FRCA Notes

Neuropathic Pain

The syllabus requires knowledge of the "mechanisms of pain... neuropathic" and "the ability to recognise and manage neuropathic pain".

Resources

  • Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system
    • There is no requirement for the pain to be chronic, although it is often assumed to be so
    • Affects 7-10% of the general population and has a greater impact on quality of life than most other chronic pain types
    • Typically described as burning, shooting, electric shock-like, tingling or pins and needles, often with numbness in the same area
    • Responds poorly to conventional analgesics such as NSAIDs and opioids
    • Pain arising from altered nociception without evidence of a nerve lesion (e.g. fibromyalgia, CRPS type 1, irritable bowel syndrome) is now termed nociplastic pain rather than neuropathic

  • The IASP classification of chronic neuropathic pain is now incorporated into the WHO ICD-11, and divides conditions into central and peripheral

Central neuropathic pain

Peripheral neuropathic pain

  • Arises from a lesion or disease anywhere in the peripheral nervous system, including cranial nerves and spinal nerve roots
  • Examples:

Acute neuropathic pain

  • Often coexists with inflammatory pain, making recognition more difficult
  • Examples include:
    • Post-surgical pain where a nerve is damaged by the procedure
    • Acute sciatica and acute herpes zoster
    • Chemotherapy-induced peripheral neuropathy: affects up to 70% of those receiving neurotoxic chemotherapy and may force dose reduction; around a third are left with persistent symptoms
    • Guillain-Barré syndrome
    • COVID-19: neuropathic pain has been described both acutely and as part of long COVID

  • Early recognition matters as acute neuropathic pain predicts progression to chronic pain, e.g. after surgery or herpes zoster
  • Allows targeted management in at-risk patients, e.g. regional anaesthesia
  • Herpes zoster vaccination markedly reduces the risk of both shingles and post-herpetic neuralgia

  • Different aetiologies share similar symptoms and respond to the same drugs, suggesting common underlying mechanisms

Peripheral mechanisms

  • Ectopic discharge: damaged nerves accumulate abnormal Na+ channels at the site of injury and in the dorsal root ganglion, generating spontaneous firing
  • Ephaptic coupling ('cross-talk'): abnormal electrical transmission between adjacent demyelinated axons, so that touch fibres can activate nociceptive fibres
  • Collateral sprouting of uninjured neighbouring nerves into the denervated area
  • Sympathetic sprouting into the dorsal root ganglion, producing sympathetically maintained pain

Central mechanisms

  • Central sensitisation and wind-up via NMDA receptor activation (see pain pathways)
  • Disinhibition: loss of inhibitory GABAergic interneurones in the dorsal horn and reduced descending inhibition
  • Maladaptive neuroplastic changes, including Aβ fibre sprouting into superficial laminae, so that light touch is processed as pain (allodynia)
  • Central neuropathic pain is less well understood, but involves the same processes of disinhibition, sensitisation and maladaptive plasticity

Relevance to treatment

  • Most drugs used in neuropathic pain target these mechanisms:
    • Ectopic discharge: Na+ channel blockers e.g. carbamazepine, lidocaine
    • Central sensitisation: gabapentinoids, ketamine
    • Reduced descending inhibition: TCAs and SNRIs

  • Clinical features may be positive, negative or both, and typically lie within a neuroanatomically plausible distribution

Positive symptoms (abnormally increased sensation)


Symptom Definition
Hyperaesthesia Increased sensitivity to stimulation
Hyperalgesia Increased pain from a stimulus that is normally painful
Allodynia Pain from a stimulus that is not normally painful
Dysaesthesia An unpleasant abnormal sensation, spontaneous or evoked
Paraesthesia An abnormal sensation that is not unpleasant e.g. tingling, prickling

Negative symptoms (abnormally reduced sensation)


Symptom Definition
Hypoaesthesia Decreased sensitivity to stimulation
Hypoalgesia Decreased pain from a stimulus that is normally painful

  • Hyperpathia is an abnormally painful reaction to a stimulus, especially a repetitive one, often with an increased threshold; it may therefore be both a positive and a negative phenomenon
  • Altered localisation, radiation and after-sensation may also be present

Physical signs


Sign Examples
Sensory Reduced warm, cold and pinprick sensation (small fibre/spinothalamic loss); allodynia
Trophic Hair and nail changes, skin thickening
Vasomotor Temperature and colour change, oedema
Sudomotor Altered sweating
Musculoskeletal Muscle wasting, osteopenia


  • History: onset, relevant lesion or disease, distribution, character, impact on function, sleep and mood
  • Examination: map the painful area and test sensation (touch, pinprick, temperature, vibration)
  • Standard pain intensity scores (e.g. 0-10 NRS) do not capture the range of neuropathic symptoms

NeuPSIG grading system

  • Four criteria:
    • History of a relevant lesion or disease
    • Pain in a neuroanatomically plausible distribution
    • Sensory signs within that distribution
    • A diagnostic test confirming a lesion or disease of the nervous system
  • Neuropathic pain is graded as unlikely, possible, probable or definite depending on how many criteria are met
  • Mainly used in research; focuses on the lesion rather than symptoms and is not fully validated

Screening questionnaires

  • DN4 (Douleur Neuropathique en 4 questions): includes brief examination; self-completed interview version available
  • LANSS (Leeds Assessment of Neuropathic Symptoms and Signs): includes brief examination; self-completed S-LANSS available
  • PainDETECT: self-completed; originally developed for back pain
  • Sensitivity and specificity up to 80-90%; usable by non-specialists and patients themselves

Limitations of screening tools

  • Fail to identify up to 20% of neuropathic pain depending on the context
  • Limited or no clinical examination
  • Give no information about the underlying neurological lesion
  • Difficult to apply where there are multiple painful areas

Quantifying symptoms

  • Neuropathic Pain Scale (NPS) and Neuropathic Pain Symptom Inventory (NPSI) measure individual symptom dimensions, e.g. burning, paroxysmal and evoked pain
  • Used mainly in research; may be more sensitive to treatment effects than overall pain intensity

Investigations

  • Directed at confirming the lesion and finding the cause:
    • Bloods e.g. HbA1c, B12, thyroid function, alcohol-related markers
    • Nerve conduction studies (large fibres only)
    • Quantitative sensory testing and skin punch biopsy (small fibres)
    • Imaging e.g. MRI for radiculopathy, central lesions or trigeminal neuralgia

  • Diabetic peripheral neuropathy
    • The most studied neuropathic pain condition and the model for most drug trials
    • Distal, symmetrical 'glove and stocking' polyneuropathy; allodynia may occur

  • Painful radiculopathy
    • The most common cause of neuropathic pain in the general population, yet poorly represented in trials
    • Often mixed with nociceptive back pain

  • Post-herpetic neuralgia
    • Pain persisting ≥3 months after herpes zoster infection
    • Incidence increases with age; may resolve over time

  • Trigeminal neuralgia
    • Brief, paroxysmal, high-intensity, shock-like pain in the distribution of the trigeminal nerve
    • Most commonly due to vascular compression of the nerve root
    • Managed differently to other neuropathic pain: carbamazepine is first line

  • Phantom limb pain
    • Affects 60-80% of amputees, severe in around 10%

  • Complex regional pain syndrome
    • Type 1 follows an injury that does not directly damage a nerve; type 2 follows direct nerve injury
    • Features include pain at rest, allodynia, hyperpathia, hypoaesthesia, and motor and autonomic disturbance
    • Only type 2 meets the strict definition of neuropathic pain; type 1 is now considered nociplastic

  • Identify and treat the underlying cause where possible
  • Set realistic expectations: only 30-40% of patients achieve an adequate response to drug treatment, and the aim is improved function and quality of life rather than abolition of pain
  • Biopsychosocial, MDT approach with liaison between GP, specialist pain services and other teams

Non-pharmacological

  • Education and self-management
  • Physiotherapy (the cornerstone of CRPS management) and occupational therapy
  • Psychological therapies e.g. CBT, acceptance and commitment therapy
  • TENS: very low quality evidence, but very safe and patient-controlled

Prescribing principles

  • Start low and titrate slowly to effect or tolerability; dose titration also improves adherence
  • Give each drug an adequate trial (typically several weeks at a therapeutic dose) before switching
  • If one first-line drug fails or is not tolerated, switch to another first-line drug
  • Combination therapy (e.g. a gabapentinoid with an antidepressant) can be considered where monotherapy gives partial relief; however, it is associated with more side-effects and earlier discontinuation
  • Review regularly and withdraw drugs that are not working


Line Treatment
First line TCAs e.g. amitriptyline, nortriptyline
SNRIs e.g. duloxetine, venlafaxine
Gabapentinoids (α2δ ligands) e.g. gabapentin, pregabalin
Second line
(localised peripheral pain)		 Lidocaine 5% plasters
Capsaicin 8% patches or capsaicin cream
Third line Opioids, including tramadol
Botulinum toxin type A injections (peripheral pain)
rTMS of the motor cortex
Refractory (specialist) IV lidocaine
Ketamine
Intrathecal ziconotide

First-line drugs

  • There is no strong evidence favouring one first-line drug over another; choice is guided by side-effect profile, comorbidities and patient preference, e.g.:
    • Comorbid depression or anxiety: SNRI
    • Poor sleep: amitriptyline
    • Older patients: avoid TCAs where possible

  • The NICE approach in non-specialist settings is similar: amitriptyline, duloxetine, gabapentin or pregabalin first line, with tramadol only for short-term rescue
  • Carbamazepine is first line for trigeminal neuralgia, but has limited efficacy in other neuropathic pain
  • Cannabinoids are not recommended owing to lack of efficacy

  • SSRIs are not effective as analgesia relies on noradrenergic descending inhibition
  • The analgesic effect of antidepressants is independent of their effect on mood, and occurs at lower doses
  • TCAs have the lowest number needed to treat (NNT ~4.6, vs ~7.4 for SNRIs and ~8.9 for gabapentinoids), whilst gabapentinoids are best tolerated

Topical agents

  • Lidocaine 5% plaster: up to 3 plasters for 12 hours a day with minimal systemic absorption so useful in frail and elderly patients
  • Capsaicin 8% patch: TRPV1 agonist causing 'defunctionalisation' and retraction of intra-epidermal nerve endings, which is applied in hospital for 30-60 minutes every 2-3 months
    • Initial increase in pain on application and transient rise in blood pressure
  • Both are well tolerated, but have higher NNTs than first-line drugs

Others

  • Opioids: tramadol and strong opioids are third line because of risks of dependence, misuse and serotonin syndrome
  • Botulinum toxin A: intradermal or subcutaneous injection into the painful area every 3 months although effect thought to be partly central
  • Other sodium channel blockers (oxcarbazepine, lacosamide, lamotrigine) may help selected subgroups e.g. paroxysmal pain
  • Ketamine and IV lidocaine may be beneficial for short-term use in refractory pain under specialist supervision
  • Baclofen can be used in trigeminal neuralgia

Non-invasive

  • TENS: very safe; avoid in patients with a pacemaker or uncontrolled epilepsy
  • Repetitive transcranial magnetic stimulation (rTMS): high-frequency stimulation of the contralateral motor cortex in repeated sessions; side-effects mainly transient headache; contraindicated with cochlear implants and active seizures

Invasive

  • Spinal cord stimulation
  • Pulsed radiofrequency of the dorsal root ganglion or peripheral nerves
  • Motor cortex and deep brain stimulation: restricted to a few specialist centres
  • Surgical: e.g. microvascular decompression for trigeminal neuralgia, decompression for radiculopathy

Adherence and discontinuation

  • Many patients are never prescribed a recommended first-line drug
  • Adherence is moderate to poor, and the majority of patients stop treatment within 6 months; few switch to an alternative
  • Better adherence is associated with:
    • SNRIs, compared with gabapentinoids or TCAs
    • Gradual dose titration
    • Medicine reminders

  • Discontinuation is more likely with:
    • TCAs
    • Combination therapy
    • Adverse effects or lack of meaningful pain relief
    • Pain-related worry (catastrophising)
  • Patients from ethnic minorities and those without diabetes are less likely to receive recommended medication

Limitations of the evidence

  • Treatment effects are modest and have declined in more recent trials
  • Trials are dominated by diabetic neuropathy; radiculopathy and central neuropathic pain are poorly represented
  • Possible publication bias, particularly for gabapentinoids
  • Few head-to-head trials comparing active treatments
  • Interventional and device-based treatments are disadvantaged by the difficulty of blinding

Future directions

  • Personalised treatment: grouping patients by sensory phenotype (e.g. burning, paroxysmal or evoked pain) or genotype to predict drug response
  • Drug repurposing e.g. ambroxol (Nav1.7/1.8 blocker) or mexiletine for erythromelalgia
  • Drugs targeting new mechanisms, e.g. selective Nav1.7 blockers, have so far been disappointing