Neuropathic pain in cancer patients

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Neuropathic pain in cancer patients

• Mike Bennett
• St Gemmas Professor of Palliative Medicine
• University of Leeds, UK

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What causes neuropathic pain in cancer patients?
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Definitions

• Nociceptive or inflammatory pain
• caused by normal activation of pain pathways
• Toothache, cuts, burns,
• Neuropathic pain
• pain caused by damage or destruction to the
  somatosensory system
• caused by abnormal activation of pain pathways
• Post-herpetic neuralgia, painful diabetic
  neuropathy

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Mechanisms

• Standard cancer neuropathic pain
• Direct invasion and damage
• Para-neoplastic neuropathies
• New types of cancer related neuropathic pain
• Post chemotherapy
• Axonal degeneration and demyelination
• Cancer Induced Bone Pain (CIBP)
• Unique state with inflammatory and neuropathic
  elements
• Deeper understanding of these needed from animal
  models

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• In developed countries, increasingly larger
  proportion of older people

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Aetiology

• In older people
• common co-morbidities causing neuropathic pain
  include
• diabetic neuropathy
• post stroke central pain
• radiculopathy from degenerative spinal disorders
• post-surgical scar pain

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• Neuropathic cancer pain prevalence and
  associated factors from the European Palliative
  Care Research Collaborative Computerised Symptom
  Assessment study (EPCRC-CSA).
• 1051 patients assessed in 17 European centres
• 670 had pain
• 113 had neuropathic pain (17)

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Neuropathic cancer pain (n113)

• Compared to nociceptive cancer pain....
• More oncological treatment
• More likely to be on opioids
• More likely to receive adjuvant analgesia
• Poorer QOL, reduced performance status
• No overall differences in pain intensity
• No difference in disease status or survival from
  interview
• Suggesting any differences were due to pain not
  disease extent
• Fainsinger et al 2010, Rayment et al 2011

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How common is it?
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• 22 studies, 13,600 patients
• Pain type diagnosed by clinical judgement
• Estimated conservative and liberal prevalence

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• Cancer patients have 2 distinct pains on average
• 20 of pains are neuropathic in origin
• 18.7 (95 CI 15.3 to 22.1) to 21.4 (15.2
  to 27.6)
• Up to 40 of cancer patients are affected by
  neuropathic pain
• 19 (9.4 to 28.4) to 39.1 (28.9 to 49.5)

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Take 5 cancer patients..
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Aetiology of pain in cancer patients
All cancer pain patients Neuropathic pain patients only
Direct effect of cancer 76 64
Cancer treatment 11 20
Indirect effects 5 4
Co-morbid conditions 8 12

• Grond et al, 1996
• Bennett et al 2012

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Terminology

• Neuropathic cancer pain?
• ....or neuropathic pain in a cancer patient?
• treatment neuropathies
• co-morbid conditions
• Need to be clear for epidemiological, clinical
  and research purposes

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What are the assessment challenges?
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Assessment

• Neuropathic pain mechanisms and symptoms exist as
  a spectrum
• especially in advanced cancer
• mix of inflammatory and neuropathic mechanisms
• More useful to ask yourself
• is this pain more or less neuropathic?
• does this patients have pain of predominantly
  neuropathic origin?
• POPNO

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IASP grading system for neuropathic pain Treede
et al 2008
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IASP grading system for neuropathic pain Treede
et al 2008

• History
• 1. pain in a neuro-anatomically plausible
  distribution
• 2. relevant lesion or disease
• Examination
• 3. abnormal function
• bedside examination numbness, allodynia
• 4. abnormal structure
• MRI or ENMG demonstrating site of the nerve
  lesion

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Clinical tools to help identify neuropathic pain

• Leeds Assessment of Neuropathic Symptoms and
  Signs (LANSS)
• Neuropathic Pain Questionnaire (NPQ)
• Douleur Neuropathique en 4 questions (DN4)
• painDETECT
• ID-Pain

1. Bennett MI et al. Pain 2007 127199-203
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Common Features of Screening Tools
LANSS NPQ DN4 Pain Detect ID Pain
Symptoms
Pricking, tingling, pins, and needles
Electric shocks or shooting
Hot or burning
Numbness
Pain evoked by light touching
Painful cold or freezing pain
Clinical examination
Brush allodynia
Raised soft touch threshold -
Raised pinprick threshold
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How good is current assessment in cancer pain?
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Prevalence systematic review

• 22 studies
• 10/22 neuroanatomical distribution
• 13/22 relevant lesion
• ...but only 9 had both
• 14/22 demonstrated neurological abnormality
• 7/22 demonstrated confirmatory diagnosis
• Only 8 studies met criteria for at least probable
  NP
• Bennett et al, Pain 2012

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Effect on prevalence estimates?

• Prevalence of cancer patients with neuropathic
  pain....
• All 22 studies 19 (pure) to 39.1 (mixed)
• 8 studies meeting IASP criteria 13.2 (pure) to
  35.8 (mixed)

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• 7 studies used confirmatory testing
• 4 studies definite NP
• 3 probable NP

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Summary of 31 studies (n 13,600 351)

• Met both history criteria
• Distribution plus lesion 18 / 31
• Met at least one examination criteria
• Abnormal function 20 / 31
• Abnormal structure 8 / 31
• Reached at least probable NP
• 15 of 31 studies

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Screening tool performancein neuropathic cancer
pain

• LANSS, DN4, painDETECT
• Much lower scores for definite NP compared to
  non-cancer populations
• Sensitivity 30-58 normally 75-85
• Mercadante et al 2009
• Paredes et al 2011
• Rayment et al 2011

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• Do screening tools perform poorly in cancer pain
  populations?
• item content is different?
• cut-off scores need to be adapted?
• ...is neuropathic cancer pain different to other
  types of NP?
• OR
• is clinical assessment not standardised and
  therefore inconsistent?
• what were the clinical diagnoses in these
  studies?
• ?cancer, chemotherapy induced neuropathy, other

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An approach to neuropathic pain assessment...

• S Site meets IASP criterion 1 (distribution),
  use of body map in practice
• O Onset meets IASP criterion 2 (relevant
  disease, treatment or co- morbid aetiology)
• N Neuropathic characteristics descriptors
  (screening tools, SF-McGill),
• I Impact severity, interference, mood,
  incident pain
• C Confirmatory testing meets criteria 34
  (abnormal function and structure), bedside
  testing for numbness, allodynia MRI / CT

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Why identify neuropathic cancer pain?
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Neuropathic pain.

• Worse quality of life compared to nociceptive
  pain
• Poorer physical, cognitive and social function
• Cancer and non-cancer populations
• More likely to be on opioids, at higher doses
• and greater use of adjuvants
• Poorer pain outcomes
• and longer to titrate analgesia
• Fainsinger et al 2010
• Rayment et al 2011

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But how strong is the evidence to support
identification?.....lets vote
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• Q1. Who believes that opioids are not very useful
  for NP?
• Q2. Who believes that neuropathic drugs are
  quite effective in NP?
• Q3. Who follows NICE guidance on prescribing for
  NP?

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Finnerup et al, Pain 2005
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BMJ 2009 339391-395
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Treatment recommendations for peripheral
neuropathic pain adapted from recent guidelines
and algorithms

Opioids Stage of treatment Dose range (mg/day) for maintenance Combined NNH for study withdrawal (range) Combined NNT for 50 pain relief (range)
Oxycodone 2nd or 3rd 10-120 Relative risk not significant 2.6 (1.9-4.1)
Morphine 2nd or 3rd 15-300 Relative risk not significant 2.5 (1.9-3.4)
Tramadol 2nd or 3rd 200-400 9 (6.0-17.5) 3.9 / 4.8 (2.6-26.9)
Methadone 2nd or 3rd 15 N/A N/A
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Neuropathic pain........

• Is probably driven by more diverse mechanisms
  than nociceptive pain
• and is therefore more difficult to treat
• But no drug is specific for neuropathic pain
• Opioids and adjuvants are generally
  indiscriminate in their analgesic activity
• Secret to better neuropathic pain management is
  combination treatment
• Using drugs with different mechanisms of action

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Management

• 593 cancer pain patients treated with WHO
  guidelines (opioids /- co-analgesia)
• 213 with neuropathic mechanisms
• NeuP no more intense than nociceptive group
• 96 had opioids
• 53 had adjuvants (sig more than nocicept group)
• VAS decreased from 70mm to 28mm
• Grond et al Pain 1999

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Making better use of combinations
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Main findings

• Addition of adjuvant
• Significant but modest benefit on pain within 8
  days
• Unlikely to be greater than 1 point difference on
  0-10 rating scale
• Increase in adverse events
• Strongest evidence supports gabapentin
• Opioids alone are effective

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But.

• 3 studies reported
• Reduced opioid /- adjuvant doses in combination
  arm
• Same or better pain control
• Fewer adverse events in combination arm
• 5 studies reported
• Fixed doses of opioids when adjuvant added
• Modest improvements in pain
• More adverse events in combination arm

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• Pain scores at end of each arm (5.7 at baseline)
• placebo 4.5
• gabapentin 4.2
• morphine 3.7
• M GP 3.1

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• 24 patients already on opioids (16 taking
  antidepressants)
• Maximum daily doses of gabapentin
• 400mg 11pts
• 600mg 8pts
• 800mg 3pts
• 900mg 1pt
• 1200mg 1pt

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DRUG Baseline End Mean change
Amitriptyline 7.8 3.2 4.6
Gapapentin 7.5 3.1 4.4
Pregabalin 7.8 2.5 5.3
Placebo 7.5 3.4 4.1
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Summary

• Population characteristics
• Older patients with evolving mixed pains,
• Co-morbidities and cancer treatments are
  important causes of neuropathic pain in cancer
  patients
• Assessment challenges
• Is this pain more or less neuropathic?
• Use standardised approach to assessment
• Why identify neuropathic cancer pain?
• Opioids work, but better outcomes when combined
  with adjuvants, skilfully prescribed

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• Thank you
• m.i.bennett_at_leeds.ac.uk