANALGESIA

59
TOLERANCE

 DOSE ESCALATION AND TIME DEPENDENT

REDUCTIONS IN THERAPEUTIC INDEX ARE

REVERSED BY

 CHANGE IN ROUTE

 CHANGE IN DRUG

60
TOLERANCE

 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

61
 Response Toxicity

E50

Dose

62
 Response
Toxicity

E50

Dose

63
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

64
OPIOID INSENSITIVITY

 BLADDER AND RECTAL TENESMUS

 CUTANEOUS PAIN

 DELERIUM

 DEPRESSION

 SOMATIZED EXISTENTIAL PAIN

65
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

66
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
67
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

68
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

69
CASES

70
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

71
CASE 1

 FLUMAZENIL TO REVERSE THE BENZODIAZEPINE

 METHYLPHENIDATE

 NALOXONE 40MCG EVERY 3 MINUTES TO RR > 10

 NALOXONE INFUSION

72
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

73
CASE HISTORY 2

 PHYSICAL EXAMINATION
 ALLODYNIA WHICH IS IN BOTH LOWER EXTREMITIES

 NO NEW FINDINGS

 MRI (WITHOUT CONTRAST)

 BONE METASTASES

 NO CORD COMPRESSION

74
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

75
QUESTIONS

76