Neuropathic pain in cancer patients

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 • 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 • ‘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…..

13. Aetiology of pain in cancer patients *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; 127:199-203

24. Common Features of Screening Tools

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. 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 Screening tool performancein neuropathic cancer pain

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; 339:391-395

40. Treatment recommendations for peripheral neuropathic pain adapted from recent guidelines and algorithms

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: • 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: • 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