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NEUROPATHIC PAIN
Dr. Mike Bennett
Senior Clinical Lecturer in Palliative MedicineSt. Gemma's Hospice and University of Leeds
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In the next 40 minutes:
• Definitions and mechanisms – a refresher
• Identification – the LANSS Pain Scale
• Therapeutics– what’s new?
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Definitions
Neuropathic pain is:Pain due to a disturbance of function or pathological change
in a nerveMerskey 1986
Pain in an area of abnormal or absent sensationGlynn 1989
The distribution of pain with associated sensory abnormalities that jointly and in a clinical context point to a neurological condition
Hansson 1996
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Definitions• Neuropathic pain is the preferred term
– neurogenic or deafferentation terms are confusing
• Neuropathic pain can arise : – peripherally = peripheral nerves and posterior roots
– centrally = spinal cord and brain
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Mechanisms
• Peripheral– nociceptor sensitization
– abnormal axonal responses
• Central– disinhibition
– hyperexcitability
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Identification
• Positive phenomena– Spontaneous pains
• Continuous– Cutaneous, deep, visceral
• Paroxysmal
– Evoked pains • Quantitative - hyperalgesia
• Qualitative - allodynia
• Temporal - hyperpathia
• Spatial - radiation, dyslocalisation
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Identification
• Negative phenomena– impaired soft touch, pin-prick and thermal sensibility
• Autonomic features– Vasomotor
– Sudomotor
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Identification
LANSS Pain Scale
• 5 symptom groups– Dysaesthesias (5)
– Autonomic changes (5)
– Evoked pain (3)
– Paroxysmal (2)
– Thermal sensations (1)
• 2 sensory examination items – Allodynia (5)
– Altered PPT (3)Bennett Pain 2001
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Summary of LANSS Pain Scale
• Assesses the probability that neuropathic mechanisms contribute to the patient’s pain experience
• Reliable and validated scale that provides immediate clinical information– emphasises relative dominance of neuropathic
mechanisms
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Therapeutics
• ‘An area of clinical practice marked more by polarised views and contention than consensus’
• Frequent treatment failure– inadequate titration– early termination
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Therapeutics
Karolinska Institute audit
• Audit of 153 cancer patients in major hospital
• 61% had pain, VAS 2.4-6.6• Problems
– lack of pain diagnosis– failure to detect neuropathic pain components– under dosing of opioids
Arner et al, Lakartidningen 1999
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Therapeutics
WHO guidelines• 593 cancer pain patients surveyed
• Treatment based on opioids +/- adjuvants– 36% of patients had neuropathic component
• 5% pure and 31% mixed
– no more intense than nociceptive group– 96% had opioids– 53% had adjuvants – VAS decreased from 70mm to 28mm
Grond et al, Pain 1999
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Therapeutics Opioid responsiveness
– is satisfactory analgesia without un-manageable side-effects after dose titration
– is a continuum determined by• patient, pain and drug related factors
• Neuropathic pain reduces responsiveness– but does not confer resistance
Bruera 1989, Portenoy 1994
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Therapeutics
Opioids
• Intrathecal route less effective for neuropathic pain than nociceptive pain?– 43 cancer pain patients
Nociceptive Neuropathic Patients : 23 20
Duration of treatment: 5 months 2.5 months
Initial mean reduction in pain: 77% 61%
Continuing mean pain reduction: 66% 11%
Becker et al, Stereotactic F Neurosurg 2000
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Therapeutics
Fentanyl• IV fentanyl v active placebo
• 48 patients with NP
• Significantly more relief with fentanyl
• But less impressive follow up with patch– 13/48 had ‘substantial relief’ (correlate with IV)
– 5/48 had moderate relief
– so 30/48 had no relief or side effects (18 withdrew)
Dellemijn et al, Lancet 1997, JPSM 1998
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Therapeutics
Alfentanyl
• 12 patients with NP - post nerve injury • IV alfentanyl vs ketamine vs active placebo• alfentanyl similar to ketamine
– significantly better than placebo – dose dependent reduction in spontaneous and evoked
pains– suggestion of both peripheral and central mechanisms
Leung et al, Pain 2001
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Therapeutics
Oxycodone
• 38 patients with PHN
• Oxycodone vs inactive placebo, 4 weeks each
• All patients had stable doses of adjuvants
• 22/38 better on oxycodone (7/38 placebo)– significant reduction in spontaneous and evoked
pain
Watson and Babul, Pain 1998
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Therapeutics
Opioids with NMDA activity
• Dextromethorphan– 60 cancer pain pts– WHO (no adjuvants) vs WHO + DM– no advantage with DM– no difference between nociceptive and
neuropathic pain responses
Mercadante et al JPSM 1998
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Therapeutics
Opioids with NMDA activity
• Methadone– Hypothesis - if NMDA activity important, then
less methadone needed in NP after switching from morphine or hydromorphone
– 34 cancer pain patients - 22 with NP– no difference in ratios between two groups
Gagnon and Bruera JPSM 1999
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Therapeutics
Venlafaxine
• ‘Cleaner amitriptyline’
• 16 volunteers studied – 4 doses of 37.5mg v placebo
• Laboratory pain tests
• Significant effects for venlafaxine– increased tolerance for electrical nerve
stimulation and pain summation (rpt stimuli)Enggaard et al, Clin Pharm Therap 2001
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Therapeutics
Antiepileptics
• Gabapentin– 2 important studies with 390 patients– significant benefit in DN and PHN
• Topiramate– 3 blinded studies– no benefit in DN
Rowbotham et al JAMA 1998,
Backonja et al JAMA 1998
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Lamotrigine (glutamate antagonist)
• Refractory TN – 11/13 patients preferred it over placebo– used as add on to carbamazepine or phenytoin
• Spinal cord injury – 22 patients, no overall effect– but incomplete SCI - reduced evoked pain
Zakrzewska et al Pain 1998
Finnerup et al Pain 2002
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Therapeutics
Antiarrhythmics
• IV Lidocaine– substantial body of evidence now for efficacy– difficult to maintain effects
• Topical lidocaine patch– effective at local and central levels– 25 / 32 PHN pts benefited (compared to 3 /32
on placebo)Galer et al Pain 1999
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Therapeutics
Antiarrhythmics
• Mexiletine– earlier evidence of effectiveness 1988-1997
• 216 DN patients (675 mg daily)
• 11 peripheral nerve injury pts (750mg daily)
• 95 DN pts (450 mg daily)
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Therapeutics
Antiarrhythmics
– but growing evidence of ineffectiveness 1998-2002
• spinal cord injury
• HIV neuropathy
• heterogenous NP
• capsaicin induced pain
• cancer pain (not NP)
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Therapeutics
Ketamine
• Many small studies supporting efficacy
• Adverse effects limit its use
• Oral route may be better tolerated
• In cancer pain– 10 /10 patients benefited from IV bolus, 6 had
side effects – enhanced opioid analgesia in neuropathic pain
Mercadante et al JPSM 2000
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Therapeutics
CCK antagonists• CCK
– is an anti-opioid peptide– diminishes opioid sensitivity via CCK receptors
• In inflammatory states– actions of spinal morphine increased as CCK
activity is reduced
• In neuropathic pain– up-regulation of CCK – reduced response to opioids
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Therapeutics
CCK antagonists
• Devacade vs placebo– IV and oral dosing studies – 41 NP patients– significant benefit over placebo
Simpson et al 2002 (in press)
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Therapeutics
Cannabis
• No specific study in NP
• Systematic review of all chronic pain– including cancer and neuropathic pain
• No more effective than codeine– more adverse effects
• ‘Further trials needed before use in spasticity or NP’
Campbell et al BMJ 2001
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Therapeutics
Magnesium
• Blocks NMDA receptor– Mg might reduce wind-up
• Observational study, Mg infusion – 12 cancer pain patients– well tolerated– overall: 4 complete relief, 6 partial, 2 none
Crosby et al JPSM 2000
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NNTs and all that
• Useful measure• 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
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NNTs and all that
• WHO ladder– oxycodone 2.5 (1.6-5.1)
• 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)
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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 and NNH may be lower in
this group
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A therapeutic approach
A. Initial steps
3. GABAPENTIN
[add in or replace]
2. AMITRIPTYLINE
[add in or replace]
1. W.H.O. LADDER
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A therapeutic approach
B. Advanced steps ‘The unlit loft at the top of the ladder’
6. METHADONE
5. ANAESTHETIC APPROACHES
4. KETAMINE [with opioid]
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Summary
• Assess thoroughly– remember taxonomy and clinical features
• Use a total pain model
• Prescribe sensibly– evidenced based, up the ladder and monitor side effects
• Seek advice if it’s going pear shaped
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