1. Neuropathic pain in cancer patients
Mike Bennett
St Gemma’s Professor of Palliative Medicine
University of Leeds, UK

2. What causes neuropathic pain in cancer patients?

3. Definitions Nociceptive or inflammatory pain Neuropathic 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

4. Mechanisms ‘New’ types of cancer related neuropathic pain:
‘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

5. In developed countries, increasingly larger proportion of older people

6. 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

7. 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%)

8. Neuropathic cancer pain (n=113)
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

9. How common is it?

10. 22 studies, 13,600 patients
Pain type diagnosed by clinical judgement
Estimated ‘conservative’ and ‘liberal’ prevalence

11. 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%)

12. Take 5 cancer patients….. 1
Noci
Neuro 2 3 4
Noci 5

13. 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

14. 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

15. What are the assessment challenges?

19. 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

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

22. 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

23. 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; 127:

24. 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

25. How good is current assessment in cancer pain?

26. 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

27. 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)

29. 7 studies used confirmatory testing
4 studies = definite NP
3 = probable NP

30. 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

31. Screening tool performance in 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

32. 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

33. 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 3+4 (abnormal function and structure), bedside testing for numbness, allodynia; MRI / CT

34. Why identify neuropathic cancer pain?

35. 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

36. But how strong is the evidence to support identification?.... ….let’s vote

37. 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?

38. Finnerup et al, Pain 2005

39. BMJ 2009; 339:

40. 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 ( )
Morphine
15-300
2.5 ( )
Tramadol
9 ( )
3.9 / 4.8 ( )
Methadone 15
N/A

43. 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

44. 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

45. Making better use of combinations

46. Main findings Addition of adjuvant: Opioids alone are effective
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

47. But…. 3 studies reported: 5 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

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

53. 24 patients already on opioids (16 taking antidepressants)
Maximum daily doses of gabapentin:
400mg = 11pts
600mg = 8pts
800mg = 3pts
900mg = 1pt
1200mg = 1pt

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

58. Summary Population characteristics Assessment challenges
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

59. Thank you