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

What causes neuropathic pain in cancer patients?

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

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

In developed countries, increasingly larger proportion of older people

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

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%)

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

How common is it?

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

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%)

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

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

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

What are the assessment challenges?

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

IASP grading system for neuropathic pain Treede et al 2008

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

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

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

How good is current assessment in cancer pain?

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

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)

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

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

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

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

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

Why identify neuropathic cancer pain?

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

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

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?

Finnerup et al, Pain 2005

BMJ 2009; 339:391-395

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 15-300 2.5 (1.9-3.4) Tramadol 200-400 9 (6.0-17.5) 3.9 / 4.8 (2.6-26.9) Methadone 15 N/A

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

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

Making better use of combinations

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

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

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

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

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

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

Thank you m.i.bennett@leeds.ac.uk