Complex Pain

1
Complex Pain

• S. Lawrence Librach MD,CCFP,FCFP
• Head, Division of Palliative Care, Dept. Of
  Family Community Medicine W, Gifford-Jones
  Professor of Pain Control Palliative Care,
  University of Toronto
• Director, Temmy Latner Centre for Palliative Care

2
Objectives

• Why discuss concepts of complex pain?
• Concepts of complex pain?
• Mechanism based pain
• Pharmacogenetics
• Other pharmacokinetic pharmacodynamic issues
• Discuss opioid induced hyperalgesia
• Discuss psychosocial influences on pain

3

• What is pain?
• Why talk about complex pain?

4
Cancer pain mechanisms
5

• Pain is a complex biopsychosocial event
• Genetic factors involved
• Interactions between tumors nerves that are
  complex whose clinical relevance has yet to be
  delineated
• Humans vs. rats!
• Things are not as simple as we make them out to
  be
• Tend to think of causes of cancer pain but not
  the basic mechanisms that underlie them

6
Mechanisms of cancer pain

• Clinical questions do arise though when one
  considers the mechanisms of cancer pain
• Why are only 25 of bone mets painful?
• Why do patients with similar disease present with
  very different pain?
• Why doesnt every patient respond to opioids?

7
Symptoms, signs, mechanisms

• These may be related but not directly
• In many cases, there may be several mechanisms
  operating
• Therefore cannot predict symptoms
• Not possible to classify pain on basis of
  symptoms or location alone

8
Physical

• Invasion of tissues
• Expansion of tissues
• Pressure on nerves
• Expansion of capsules
• Mechanical changes
• Pathological fractures
• Acute pain

9
(No Transcript)
10
(No Transcript)
11
Paracrine interactions-prostanoids

• Prostaglandins related compounds such as
  thromboxane
• Products of cyclo-oxygenase metabolism of
  arachidonic acid
• Produced by the body (inflammation) also by
  tumours

12
Paracrine interactions-nerve growth factor
cytokines

• NGF
• Can be directly secreted by tumours
• Implicated in nociception
• CYTOKINES
• TNF, interleukins, transforming growth factor,
  GM-CSF
• Affect excitability of neurons

13
Paracrine interactions

• ENDOTHELIN-1
• Experimental evidence that can cause acute pain
• Produced by tumours
• OTHER MEDIATORS
• Quite a number of substances released by tumours
  at sites of inflammation are algogens

14
Neuropathic pain

• Multiple mechanisms
• Paracrine influences
• Neuron excitability
• Neuron damage
• Spinal DRG receptors

15
Mechanisms of bone pain
16
Pathophysiology of bone metastases bone pain

• Hematogenous spread most common
• Mechanism is not fully understood seems to be
  quite complex
• Chemotactic attraction to bone matrixstimulation
  of tumour growth by bone matrixrelease of
  paracrine factors to ? osteoclast activity

17
Protons

• Both the intracellular extracellular pH of
  solid tumours are lower than that of surrounding
  normal tissues
• Osteolysis is acidic
• Sensory neurons can be directly excited by
  protons or acid express different acid-sensing
  ion channels (vanilloid receptors VR1) which are
  sensitized excited by a decrease in pH

18
Nerve damage

• Rapid tumour growth frequently entraps injures
  nerves, however, causing mechanical injury,
  compression, ischaemia or direct proteolysis
• Proteolytic enzymes that are produced by the
  tumour cells can also cause injury to sensory
  sympathetic fibres, causing neuropathic pain

19
Nerve damage

• Capacity of tumour cells to injure destroy
  peripheral nerve fibres has been directly
  observed in an experimental model of bone cancer
• As tumour cells grow in the marrow space which is
  also innervated by sensory fibres, first compress
  then destroy both the haematopoietic cells that
  normally comprise the marrow the sensory fibres
  that normally innervate the marrow mineralized
  bone

20
Case-Janine

• 44 yr old woman with leukemia
• Recurrent after BMT
• Pain in both legs
• Described as burning, tender with sharp pains at
  times not necessarily related to movement
• Not responsive to opioids
• Responds to desipramine

21
Mechanism based pain classification
22
Mechanisms of cancer pain

• More commonalities between nociceptive pain
  neuropathic pain than we first understood

23
Classification of pain

• Changing concepts
• Term nociceptive may be meaningless since means
  painful pain
• More attention being paid to mechanism based pain

24
Backonja Anesth Analg 2003
25
Implications for practice

• Rigid definition of pain class may exclude the
  use of appropriate adjuvants
• Inflammatory nature of cancer pain must be
  considered but NSAIDs only one possibility

26
Pain assessment tools
27

• Can we measure pain accurately?
• How good are scales?

28
Pain assessment scales

• Mounting evidence that assessment scales
  especially single verbal or visual analog scales
  are quite problematic

29
Single dimension self report category scales

• Use descriptors patients choose the best word
• Mild, discomforting, distressing, horrible
  excruciating
• Faces scale
• Choose a picture
• Limitations as far as language, education, range
  expressed, tendency for the middle

30
Multi-Dimensional Self Report

• May be given in different languages
• Do assess the sickness effect
• May be too long for severely ill patients to
  complete
• Cultural issues may interfere

31
Limitations in pain measurement

• Pain is multidimensional
• No clear objective measures
• Intrinsic problem of measuring subjective states
• What is a clinically meaningful reduction in pain?

32
opioids
33
Pharmacology of opioids

• Hallmark of the clinical treatment of pain
  remains individualization of therapy
• Wide variability in responses of patients to
  opioids
• Patients vary in terms of their sensitivity to a
  specific drug, with some needing higher, others
  lower, doses to achieve optimal effects.

34
Pharmacology of opioids

• Patients often report that one opioid works
  whereas another does not
• Drug that is best for one patient may not best
  for another
• Patients often switched from one opioid to
  another to identify most effective drug

35
Pharmacology of opioids

• Cross-tolerance among opioids is incomplete
  conversion from one opioid to another may be
  difficult
• Part of the difficulty arises from the
  limitations inherent in equianalgesic table
• Source of table
• Most useful in opioid naive

36
What is the equivalence of morphine to
hydromorphone?

• In Canada? 51
• In USA? 71
• In UK ? 31
• Who is right?

37
Pharmacology of opioids

• When switching tolerant patient from one drug to
  another, equianalgesic ratio may be incorrect
• Not uncommon to calculate equianalgesic dose
  based upon naive drug tables then cut
  calculated dosage by gt50
• Contributes to conclusion that the µ opioid
  analgesics differ from one another

38
µ opioid receptors

• Almost all opioid analgesics widely used
  clinically selectively label µ receptors,
  although there are several that interact with ?
  receptors
• Selectivity of analgesics for µ receptors not
  easily reconciled with their clinical pharmacology

39
µ opioid receptors

• Multiple splice variants of the µ opioid receptor
  identified
• Need to correlate these individual µ variants to
  specific functions
• Presence of splice variants provides a basic
  understanding for variable sensitivity of
  patients opioids possibly incomplete cross
  tolerance effectiveness of opioid rotation
• Genetically determined

40
Pharmacogenetics

• Describes genetically determined variability in
  the metabolism of drugs
• These variations might lead to ADR, toxicity or
  therapeutic failure of pharmacotherapy
• Genetically determined

41
Pharmacogenetics

• Number of identified polymorphisms in genes
  encoding drug metabolising enzymes, drug
  transporters receptors is rapidly increasing
• These genetic factors have major impact on
  pharmacokinetics pharmacodynamics of a
  particular drug, especially in case of a narrow
  therapeutic index

42
Implications for practice

• Individuals differ in their pharmacokinetics
  pharmacodynamics of analgesics
• No best drug
• Not able to predict ahead of time
• Individualization of dosage is important close
  monitoring is very important

43
Implications for practice

• Issues of tolerance need to be considered more
  often
• Accounting for cross tolerance is important in
  managing these patients
• Methadone may be the most effective drug to
  rotate to

44
Implications for practice

• Certain drugs like codeine tramadol may be less
  effective because of lack of enzymes to
  metabolize them to active drugs-genetically
  determined

45
Case-Jane

• 52 yr old with metastatic breast cancer to bone,
  liver lung
• Significant bone and liver pain
• Disease stable but morphine requirements
  increasing
• Gets 5-7 days better pain control from each
  increase but then needs more
• On a total of 800mg of morphine daily

46
Case-Jane

• Switch to methadone with complete and sustained
  pain relief from 5mg q12h

47
Opioid induced hyperalgesia

• Decline in analgesic efficacy has traditionally
  been thought to result from development of
  pharmacological tolerance or disease progression,
  best overcome by dose escalation

48
Opioid induced hyperalgesia

• But, opioids can also activate a pro-nociceptive
  mechanism resulting in heightened pain
  sensitivity or opioid-induced hyperalgesia (OIH)
• This paradoxical opioid-induced pain sensitivity
  may contribute to reduced opioid analgesic
  efficacy

49
Opioid induced hyperalgesia

• OIH mediated through distinct cellular
  mechanisms, including endogenous dynorphin,
  glutamatergic system, descending facilitation

50
Opioid induced hyperalgesia

• Cellular mechanisms of OIH have much in common
  with those of neuropathic pain opioid tolerance
• e.g. both peripheral nerve injury and repeated
  opioid administration can activate a similar
  cellular pathway involving activation of the
  central glutamatergic system

51
Opioid induced hyperalgesia

• Empirical observation has long suggested that
  pain sensitivity ? in individuals with opioid
  addiction
• Addicts on methadone maintenance reported higher
  pain sensitivity compared to demographically
  matched opioid addicts who were not taking
  methadone

52
Clinical implications of OIH

• Diminished opioid analgesic efficacy during the
  course of opioid therapy has long been considered
  a sign of pharmacological opioid tolerance or of
  worsening of existing pain state
• Thus, opioid dose escalation has been a logical
  approach to restoring effectiveness of opioids

53
Clinical implications of OIH
54
OIH vs pre-existing pain

• OIH may differ from pre-existing
• pain in its quality, location, and distribution
  pattern
• Hallmark of pathological pain in hyperalgesia in
  a dermatomal or generalized distribution

55
OIH vs pre-existing pain

• Quantitative sensory testing may reveal
  abnormalities in the threshold, tolerability
  distribution patterns of pain
• Difference between neuropathic pain OIH might be
  that for many neuropathic pain conditions
  hyperalgesia arises in a distinct anatomical
  distribution, whereas OIH could be generalized in
  its distribution

56
OIH vs pre-existing pain

• This type of testing is in its infancy, but it
  may eventually reveal whether OIH is a completely
  separate phenomenon or can worsen existing
  neuropathic pain

57
OIH vs pre-existing pain

• OIH may intensify with opioid dose escalation but
  improve after supervised opioid tapering
• In contrast, under-treatment of pre-existing pain
  pharmacological opioid tolerance may be
  overcome by trial of opioid dose escalation

58
OIH vs pre-existing pain

• Opioid regimens may influence the development of
  OIH
• Morphinegtmethadone
• OIH more likely to develop in patients receiving
  high opioid doses with a prolonged treatment
  course, although it has also arisen in patients
  receiving short course of highly potent opioids

59
OIH summary

• Increasing opioid dose may not always be the
  answer to ineffective opioid therapy
• Under certain circumstances a smaller amount of
  opioid may lead to more effective pain reduction

60
Case-Jeremy

• Jeremy is a 67 yr old man with metastatic hormone
  refractory prostate cancer
• Multiple mets to spine especially in lumbar area
• Sudden collapse of L3 necessitating hospital
  admission

61
Case-Jeremy

• Previously on hydromorphone SR 18mg q12h with
  good pain control
• In hospital started on IV hydromorphone at 1 mg /
  hr and very quickly dose was increased over 10
  day period to 20mg/hr with unrelieved
  excruciating pain

62
Case-Jeremy

• Pain all over as well as severe back pain
• skin feels like something is crawling under it
• Diagnosis of OIH vs. tolerance
• IV HM reduced slowly with no change in pain
• Methadone 25mg q8h controlled his pain

63
Psychosocial complexities
64
How do emotions influence pain

• Influence through known unknown mechanisms
• affective pain system (which comprises the
  medial thalamus, amygdala, caudate nucleus,
  insula, cingulate gyrus, orbitofrontal cortex)
  has high opioid receptor concentrations

65
Other factors

• Previous experiences with pain
• Gender
• Genetic influences

66
Social issues

• Family dysfunction
• Economics
• Addiction

67
Addiction as a complexity

• More cases of drug abuse diversion in practice
  as more patients are treated with potent opioids
• Need for universal precautions as an issue of
  patient social safety

68
Universal Precautions

• Douglas L. Gourlay, Howard A. Heit, Abdulaziz
  Almahrezi, Universal Precautions in Pain
  Medicine A Rational Approach to the Treatment of
  Chronic Pain. PAIN MEDICINE 2005 6(2)107-112

69
Universal Precautions

• 1. Make a diagnosis with appropriate differential
• 2. Psychological assessment including risk of
  addictive disorder
• Informed consent

70
Universal Precautions

• 4. Treatment agreement
• 5. Pre- and post-intervention assessment of pain
  level function
• 6. Appropriate trial of opioid therapy
  /adjuvant medication

71
Universal Precautions

• 7. Reassessment of pain score and level of
  function
• 8. Regularly assess the Four As of pain
  medicine
• Routine assessment of analgesia, activity,
  adverse effects, aberrant behavior

72
Universal Precautions

• 9. Periodically review pain diagnosis co-morbid
  conditions, including addictive disorders
• 10. Documentation

73
Case Eric

• 48 yr old man with supraglottic cancer
• Needed tracheotomy because of airway obstruction
• Difficulty swallowing
• History of alcohol, cigarette and cocaine
  addiction in the past
• Severe pain

74
Case-Eric

• 1st opioid prescription stolen
• FP gives him 30 T3 but used all in one day-wife
  had a toothache she needed meds
• Assessed in clinic and contract re opioids
• Given 2nd prescription that should have lasted 2
  weeks but calls after 5 days that he has run out

75
Case Eric

• Refuses radiation cancels CT scan
• No show for appointment for psycho-oncology
  assessment
• Wife calling daily saying he is in terrible pain
• Tumour not operable
• He is dying so how do we manage his pain?

76
Implications for practice

• Effective pain management requires that
  psychosocial factors be elucidated addressed
• Addiction /or diversion of opioids is a problem
  in our population
• Need for universal precautions
• Risk management is everyones business

77
Summary

• Pain is always complex
• Managing pain needs to take this into
  consideration
• Responses to opioids may be governed by genetics
• OIH is an entity
• Addication is an issue even in palliative care

78

• larry.librach_at_utoronto.ca