Pain Management in the ESRD Patient

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Pain Management in the ESRD Patient
Richard Dart, MD Marshfield Clinic Marshfield, WI
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Pain Management
in the ESRD Patient

• Clinical Scenarios
• General Principles
• Factors affecting response to pain therapy
• Drug Selection
• Associated symptoms
• Barriers to successful therapy
• Conclusions

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General Principles

• Pathophysiology
• Pain types nociceptive, neuropathic
• Assessment
• Management

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General Principles

• Pain pathophysiology
• Acute pain
• identifiable event, resolves daysweeks
• usually nociceptive
• Chronic pain
• cause often not easily identified,
• multifactorial, indeterminate duration
• nociceptive and / or neuropathic

EPEC Module 4, 1999
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Nociceptive pain . . .

• Direct stimulation of intact nociceptors
• Transmission along normal nerves
• Sharp, aching, throbbing
• somatic
• easy to describe, localize
• visceral
• difficult to describe, localize
• Tissue injury apparent
• Management
• opioids adjuvant / coanalgesics

EPEC Module 4, 1999
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Neuropathic pain . . .

• Disordered peripheral or central nerves
• Compression, transection, infiltration, ischemia,
  metabolic injury
• Varied types
• peripheral, deafferentation, complex regional
  syndromes
• Pain may exceed observable injury
• Described as burning, tingling, shooting,
  stabbing, electrical
• Management
• opioids adjuvant / coanalgesics often required

EPEC Module 4, 1999
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General Principles

• Pain assessment
• Character burning, steady, aching, etc.
• Location
• Relief
• Aggrevation
• Intensity
• Numeric scale (1 - 10 least - worst)
• Descriptive scale (Moderate, bad, worst)

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General Principles contd

• Learn a basic few drugs in each category
• Learn weaknesses, limitations and best
  situations to apply
• Become familiar and comfortable in use
• Learn starting doses and how to re-assess pt.
• Adjust and / or change therapy as needs dictate

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Factors affecting response to pain therapy

• Opioid pharmacology
• Route of administration
• GI
• Gut
• Hepatic
• Renal
• Volume
• Plasma binding

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
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Factors

• Route of administration
• IV
• Rapid onset of action
• Subcutaneous, IM
• Oral

Modified EPEC Module 4, 1999
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Opioid pharmacology

• Cmax after
• po ? 1 h
• SC, IM ? 30 min
• IV ? 6 min
• half-life at steady state
• po / pr / SC / IM / IV ? 3-4 h

EPEC Module 4, 1999
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IV
SC / IM
Cmax
po / pr
Plasma Concentration
0
Time
Half-life (t1/2)
EPEC Module 4, 1999
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• Drug Selection

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Factors

• GI
• Symptoms common
• Gut function - little info
• Gastric alkalization
• Histamine H2 block
• Decr. small bowel absorption

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
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Factors contd

• Hepatic effects
• Altered first pass metabolism in uremia
• Dec. biotransformation -- inc. circulating
  active drug-- bio-availablity
• Impaired plasma protein binding inc. free drug
  -- more removal during hepatic first pass
• Interactions of absorption and first pass complex

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
16
Factors

• Renal failure
• Substantially effects biotransformation
• Slowed reduction and hydrolysis reactions
• Glucuronidation, sulfated conjugation and
  microsomal oxidation -- unaffected
• Active and toxic drug metabolites retained.
• High incidence ADR

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
17
Factors contd

• Volume of distribution
• Protein binding
• Albumin or glycoprot. reversible
• Effects vol of dist.
• Effects quantity of free drug available
• Effects degree of excretion by kidney or liver
• Water vs lipid solubility

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
18
Factors contd

• Edema and ascites inc. apparent VOD (often low
  plasma levels).
• Dehydration, muscle wasting dec. apparent vol of
  distributionwater soluble drugs (High plasma
  conc. of drugs).
• Drug an organic acid vs organic base effects drug
  binding acid--single, base--multiple binding
  sites

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
19
Factors contd

• Drugs of organic acid dec. binding in uremia,
  organic bases, less effected.
• Reduced plasma protein binding attributed to
• Dec. serum albumin
• Reduction in albumin affinity for drug.
• ? Uremia-induced structural orientation of
  albumin molecule or endogenous inhibitors that
  compete for binding sites

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
20
Factors contd

• Predicting clinical consequences of altered
  protein binding in uremia is difficult
• Decreased binding more free drug
• Volume of distribution may be increased--reducing
  plasma concentrations
• Because more unbound drug available for
  metabolism, half-life may be decreased.

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
21
WHO 3-stepLadder
3 severe
Morphine Hydromorphone Methadone Levorphanol Fenta
nyl Oxycodone Adjuvants
2 moderate
A/Codeine A/Hydrocodone A/Oxycodone A/Dihydrocodei
ne Tramadol Adjuvants
1 mild
ASA Acetaminophen NSAIDs Adjuvants
EPEC Module 4, 1999
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Adjuvant analgesics

• Adjuvants refers either to medications that
  are coadministered to manage an adverse effect of
  an opioid, or to so-called adjuvant analgesics
  that are added to enhance analgesia

EPEC Module 4, 1999
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Acetaminophen

• Step 1 analgesic, co-analgesic
• Site, mechanism of action unknown
• minimal anti-inflammatory effect
• Hepatic toxicity if 4 g / 24 hours
• increased risk
• hepatic disease, heavy alcohol use

EPEC Module 4, 1999
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NSAIDs . . .

• Step 1 analgesic, coanalgesic
• Inhibit cyclo-oxygenase (COX)
• vary in COX-2 selectivity
• All have analgesic ceiling effects
• effective for bone, inflammatory pain
• individual variation, serial trials

EPEC Module 4, 1999
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. . . NSAIDs

• Highest incidence of adverse events
• Gastropathy
• gastric cytoprotection
• COX-2 selective inhibitors

EPEC Module 4, 1999
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NSAID adverse effects

• Renal insufficiency
• maintain adequate hydration
• COX-2 selective inhibitors
• Inhibition of platelet aggregation
• assess for coagulopathy

EPEC Module 4, 1999
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Sedatives, Hypnotics and
Narcotics A
selective review

• Highly selected examples for the various groups
• Focus on the more commonly used drugs in these
  classes
• Examine the potential for toxicity
• Modifications of dosage in ESRD on dialysis,
  where applicable

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Sedatives, Hypnotics (Benzodiazepines)

• Very commonly used, familiarity
• Low side-effects, safe, generally
• Effective

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
29
Sedatives, Hypnotics (Benzodiazepines)

• Many, many forms available
• Alprazolam - Xanax Triazolam - Halcion
• Clonazepan - Klonopin Clorazepate - Tranxene
• Diazepam - Valium Estazolam - ProSom
• Flurazepam - Dalmane Lorazepam - Ativan
• Midazolam - Versed Oxazepam - Serax
• Quazepam - Doral Temazepam - Restoril
• Chlordiazepoxide - Limbitrol

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
30
Sedatives, Hypnotics (Benzodiazepines)

• Features common to this class of drugs
• Most require no dose change over entire spectrum
  of renal function
• Exceptions Chlordiazepoxide (Limibitrol) and
  Midazolam (Versed) at least 50 with ESRD
  patients.
• Half-life is highly variable, some very prolonged
• Choice should be based on desired therapeutic
  effect while limiting over-sedation

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
31
Sedatives, Hypnotics (Benzodiazepines)

• Supplementation for dialysis is highly variable
  and in most instances either no data exists or no
  supplements are needed

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
32
Narcotics and Narcotic Antagonists

• Narcotic agents commonly used
• Codeine (multiple forms and combinations)
• Fentanyl - Duragesic (patch, SQ, IV and buccal)
• Hydromorphone - Dilaudid (SQ, IV, and PO)
• Morphine Sulphate (SQ, IV, and PO)
• Meperidine - Demerol
• Methadone - Dolophine
• Propoxyphene - Darvon
• Antagonists
• Naloxone - Narcan

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
33
Narcotics and Narcotic Antagonists

• Class characteristics
• Most drugs require dose reduction
• (GFR 10-50) usually give 75 of standard dose.
  
• (GFR
• Titrate carefully to patients needs and monitor
  for toxicity (particularly true for MS and HM,
  due to dec. clearance and accumulation of
  metabolites)
• Nausea / delirium
• Respiratory depression
• Myoclonic jerkiness

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
34
Narcotics and NarcoticAntagonists

• Some of these drugs are best NOT used
• Meperidine - Demerol Propoxyphene - Darvon
  both have toxic metabolites that accumulate in
  ESRD patients.
• Antagonists
• Naloxone - Narcan
• Safe, can be used at standard dose over entire
  range of renal function.
• Can induce symptoms of narcotics if excessive
  dose given

Aronoff, et al., Drug Prescribing in Renal
Failure, 4th Edition 1999
35
Routine oral dosingimmediate-release preparations

• Codeine, hydrocodone, morphine, hydromorphone,
  oxycodone
• dose q 4 h
• adjust dose daily
• mild / moderate pain ? 2550
• severe / uncontrolled pain ? 50100
• adjust more quickly for severe uncontrolled pain

EPEC Module 4, 1999
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Routine oral dosingextended-release preparations

• Improve compliance, adherence
• Dose q 8, 12, or 24 h (product specific)
• dont crush or chew tablets
• may flush time-release granules down feeding
  tubes (Kadian)
• Adjust dose q 24 days (once steady state reached)

EPEC Module 4, 1999
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Routine oral dosinglong-half-life opioids

• Dose interval for methadone is variable (q 6 h or
  q 8 h usually adequate)
• Adjust methadone dose q 47 days

EPEC Module 4, 1999
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Changing routesof administration

• Equianalgesic table
• guide to initial dose selection
• Significant first-pass metabolism of po / pr
  doses
• codeine, hydromorphone, morphine
• po / pr to SC, IV, IM
• 23 1

EPEC Module 4, 1999
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Equianalgesic Doses - Opioid Analgesics
(Selective Commonly used)
Modified from EPEC Module 4, 1999 Aronoff, et
al.
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Opioid adverse effects

• Common Uncommon
• Constipation Bad dreams / hallucinations
• Dry mouth Dysphoria / delirium
• Nausea / vomiting Myoclonus / seizures
• Sedation Pruritus / urticaria
• Sweats Respiratory depression
• Urinary retention

EPEC Module 4, 1999
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Constipation . . .

• Common to all opioids
• Opioid effects on CNS, spinal cord, myenteric
  plexus of gut
• Easier to prevent than treat
• Prokinetic agent
• metoclopramide, cisapride
• Osmotic laxative
• MOM, lactulose, sorbitol, Miralax, Golytely
• Other measures

EPEC Module 4, 1999
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. . . Constipation

• Diet usually insufficient
• Bulk forming agents not recommended
• Stimulant laxative
• senna, bisacodyl, glycerine, casanthranol, etc
• Combine with a stool softener
• senna docusate sodium

EPEC Module 4, 1999
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Barriers . . .

• Not important
• Poor assessment
• Lack of knowledge
• Fear of
• addiction
• tolerance
• adverse effects

EPEC Module 4, 1999
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. . . Barriers

• Regulatory oversight
• Patients unwilling to report pain
• Patients unwilling to take medicine

EPEC Module 4, 1999
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Pain Management in ESRD Patients
Conclusions

• Treat pain AND associated symptoms
• Start low and progress as re-assessment dictates
• Toxic side-effects common, (elderly and those
  with marked decrease in GFR / ESRD )
• Drug versus uremic signs / symptoms often
  difficult to separate out
• If ???, err on the side of changing drug therapy
  as a trial
• If death anticipated in less than a week morphine
  may be a good choice for pain management