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Neuropathic pain

Red flags

New back pain + bilateral leg symptoms + bladder or bowel change = cauda equina - MRI today
Thoracic or band-like pain with a sensory level = cord compression - image the whole spine
Progressive pain + weight loss + night pain + known cancer = metastatic or leptomeningeal disease
Mononeuritis multiplex - painful, asymmetric, sequential named nerve lesions = vasculitis until proven otherwise; needs urgent immunosuppression, not an outpatient nerve conduction study
Fever, back pain, raised CRP, IVDU or bacteraemia = epidural abscess/discitis
New severe facial pain in a patient under 50, bilateral, or with any sensory loss or other cranial nerve sign = **not classical trigeminal neuralgia - MRI**
Acutely painful, cold, pulseless limb = ischaemia, not neuropathy
Rapidly progressive painful neuropathy with weight loss - diabetic radiculoplexus neuropathy, vasculitis, paraneoplastic, amyloid, HIV
Zoster in the V1 dermatome (Hutchinson sign - tip of the nose) -> ophthalmic involvement; same-day ophthalmology

Differential by mechanism

Neuropathic pain = pain caused by a lesion or disease of the SOMATOSENSORY nervous system
- Not simply "pain that burns". The anatomy must be plausible and there must be confirmatory sensory signs

Peripheral

Group	Examples
Painful polyneuropathy	Diabetes mellitus (the commonest), alcohol excess, vitamin B1 or B12 deficiency, carcinoma (paraneoplastic), porphyria, arsenic poisoning; also HIV, chemotherapy (platins, taxanes, bortezomib, vincristine, thalidomide), amyloidosis, Fabry, hereditary sensory neuropathy
Post-herpetic neuralgia	Pain >=3/10 persisting >=90 days after the onset of the zoster rash, in the affected dermatome; numbness, dysaesthesia, pruritus and allodynia
Radiculopathy	Disc, foraminal stenosis, zoster, malignant infiltration, diabetic radiculoplexus neuropathy
Entrapment/mononeuropathy	Carpal tunnel, ulnar, meralgia paraesthetica, common peroneal
Trigeminal neuralgia	Paroxysms of seconds, electric, V2/V3, triggered by touch/chewing/cold air; neurovascular conflict, or MS/tumour in the young and atypical
Plexopathy	Neuralgic amyotrophy (severe pain then weakness), radiation, malignant infiltration, trauma
Traumatic/surgical	Post-thoracotomy, post-mastectomy, post-amputation (stump and phantom limb pain)

Central

Central post-stroke pain (thalamic/Dejerine-Roussy) - may begin weeks-months after the stroke
Spinal cord injury, syringomyelia
Multiple sclerosis - central pain and trigeminal neuralgia
Parkinson disease

Mimics - the things that are NOT neuropathic pain

Nociceptive/inflammatory - arthritis, myofascial pain, referred visceral pain
Nociplastic pain - fibromyalgia, chronic widespread pain, IBS (no demonstrable lesion; central sensitisation)
Vascular claudication (exertional, relieved by standing still - vs neurogenic claudication, relieved by flexion)
Complex regional pain syndrome - allodynia + autonomic and trophic change, out of proportion to the injury
Restless legs syndrome - an urge to move, not pain
Muscle cramps, nocturnal leg cramps

Focused history

Characterise the pain

Quality - burning, shooting, electric shock, lancinating, "like walking on broken glass", freezing
Positive phenomena - allodynia (pain from a non-painful stimulus - bedsheets, clothing, wind), hyperalgesia, paraesthesia, dysaesthesia
Negative phenomena - numbness, deadness (the coexistence of numbness AND pain in the same territory is highly suggestive)
Distribution - does it match a nerve, root, plexus, cord level or hemisensory pattern?
Timing - constant burning vs paroxysmal shocks; worse at night is characteristic
Screening tools: DN4, painDETECT, LANSS - useful to formalise the impression

Then

Onset relative to an event - shingles, surgery, trauma, chemotherapy cycle, stroke, diagnosis of diabetes
Alcohol history quantified; diet (vegan, bariatric surgery, nitrous oxide)
Drugs - chemotherapy, metronidazole, isoniazid, nitrofurantoin, amiodarone, excess pyridoxine
Systemic - weight loss, sicca, rash, arthralgia, Raynaud, sweats, HIV risk, travel
Family history of neuropathy; look at the patient's feet and their parents' feet
Function and mood - sleep, work, mobility, depression, anxiety and catastrophising; suicidal ideation
Previous analgesic trials - drug, dose actually reached, duration, why stopped (most "failed" drugs were never titrated to an adequate dose)
Opioid and benzodiazepine history; check the real-time prescription monitoring record

Focused examination

Confirm the somatosensory lesion

Map the territory and decide whether it is a nerve, root, plexus, cord or brain distribution
Test each modality separately
- Pinprick and temperature (small fibre, spinothalamic)
- Vibration and joint position sense (large fibre, dorsal column)
- Light touch
Bedside signs of neuropathic pain
- Dynamic mechanical allodynia - lightly stroke the skin with cotton wool
- Hyperalgesia to pinprick; temporal summation (repeated pinprick becomes progressively more painful)
- Cold allodynia with a cold tuning fork
Reflexes, power, wasting, fasciculation; gait
Autonomic/trophic change - skin colour and temperature, sweating, hair and nail change, oedema (CRPS)

Look for the cause

Feet - ulcers, callus, deformity, pes cavus, pulses, Charcot joint
Skin - shingles scarring in a dermatome, vasculitic purpura, angiokeratoma (Fabry)
Palpate nerves (thickened - CMT, leprosy, amyloid, CIDP)
Trigger a trigeminal neuralgia paroxysm carefully; check corneal reflex and facial sensation (loss of either points away from classical TN)
General: lymph nodes, breast/prostate/testes, hepatosplenomegaly, macroglossia (amyloid)

Investigation strategy

Basic - the reversible causes

HbA1c or OGTT (impaired glucose tolerance alone causes painful small-fibre neuropathy), B12 with active B12/homocysteine/methylmalonic acid, folate, TFT, UEC, LFT, FBE
ESR/CRP, serum protein electrophoresis + immunofixation + free light chains - do not omit the paraprotein screen
HIV, hepatitis B/C and syphilis serology where risk factors exist

Directed

Nerve conduction studies and EMG - confirm and characterise (axonal vs demyelinating, symmetric vs multifocal)
- *Normal in pure small-fibre neuropathy - a normal study does not exclude neuropathic pain*
Skin punch biopsy for intraepidermal nerve fibre density - the test for small-fibre neuropathy; quantitative sensory testing
MRI of the relevant neuraxis - spine for radiculopathy/myelopathy, brain for central pain, MRI with trigeminal protocol for facial pain
Autoimmune/vasculitic screen if mononeuritis multiplex: ANA/ENA, ANCA, RF, cryoglobulins, complement, hepatitis C; consider nerve or muscle biopsy
Paraneoplastic antibodies + CT chest/abdomen/pelvis +/- PET if subacute sensory neuronopathy
Genetic testing - PMP22; transthyretin (ATTRv) in progressive axonal neuropathy with autonomic, cardiac or carpal tunnel features
Porphyrins (acute attack), heavy metals including arsenic, thiamine

Management

A. Treat the cause and set the frame

Glycaemic and cardiovascular risk-factor control; alcohol cessation and thiamine; B12 replacement; stop the offending drug; decompress the entrapment; immunosuppress the vasculitis
Explain the mechanism and set realistic goals from the first consultation
- *A 30-50% reduction in pain, with improved sleep and function, is a good outcome. Complete abolition is not the target and promising it guarantees failure*
Non-drug from the outset: exercise and graded activity, sleep, pacing, CBT/ACT, treat depression and anxiety, weight, footwear, physiotherapy, TENS

B. First-line pharmacotherapy - equivalent efficacy, choose by comorbidity

Agent	Start	Choose when
Amitriptyline	10 mg nocte (5 mg if frail), inc by 10 mg every 5-7 days to 25-75 mg	Insomnia, coexisting depression, low cost. Anticholinergic, falls, urinary retention, QT prolongation - caution over 65
Duloxetine	30 mg daily x1 week -> 60 mg	Best evidence in painful diabetic neuropathy; coexisting depression
Gabapentin	300 mg nocte -> 900-1800 mg/day in 3 divided doses (max 3600)	Renal dose adjustment; sedation, oedema, weight gain
Pregabalin	75 mg bd, titrate to 150-300 mg bd	Faster titration, more predictable kinetics. Misuse and diversion; a monitored medicine under Australian real-time prescription monitoring

Try one at an adequate dose for an adequate duration (4-8 weeks), then SWITCH to another first-line agent
Combine (e.g. a gabapentinoid plus an antidepressant) only after monotherapy at a tolerated maximum has failed (OPTION-DM)
*Nortriptyline is a better-tolerated tricyclic in older patients*

C. Condition-specific exceptions - the high-yield ones

Condition	Treatment
Trigeminal neuralgia	*Carbamazepine is first-line[[c2]] (start 100 mg bd, titrate); oxcarbazepine, lamotrigine, baclofen. MRI in everyone. Microvascular decompression* is the most durable procedure; gamma knife or radiofrequency rhizotomy if unfit
Post-herpetic neuralgia	RCT evidence for: topical lidocaine 5%, gabapentin and pregabalin, tricyclic antidepressants, topical capsaicin (8% patch), and opioids. Prevention is far better: recombinant zoster vaccine (Shingrix), and aciclovir/valaciclovir within 72 h of the rash
Localised peripheral pain	Lidocaine 5% patch or capsaicin 8% patch - useful where systemic drugs are poorly tolerated
Chemotherapy-induced	Duloxetine has the only positive evidence; dose reduction or cessation of the neurotoxic agent; nothing prevents it
Central post-stroke pain	Amitriptyline, pregabalin; often refractory
Complex regional pain syndrome	Early mobilisation and graded motor imagery/mirror therapy; multidisciplinary pain service
Phantom limb pain	Mirror therapy, pregabalin/amitriptyline, prosthetic fit review

D. What NOT to do

*Opioids are not first-line, give no benefit in most neuropathic pain, and cause harm* - if used at all, short trial, immediate-release, defined stop date, and never for fibromyalgia or nociplastic pain
*Paracetamol and NSAIDs do not work in true neuropathic pain*
Do not add a fourth agent - refer instead
Avoid benzodiazepines; avoid stacking sedating drugs in the elderly

E. Escalation

Multidisciplinary pain service where the pain is refractory, function is deteriorating, or opioid or gabapentinoid use is escalating
Interventional: nerve block, epidural steroid (acute severe radicular pain), spinal cord stimulation in selected refractory cases, sympathectomy (rarely)
Deprescribe what is not working - a drug that has not helped at an adequate dose should be stopped, not left on the list

Traps

*A normal nerve conduction study does not exclude neuropathic pain* - small fibres are invisible to it. Skin biopsy or QST is the test
"Failed" first-line drugs were usually never titrated - always ask the dose actually reached and for how long
*Do NOT give gabapentin or pregabalin for sciatica* - NICE recommends against them and the PRECISE trial was negative; this is a common and confidently made error
Trigeminal neuralgia is the exception to the neuropathic pain ladder - carbamazepine, not amitriptyline
Bilateral or young-onset trigeminal neuralgia, or any sensory loss, means MRI and think MS or tumour
Mononeuritis multiplex is vasculitis until proven otherwise - a delay of weeks costs axons permanently
Painful neuropathy with weight loss and diabetes may be diabetic radiculoplexus neuropathy (amyotrophy) - it is self-limiting, but do not miss the vasculitic mimic
Post-herpetic neuralgia is far better prevented than treated - check zoster vaccination status in every patient over 50 and every immunosuppressed patient**
Impaired glucose tolerance, not just overt diabetes, causes painful small-fibre neuropathy - do an OGTT if the HbA1c is normal
Do not treat allodynia with opioids - escalating dose, opioid-induced hyperalgesia, and no functional gain
Fibromyalgia is nociplastic, not neuropathic - exercise, sleep, CBT and duloxetine or amitriptyline; opioids are contraindicated
Screen for depression and suicidality - untreated mood disorder makes every analgesic look ineffective

Talk track

1. Establish that it IS neuropathic

"I'd want the pain to be in a neuroanatomically plausible distribution with confirmatory sensory signs - burning or electric quality, allodynia, and numbness in the same territory - rather than just describing it as burning."

2. Localise

"Then I'd localise: nerve, root, plexus, cord or brain. That determines both the investigation and whether there is a structural cause to reverse."

3. Find the reversible cause

"I'd screen for diabetes or impaired glucose tolerance, alcohol, B12 including nitrous oxide use, thyroid, a paraproteinaemia, HIV, and drugs - and I'd take an asymmetric painful neuropathy as vasculitis until proven otherwise."

4. Set expectations before prescribing

"I'd tell the patient we're aiming for a 30 to 50 per cent reduction in pain with better sleep and function, not for the pain to go away, because promising more guarantees a failed consultation."

5. Pharmacology, honestly

"Amitriptyline, duloxetine, gabapentin and pregabalin are equivalent first-line, so I choose by comorbidity - duloxetine for diabetic neuropathy or coexisting depression, amitriptyline if sleep is disturbed. I'd switch rather than combine at first, and I'd avoid opioids. Trigeminal neuralgia is the exception and gets carbamazepine."

6. Beyond the prescription

"And I'd address exercise, sleep, mood and pacing, refer to a multidisciplinary pain service if it's refractory, and deprescribe anything that hasn't worked at an adequate dose."

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