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 Neuralgia Analgesia Allodynia
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 Noxious stimulus Nociceptors
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 mg 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 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 CSCI (continuous sub-cut infusion) -
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 mg 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 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? If non-opioid responsive, or clearly NP process:
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?