Neuropathic pain in cancer patients

Mike BennettSt Gemma’s Professor of Palliative Medicine

University of Leeds, UK

What causes neuropathic pain in cancer patients?

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

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

• 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…..

Aetiology of pain in cancer patients

*Grond et al, 1996**Bennett et al 2012

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%

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 ToolsLANSS NPQ DN4 Pain

DetectID Pain

SymptomsPricking, tingling, pins, and needles

* * * * *

Electric shocks or shooting * * * * *

Hot or burning * * * * *

Numbness * * * *

Pain evoked by light touching * * * *

Painful cold or freezing pain * *

Clinical examinationBrush 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 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 2009Paredes 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 2010Rayment 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 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

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 28mmGrond et al Pain 1999

Making better use of combinations

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

But….3 studies reported:

Reduced opioid +/- adjuvant doses in combination armSame or better pain controlFewer adverse events in combination arm

5 studies reported:Fixed doses of opioids when adjuvant addedModest improvements in painMore adverse events in combination arm

Pain scores at end of each arm (5.7 at baseline):placebo 4.5gabapentin 4.2morphine 3.7M + 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 7.8 2.5 5.3

Placebo 7.5 3.4 4.1

Summary Population characteristics

Older patients with evolving mixed pains, Co-morbidities and cancer treatments are important causes of

neuropathic pain in cancer patients

Assessment challengesIs 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