Neuropathic Pain - A Palliative Care Approach

1. Neuropathic Pain - A Palliative Care Approach Dr Reema Patel Staff Grade in Palliative Medicine

2. Content • Introduction • Pathophysiology of neuropathic pain • Management of neuropathic pain • The evidence • What to do in Clinical practice

3. What is Palliative Care? • The active, total care offered to a patient and their families, when it is recognised that their illness is no longer curable • It concentrates on the quality of life and alleviation of distressing symptoms within the framework of a coordinated service WHO Classification

4. What is pain? • “An unpleasant sensory and emotional experience associated with actual or potential tissue damage” Merksey 1979 • It is a subjective feeling, rather than objective

5. Why is neuropathic pain important? • Relatively common and can be difficult to treat • 34% of cancer patients referred to pain service (Grond 1999) • 30% of lung cancer patients (Potter 2004) • Up to 40% of all cancer-related pain may have a neuropathic mechanism involved (Caraceni 1999)

6. Definitions • Neuropathic pain • Pain initiated or caused by a primary lesion/dysfunction in the nervous system • Neuralgia • Pain in the distribution of the nerves • Analgesia • Absence of pain in response to stimulation which would normally be painful • Allodynia • Pain due to a stimulus that does not normally provoke pain

7. Hyperalgesia • Increased response to stimulus that is not normally painful • Noxious stimulus • One which is damaging to normal tissue • Nociceptors • Receptor preferentially sensitive to noxious stimulus (thermal, chemical or mechanical)

8. What is normal - how is pain conveyed? • Nociceptors - connect to nerve fibres and carry sensation of pain to the dorsal horn in the spinal cord • These signals then cross the spinal cord and are transmitted to the brain in the spinothalamic tract

9. Normal Pain Pathways

10. Nerve fibres • A fibres - small diameter, myelinated • C fibres - small diameter, unmyelinated • A fibres - large diameter, myelinated (Fordham 1986)

11. A fibres • Mainly found in or just under the skin • Activated by noxious stimuli • Intense heat, cold, mechanical and chemical • Fast or first pain

12. C fibres • Usually in a single receptive area • Convey messages generated by damaged tissue • Slow or second pain

13. A fibres • Responds to light touch or mechanical stimulation (mechanoreceptors) • Vibration, touch and pressure • Not normally unpleasant

14. As a rule, C fibres are opioid sensitive and A fibres are not

15. What happens in neuropathic pain? • The nerve fibres are damaged or dysfunctioning • This causes over activity of the nerve (even after noxious stimulation has gone)

16. Pathophysiology • The nerve can generate impulses randomly and “fire-off’ • There is failure or reduction of the usual inhibitory mechanisms (disinhibition) • The brain and spinal cord may become unusually sensitive (central sensitisation) to the nerve impulses (NMDA involved in this)

17. Causes of nerve damage • Peripheral • Central (Scadding 2003)

18. Peripheral causes • Trauma - post thoracotomy • Diabetes • Nutritional - alcoholic • Drugs - Cisplatin, Isoniazid • Infective - Guillain Barre • Direct infiltration - Pancoast’s tumour

19. Central causes • Spinal cord compression • Multiple Sclerosis • Intrinsic spinal cord tumours and syringomyelia • Spinal root - disc prolapse, trigeminal neuralgia

20. How does it feel? • Can be difficult to describe • ‘Shooting,’ ‘burning,’ ‘toothache,’ electrical impulse’ • Often in one set place • Can follow the path of the affected nerve (common in root pain from spinal cord compression)

21. How do we treat it? • Often with multiple treatment modalities • Multidisciplinary team approach is also valuable in complex pain

22. Treatment modalities • Psychological • Spinal (epidural or intrathecal) • Surgery (decompression) • Block (nerve, plexus, root) • Pharmacological • TENS • Topical

23. TENS • Transcutaneous Electrical Nerve Stimulation • Works in 2 ways • Electrical impulses stimulate A fibres (mechanical) • A fibre activity is greater than A and C fibre ‘pain’ activity, thereby closing the ‘pain gate’ • Stimulates the body to release its own natural pain killers (endorphin and enkephalin)

24. Gate theory of pain (Melzack and Wall) • Stimulating large A fibres can inhibit pain response via interneuron.

25. What drugs do the Palliative Care Physicians use? • Recent questionnaire to doctors on the Specialist Register for Palliative Care (2005) • ‘What are your choices for managing NP in palliative care?’ • Asked to give 1st, 2nd and 3rd line choices • To state maximum dose used

26. Results • 82 questionnaires sent out • 68% reply rate

27. Most popular drugs • Gabapentin • Amitriptyline • Ketamine • Methadone • Dexamethasone • Clonazepam (excluding opioids other than methadone)

28. Summary of anti-neuropathic agents • Pharmacokinetics • Dosing • Evidence

29. 1. Gabapentin • Calcium channel blocker • It is excreted unchanged by the kidneys and hence accumulates in renal failure • Doses • Rapid • 300mg OD day 1, BD day 2 and TDS day 3, adding 300mg a day as required to 600-1200mg TDS • Slow • 100mg TDS Day 1, 300mg TDS day 7, 600mg TDS day 14, 900mg TDS day 21

30. Gabapentin • Cochrane review, Wiffen 2005 • 14 studies included (one study acute pain, one study cancer-related pain) • NNT = 4.3 • Evidence to show that gabapentin is effective

31. Pregabalin • Related to gabapentin • Sabatowski 2004 - large study (192) in post herpetic neuralgia • Significant response Vs placebo at 2 dose levels: 150mg/d and 300mg/d

32. 2. Amitriptyline • Tricyclic antidepressant • Blocks pre-synaptic reuptake of serotonin and noradrenaline • Dose • 10mg ON initially, increasing to 150mg ON over 7-8 weeks

33. 2. Amitriptyline • 1996 systematic review McQuay et al • 17 RCTs • NNT for TCAs = 2.9 • SSRI are less effective that TCAs • Efficacy in burning Vs shooting pain not supported

34. 3. Ketamine • Partial NMDA antagonist • Useful in neuropathic, inflammatory or ischaemic pain • Can also be useful in terminal uncontrolled pain

35. Ketamine • Routes • PO • 10mg QDS and increase by 10mg increments OD to BD up to 50mg QDS • CSCI (continuous sub-cut infusion) - • 50-100mg/24 hours, increasing by 50-100mg every 72 hours up to 500mg/24hrs Always co-prescribe an antipsychotic, either haloperidol or midazolam due to the common S/E of dysphoria

36. NMDA antagonists - Ketamine • Cochrane review, Bell 2003 • 2 RCTs of adults with cancer pain on opioids receiving ketamine • Mercadante 2000 - in cancer NP; 10 patients unrelieved by morphine, given IV ketamine with significant pain relief. 6 patients suffered central adverse effects

37. 4. Methadone • Opioid that acts as a NMDA receptor antagonist + serotonin re-uptake inhibitor • Long and variable half life • Inactive metabolites therefore lower toxicity in renal failure • Faecally excreted • Can take up to 10 days to reach steady state

38. When to use methadone • Pain partially responsive to morphine • Renal failure • Morphine tolerance Specialist prescribing + requires hospital admission

39. Conversion of methadone • Stop all opioids • Loading dose: 5 to 10% of the 24hour PO morphine or equivalent, to a max of 30mg • Same dose as PRN but 3hourly • On day 6, add total dose of methadone in last 24hours and give 12hourly

40. Conversion of methadone • Dose changes are at a percentage increment as for morphine every 4-6 days • Re-assess as accumulation can occur up to 10days after commencing/dose changing • CSCI - half the dose and dilute (very acidic) • Can exacerbate asthma and can cause a diuresis

41. Methadone • Nicholson systematic review 2004 • Cancer pain (not NP specifically) • 8 studies • ‘Not possible to draw conclusions on relative merits of methadone compared to other opioids in the management of NP pain’

42. 5. Dexamethasone • Steroid • Used as adjunct for acute NP • Anti-inflammatory • Dose - 6 to 12 mg daily

43. 6. Clonazepam • Benzodiazepine • GABA potentiating actions in CNS, notably spinal cord, hippocampus, cerebellum and cerebrum • Reduces neuronal activity • Dose • 500mcg ON increasing to 4mg (half life 20-60hours)

44. Conclusions drawn • Large number of different agents used • Lack of concurrence particularly after 1st/2nd line choices • Maximum doses of drugs were low (when compared to evidence) • Evidence based on non-cancer, peripheral NP pain models

45. What about opioids? Multiple mechanisms of pain • Used in conjunction with classical NP drugs • Kalso 2004 systemic review (15 RCTs) • Mean decrease in pain intensity in most studies was at least 30% both for NP and musculoskeletal pain • Opioids included oxycodone, morphine, methadone and fentanyl Therefore always worth trying opioids

46. In clinical practice • Are neuropathic mechanisms present? • Pain in area of altered sensation • Rapidly escalating doses of opioids with no significant improvement in pain • S-LANSS questionnaire

47. Leeds Assessment of symptoms and signs - self report (S-LANSS) • Scored out of 24 • Scores of 12 or more are strongly suggestive of neuropathic pain • Questionnaire has been validated in The Journal of Pain (Bennett M et al (2001, 2005)

48. What can you do? • Identify NP (hx/ S-LANSS) • Think about WHO pain ladder initially (esp. if multiple mechanisms of pain) Non opioid, weak opioid, strong opioid If non-opioid responsive, or clearly NP process: • If mild pain and no CI, AMITRIPTYLINE • If moderate to severe pain, GABAPENTIN • Consider DEXAMETHASONE at the same time • If pain continues refer for specialist input

49. Any Questions?