2. Cancer and Neuropathic Pain Mike Bennett Professor of Palliative Medicine Lancaster University

3. Case history 52 year old man Six month history of colon cancer Recent progression on chemotherapy – liver and lung metastases

4. Case history Presents to your clinic with mass in left chest wall – constant aching pains in chest occasional paroxysmal pain radiating around chest – dysaesthesias over left chest wall – non-tender mass but dynamic mechanical allodynia in T7-8 dermatomes

7. Hb = 9.4 WCC = 4 (1.2 neut) Plat = 117 Barthel score = 72 / 100 Pain helped initially by codeine, but pain now more intense

8. TASK What is your pain diagnosis? – any other information needed What other investigations or assessments would you request? What is your management plan? What is your main outcome measure of success?

9. Neuropathic pain Definitions Neuropathic pain – Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system – = abnormal activation of pain pathways Nociceptive pain – inflammatory pain – normal activation of pain pathways.

10. Neuropathic pain Key features Symptoms – Spontaneous pains (pain without stimulation) Continuous = dysaethesias; burning, tingling Paroxysmal = shooting, electric shocks – Evoked pains ‘hypersensitive skin’; can’t bear to be touched

11. Neuropathic pain Key features Signs – Abnormal response to stimulation Allodynia = pain after non-noxious stimulus Hyperalgesia = exaggerated pain after noxious stimulus Hyperpathia = temporal and spatial abnormalities – Loss of sensation – Autonomic changes Mottled, flushed, sweating

12. Mechanisms Peripheral – nociceptor sensitization – abnormal axonal responses Central – disinhibition – hyperexcitability

13. Neuropathic pain in cancer - the issues Epidemiology Assessment – is it different to NeuP in non-cancer patients? – how to recognise it – patient related factors Management principles

14. Epidemiology Neuropathic pain probably affects 40% of patients with cancer pain – vast majority have mixed mechanism pain …and is associated with greater pain intensity Caraceni and Portenoy Pain 1999 Grond et al Pain 1999

15. Epidemiology Compared with nociceptive pain: – less pain relief with single doses of opioids – more likely to escalate opioid doses – likely to have poorer outcome with treatment – ….even spinal analgesia is less effective Cherny et al Neurology 1994 Vigano et al Cancer 1998 Mercadante et al 2000 Supp Care Cancer Becker et al 2000 Stereo Funct Neurosurg

16. Epidemiology Aetiology – direct effects of cancer – indirect effects of cancer – cancer treatment – co-morbid conditions

17. Assessment Clinically – pains are often mixed, evolving quickly Pathologically – similar peripheral and spinal mechanisms as in non-cancer patients Pharmacologically – frail patients; cognitive, hepatic and renal impairment Psychologically – preparing for prognosis of weeks to months

18. Assessment Patterns of pain are varied – slowly evolving over weeks – acute on chronic exacerbation over days – sudden onset Screen for cognitive, hepatic and renal impairment

19. Assessment Are neuropathic mechanisms present? – Pain in an area of altered sensation Glynn Pall Med 1989 – Positive and negative phenomena Ochoa 1987 – LANSS Pain Scale Bennett Pain 2001 – S-LANSS (self report LANSS) Bennett et al J Pain 2005

20. Diagnosis is clinically based Screening tools exist – LANSS pain scale 7 item tool – 5 questions, 2 examination items Validated – worldwide – in variety of chronic pain states

21. Assessment Current screening tools Content – short lists of classic descriptors or symptoms – some have brief clinical examination Usually physician administered – but several patient self-report versions Easy to complete – total score suggests presence or absence of neuropathic pain mechanisms

22. Assessment Current screening tools LANSS and S-LANSS – Bennett, Pain 2001 – Bennett et al, J Pain 2005 Neuropathic Pain Questionnaire (NPQ) – Krause, Backonja, Clin J Pain 2003 DN4 – Bouhassira et al, Pain 2005 ID Pain – Portenoy, Curr Med Res Opin 2006 PainDetect – Freynhagen et al, Curr Med Res Opin 2006

23. Common Features of Screening Tools LANSSNPQDN4Pain 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* – * ––

24. Clinician Certainty Ratings of Presence of Neuropathic Pain 0 10 20 0 102030405060708090 100 Clinician VAS Score SD = 35.6 Mean = 48.9 N = 200 Bennett et al. Pain. 2006;122:289-94.

25. Certainty of clinician ratings, S-LANSS score, and composite NPS score (median, IQR) “Unlikely NeuP” (n = 67) “Possible NeuP” (n = 67) “Definite NeuP” (n = 66) P value* Clinician rating 7 (3,13) 50 (32, 65) 88 (84, 94) < 0.001 S-LANSS3 (0, 8) 13 (6, 20) 19 (12, 23) < 0.001 NPS41 (32, 54) 53 (40, 65) 57 (48, 69) < 0.001

26. Assessment Neuropathic pain mechanisms / symptoms exist as a spectrum More useful concept (esp in cancer pain) – ‘Pain of predominantly neuropathic origin’

27. Management Diagnose pain Use multimodal approach Conventional drugs and routes help but alternatives are often necessary – this means opioids plus co-analgesics

28. Management Neuropathic pain and cancer The difference is in the patient not the pain – more frail – changing pain picture – additional renal, hepatic or cognitive impairment Toxicity may be reached before benefit – NNT may be higher – NNH may be lower

29. Management 593 cancer pain patients treated with WHO guidelines (opioids +/- co-analgesia) – 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

30. Management NNT and evidence based ladders Note that ‘50% pain relief’ can mean: – 50% reduction in VAS where measured – ‘excellent or good’ relief – but also ‘moderate’ relief Confidence intervals of NNTs important too – SSRIs 6.7 (3.4 - 435) Don’t forget NNH

32. BMJ 15 August 2009, Volume 339

34. Management NNT and evidence based ladders WHO ladder – morphine 2.5 – oxycodone 2.6 Tricyclics – amitriptyline group 2.0, NNH 3.7 Antiepileptics – gabapentin NNT 3.5, NNH 2.5 – or carbamazepine better? (NNT 2.3, NNH 3.7)

35. A pragmatic approach A. Initial steps 3. GABAPENTIN [add in or replace] 2. AMITRIPTYLINE [add in or replace] 1. WHO LADDER

36. A pragmatic approach B. Advanced steps ‘The unlit loft at the top of the ladder’ 6. METHADONE [or other opioid switch] 5. ANAESTHETIC APPROACHES 4. KETAMINE [with opioid]

37. Treatment What you can do……. – WHO ladder works for many patients no opioid is superior to another, just different – Add in co-analgesics Antidepressants = amitriptyline, duloxetine Antiepileptics = gabapentin, pregabalin

38. When to contact palliative care – Opioid switching, esp methadone – Ketamine – Inpatient admission for clinical assessment by specialist team managing distress family support

39. When palliative care teams contact pain teams – intercostal blocks – paravertebral blocks – spinal opioid infusions

40. When pain teams contact neurosurgeons – Cordotomy

41. Summary Neuropathic mechanisms in cancer pain: – are common – often present as a spectrum with nociceptive mechanisms – are caused by cancer and its treatment – are sometimes accompanied by cognitive, hepatic and renal impairment – can usually be effectively treated with opioids and co- analgesics, but sometimes need specialist help

42. Thank you m.i.bennett@lancaster.ac.uk