NEUROPATHIC PAIN

Dr. Mike Bennett

Senior Clinical Lecturer in Palliative MedicineSt. Gemma's Hospice and University of Leeds

In the next 40 minutes:

• Definitions and mechanisms – a refresher

• Identification – the LANSS Pain Scale

• Therapeutics– what’s new?

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

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

Mechanisms

• Peripheral– nociceptor sensitization

– abnormal axonal responses

• Central– disinhibition

– hyperexcitability

Identification

• Positive phenomena– Spontaneous pains

• Continuous– Cutaneous, deep, visceral

• Paroxysmal

– Evoked pains • Quantitative - hyperalgesia

• Qualitative - allodynia

• Temporal - hyperpathia

• Spatial - radiation, dyslocalisation

Identification

• Negative phenomena– impaired soft touch, pin-prick and thermal sensibility

• Autonomic features– Vasomotor

– Sudomotor

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

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

Therapeutics

• ‘An area of clinical practice marked more by polarised views and contention than consensus’

• Frequent treatment failure– inadequate titration– early termination

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

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

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

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

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

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

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

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

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

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

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

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

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

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)

Therapeutics

Antiarrhythmics

– but growing evidence of ineffectiveness 1998-2002

• spinal cord injury

• HIV neuropathy

• heterogenous NP

• capsaicin induced pain

• cancer pain (not NP)

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

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

Therapeutics

CCK antagonists

• Devacade vs placebo– IV and oral dosing studies – 41 NP patients– significant benefit over placebo

Simpson et al 2002 (in press)

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

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

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

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)

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

A therapeutic approach

A. Initial steps

3. GABAPENTIN

[add in or replace]

2. AMITRIPTYLINE

[add in or replace]

1. W.H.O. LADDER

A therapeutic approach

B. Advanced steps ‘The unlit loft at the top of the ladder’

6. METHADONE

5. ANAESTHETIC APPROACHES

4. KETAMINE [with opioid]

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

Thank you

m.bennett@st-gemma.co.uk