Neuropathic Pain - A Palliative Care Approach

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Neuropathic Pain - A Palliative Care Approach

• Dr Reema Patel
• Staff Grade in Palliative Medicine

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Content

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

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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

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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

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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)

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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

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• 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)

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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

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Normal Pain Pathways
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Nerve fibres

• A? fibres - small diameter, myelinated
• C fibres - small diameter, unmyelinated
• A? fibres - large diameter, myelinated
• (Fordham 1986)

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A? fibres

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

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C fibres

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

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A? fibres

• Responds to light touch or mechanical stimulation
  (mechanoreceptors)
• Vibration, touch and pressure
• Not normally unpleasant

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

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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)

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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)

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Causes of nerve damage

• Peripheral
• Central
• (Scadding 2003)

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Peripheral causes

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

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Central causes

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

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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)

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How do we treat it?

• Often with multiple treatment modalities
• Multidisciplinary team approach is also valuable
  in complex pain

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Treatment modalities

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

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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)

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Gate theory of pain (Melzack and Wall)

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

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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

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Results

• 82 questionnaires sent out
• 68 reply rate

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Most popular drugs

• Gabapentin
• Amitriptyline
• Ketamine
• Methadone
• Dexamethasone
• Clonazepam
• (excluding opioids other than methadone)

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Summary of anti-neuropathic agents

• Pharmacokinetics
• Dosing
• Evidence

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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

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• 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

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• 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

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2. Amitriptyline

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

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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

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3. Ketamine

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

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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

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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

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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

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When to use methadone

• Pain partially responsive to morphine
• Renal failure
• Morphine tolerance
• Specialist prescribing requires hospital
  admission

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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

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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

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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

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5. Dexamethasone

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

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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)

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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

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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

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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

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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)

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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

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Any Questions?