Neuropathic Pain - A Palliative Care Approach

Dr Reema Patel

Staff Grade in Palliative Medicine

Content

• Introduction

• Pathophysiology of neuropathic pain

• Management of neuropathic pain– The evidence– What to do in Clinical practice

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

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

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)

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

• 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)

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

Normal Pain Pathways

Nerve fibres

• A fibres - small diameter, myelinated

• C fibres - small diameter, unmyelinated

• A fibres - large diameter, myelinated(Fordham 1986)

A fibres

• Mainly found in or just under the skin

• Activated by noxious stimuli– Intense heat, cold, mechanical and

chemical

• Fast or first pain

C fibres

• Usually in a single receptive area

• Convey messages generated by damaged tissue

• Slow or second pain

A fibres

• Responds to light touch or mechanical stimulation (mechanoreceptors)

• Vibration, touch and pressure

• Not normally unpleasant

• As a rule, C fibres are opioid sensitive and A fibres are not

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)

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)

Causes of nerve damage

• Peripheral

• Central(Scadding 2003)

Peripheral causes

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

Central causes

• Spinal cord compression

• Multiple Sclerosis

• Intrinsic spinal cord tumours and syringomyelia

• Spinal root - disc prolapse, trigeminal neuralgia

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)

How do we treat it?

• Often with multiple treatment modalities

• Multidisciplinary team approach is also valuable in complex pain

Treatment modalities

• Psychological

• Spinal (epidural or intrathecal)• Surgery (decompression)• Block (nerve, plexus, root)

• Pharmacological• TENS• Topical

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)

Gate theory of pain (Melzack and Wall)

• Stimulating large A fibres can inhibit pain response via interneuron.

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

Results

• 82 questionnaires sent out

• 68% reply rate

Most popular drugs

1. Gabapentin

2. Amitriptyline

3. Ketamine

4. Methadone

5. Dexamethasone

6. Clonazepam

(excluding opioids other than methadone)

Summary of anti-neuropathic agents

• Pharmacokinetics• Dosing• Evidence

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

• 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

• 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

2. Amitriptyline

• Tricyclic antidepressant

• Blocks pre-synaptic reuptake of serotonin and noradrenaline

• Dose– 10mg ON initially, increasing to 150mg ON

over 7-8 weeks

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

3. Ketamine

• Partial NMDA antagonist

• Useful in neuropathic, inflammatory or ischaemic pain

• Can also be useful in terminal uncontrolled pain

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

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

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

When to use methadone

• Pain partially responsive to morphine

• Renal failure

• Morphine tolerance

Specialist prescribing + requires hospital admission

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

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

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’

5. Dexamethasone

• Steroid

• Used as adjunct for acute NP

• Anti-inflammatory

• Dose - 6 to 12 mg daily

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)

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

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

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

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)

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

Any Questions?