2. NEUROPATHIC PAIN Dr. Mike Bennett Senior Clinical Lecturer in Palliative Medicine St. Gemma's Hospice and University of Leeds

3. In the next 40 minutes: Definitions and mechanisms –a refresher Identification –the LANSS Pain Scale Therapeutics –what’s new?

4. Definitions Neuropathic pain is: Pain due to a disturbance of function or pathological change in a nerve Merskey 1986 Pain in an area of abnormal or absent sensation Glynn 1989 The distribution of pain with associated sensory abnormalities that jointly and in a clinical context point to a neurological condition Hansson 1996

5. 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

6. Mechanisms Peripheral –nociceptor sensitization –abnormal axonal responses Central –disinhibition –hyperexcitability

11. Identification Positive phenomena –Spontaneous pains Continuous –Cutaneous, deep, visceral Paroxysmal –Evoked pains Quantitative- hyperalgesia Qualitative- allodynia Temporal- hyperpathia Spatial - radiation, dyslocalisation

12. Identification Negative phenomena –impaired soft touch, pin-prick and thermal sensibility Autonomic features –Vasomotor –Sudomotor

13. 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

14. 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

15. Therapeutics ‘An area of clinical practice marked more by polarised views and contention than consensus’ Frequent treatment failure –inadequate titration –early termination

16. 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

17. 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

18. 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

19. Therapeutics Opioids Intrathecal route less effective for neuropathic pain than nociceptive pain? –43 cancer pain patients Nociceptive Neuropathic Patients:2320 Duration of treatment:5 months2.5 months Initial mean reduction in pain:77%61% Continuing mean pain reduction:66%11% Becker et al, Stereotactic F Neurosurg 2000

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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)

30. Therapeutics Antiarrhythmics –but growing evidence of ineffectiveness 1998- 2002 spinal cord injury HIV neuropathy heterogenous NP capsaicin induced pain cancer pain (not NP)

31. 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

32. 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

33. Therapeutics CCK antagonists Devacade vs placebo –IV and oral dosing studies –41 NP patients –significant benefit over placebo Simpson et al 2002 (in press)

34. 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

35. 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

37. 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

38. 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)

39. 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

40. A therapeutic approach A. Initial steps 3. GABAPENTIN [add in or replace] 2. AMITRIPTYLINE [add in or replace] 1. W.H.O. LADDER

41. A therapeutic approach B. Advanced steps ‘The unlit loft at the top of the ladder’ 6. METHADONE 5. ANAESTHETIC APPROACHES 4. KETAMINE [with opioid]

42. 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

43. Thank you m.bennett@st-gemma.co.uk