Download Neuropathic cancer pain (BENNETT).

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
• 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…..
1
• Noci
• Neuro
2
• Noci
• Noci
3
• Noci
• Neuro
4
• Noci
• Noci
5
• Noci
• Noci
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
Pricking, tingling, pins, and
needles
*
*
*
*
*
Electric shocks or shooting
*
*
*
*
*
Hot or burning
*
*
*
*
*
*
*
*
*
*
*
Symptoms
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 comorbid 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
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 28mm
Grond 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 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
gabapentin
morphine
M + GP
4.5
4.2
3.7
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 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
[email protected]