Neuropathic pain

Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. It describes a mechanism and is not a diagnosis. The work is to find and treat the underlying lesion and to give mechanism targeted analgesia, because paracetamol, NSAIDs and most opioids are poorly effective.

Clinical relevance. The pain is persistent, disabling and often under-treated, and it commonly coexists with poor sleep, low mood and loss of function. Pain that looks neuropathic can also come from a lesion needing urgent treatment: cord compression, vasculitis, herpes zoster ophthalmicus, limb ischaemia or compartment syndrome.

Mechanisms. Ectopic discharge from injured axons and dorsal root ganglia, peripheral and central sensitisation, loss of inhibitory control in the spinal cord and brainstem, and maladaptive cortical reorganisation.

Classification by site. Peripheral: polyneuropathy, small fibre neuropathy, mononeuropathy, radiculopathy, plexopathy, ganglionopathy. Central: spinal cord, brainstem, thalamus and cortex.

Symptom pattern. Positive symptoms are spontaneous burning, shooting or electric shock pain, paroxysmal stabbing, paraesthesia and dysaesthesia. Evoked symptoms are allodynia (pain from light touch, brushing or cold) and hyperalgesia. Negative symptoms are numbness and reduced sensation, and pain within an area of sensory loss is characteristic.

Diagnostic grading. Possible: a plausible lesion and distribution. Probable: add sensory signs in the same distribution. Definite: add confirmation of the lesion by testing.

Screening tools. DN4 (10 items, 7 from history and 3 from examination; a score of 4 or more supports neuropathic pain), LANSS (score of 12 or more out of 24) and painDETECT.

History. Quality, distribution, onset and course of pain, relation to a causative event (zoster, surgery, amputation, trauma, stroke, chemotherapy, cord injury), triggers (touch, cold, movement), night pattern, associated numbness, weakness, autonomic change (sweating, colour and temperature change, swelling), sleep, mood, function, and prior treatments with dose, duration and response.

Background. Diabetes and duration, alcohol, diet and bariatric surgery, thyroid, kidney and liver disease, HIV, hepatitis B and C, syphilis, cancer and chemotherapy, autoimmune disease, monoclonal gammopathy, amyloidosis, family history of neuropathy, and occupational toxin exposure.

Drug history. Neurotoxic drugs: platinum agents, taxanes, vinca alkaloids, bortezomib, thalidomide, isoniazid, metronidazole, nitrofurantoin, linezolid, dapsone, stavudine, didanosine, amiodarone, phenytoin, disulfiram and excess pyridoxine (over 50 mg daily). Also current analgesics, opioids, antidepressants and anticholinergic load.

Examination.

• Map sensory change in the painful area with light touch (brush), pinprick, temperature (cool object), vibration (128 Hz fork), joint position and pressure, and test for allodynia and temporal summation.
• Power, tone, reflexes, trophic and autonomic signs (colour, temperature, sweating, oedema, hair and nail change), skin lesions (zoster scars, hypopigmented anaesthetic patches), thickened nerves, Tinel sign over nerve entrapment sites, spinal examination and straight leg raise.
• Mood screen (PHQ-9), sleep, and functional impact.

Red flags

• Sudden severe pain with weakness, a sensory level, or bladder or bowel dysfunction
• Pain with fever, spinal tenderness, injecting drug use or recent spinal procedure
• Vesicular rash in the ophthalmic division or ear, or with immunosuppression
• Cancer history, weight loss, night pain, or progressive plexopathy
• Cold, pale or pulseless limb, or pain out of proportion with tense swelling
• Rapidly progressive, asymmetric or multifocal painful neuropathy (vasculitis)
• Severe burning pain, swelling and colour change after fracture or surgery (complex regional pain syndrome)
• Suicidal thoughts with chronic pain

Special groups. Older adults: start every drug at a low dose and watch for falls, confusion and anticholinergic burden. Pregnancy: avoid antiseizure drugs, antidepressants and gabapentinoids unless benefit clearly outweighs risk, with specialist advice. Kidney impairment: gabapentin and pregabalin need dose reduction. Region specific: HIV neuropathy, leprosy and diabetes are the commonest causes in many settings.

Peripheral, generalised

• Diabetic painful neuropathy and small fibre neuropathy, impaired glucose tolerance
• Chemotherapy induced and drug induced neuropathy
• HIV neuropathy, leprosy, post-herpetic neuralgia, syphilis, hepatitis C, Lyme disease
• Alcohol related and nutritional neuropathy (vitamin B12, thiamine, folate, pyridoxine)
• Amyloid, Fabry disease, erythromelalgia, Sjogren syndrome, sarcoidosis
• Paraproteinaemic, paraneoplastic and vasculitic neuropathy, chronic inflammatory demyelinating polyneuropathy
• Hypothyroidism, uraemia

Peripheral, focal

• Radiculopathy (disc, stenosis), carpal tunnel syndrome and other entrapments, meralgia paraesthetica
• Trigeminal neuralgia and glossopharyngeal neuralgia
• Brachial and lumbosacral plexopathy, malignant plexopathy
• Post-surgical neuropathic pain (post-mastectomy, post-thoracotomy, post-hernia repair, post-amputation, phantom limb)
• Complex regional pain syndrome
• Occipital neuralgia, Morton neuroma, tarsal tunnel syndrome

Central

• Central post-stroke pain, spinal cord injury pain, syringomyelia
• Multiple sclerosis, transverse myelitis
• Parkinson disease related pain, post-herpetic and thalamic pain

Mimics and urgent causes of limb pain

• Cord and cauda equina compression, spinal epidural abscess
• Vasculitis, acute limb ischaemia, peripheral arterial disease with rest pain
• Compartment syndrome, deep vein thrombosis
• Nociceptive musculoskeletal pain, fibromyalgia and other nociplastic pain, gout, osteomyelitis

Reasoning. First exclude a time critical cause. Then confirm a neuropathic pattern from history and bedside sensory examination, locate the lesion, and look for treatable causes. Neuropathic pain is a clinical diagnosis and no test is needed to start treatment.

Blood tests for polyneuropathy.

• Fasting glucose and HbA1c (diabetes at 48 mmol/mol or more; impaired glucose regulation 42 to 47 mmol/mol).
• Full blood count and film.
• Vitamin B12 (under 200 ng/L deficient; 200 to 300 ng/L borderline, with methylmalonic acid or homocysteine), and folate.
• Urea, creatinine, electrolytes, calcium, liver function, thyroid stimulating hormone.
• ESR and C reactive protein.
• Serum protein electrophoresis with immunofixation and free light chains.
• HIV, hepatitis B and C, and syphilis serology.

Add antinuclear antibody, ANCA, anti-Ro and anti-La, cryoglobulins and angiotensin converting enzyme when vasculitis or connective tissue disease is possible.

Neurophysiology. Nerve conduction studies and electromyography classify large fibre neuropathy, radiculopathy and entrapment. They are normal in small fibre neuropathy, so a normal result does not exclude the diagnosis.

Small fibre tests. Skin biopsy for intraepidermal nerve fibre density, quantitative sensory testing, and corneal confocal microscopy where available.

Imaging. MRI of the relevant spinal level for radicular or cord pain, MRI or ultrasound of plexus or nerve for focal lesions, and MRI brain for central pain.

Other tests. Vesicle swab for varicella zoster PCR, alpha galactosidase A for Fabry disease, genetic testing for hereditary neuropathy and amyloid after counselling, and slit skin smear or nerve biopsy for leprosy.

Limitations. Screening tools separate neuropathic from nociceptive pain imperfectly. A normal nerve conduction study does not exclude small fibre disease. Roughly a fifth of painful neuropathies remain without a cause after full testing.

Treat the cause.

• Glycaemic control in diabetes (avoid rapid large falls in HbA1c, which can cause treatment induced neuropathy).
• Vitamin replacement, alcohol cessation, and withdrawal of neurotoxic drugs when possible.
• Antiviral treatment.
• Decompression of entrapments or compressive lesions.
• Immunotherapy for inflammatory and vasculitic neuropathy.

Drug treatment. Start one first line drug, titrate to an adequate dose for 2 to 4 weeks, and judge response (a reduction of about 30 percent in pain score is clinically meaningful). If partly effective, add a drug from another class. If ineffective, withdraw it slowly and switch.

• Amitriptyline 10 mg orally at night, increased by 10 mg each week to 25 to 75 mg at night; maximum 75 mg daily in usual practice and up to 150 mg daily in specialist care.
• Amitriptyline precautions: check ECG at baseline for age over 40 or heart disease. Avoid with recent myocardial infarction, arrhythmia, heart block, urinary retention and angle closure glaucoma.
• Amitriptyline interacts with monoamine oxidase inhibitors, tramadol and drugs raising serotonin; selective serotonin reuptake inhibitors raise levels. Reduce the dose in hepatic impairment and in older adults.
• Overdose is dangerous, so limit quantities supplied where there is a risk of self-harm. Withdraw slowly. Nortriptyline 10 mg at night, titrated to 75 mg, is better tolerated in older adults.
• Duloxetine 30 mg orally daily for 1 week, then 60 mg daily; maximum 120 mg daily (little added benefit over 60 mg).
• Duloxetine precautions: avoid when creatinine clearance is under 30 mL/min, in hepatic impairment and in uncontrolled hypertension. Monitor blood pressure and sodium. Avoid with monoamine oxidase inhibitors and strong CYP1A2 inhibitors (ciprofloxacin, fluvoxamine). Withdraw gradually.
• Gabapentin 300 mg orally at night, increased every 3 to 7 days (300 mg twice daily, then 300 mg three times daily) to a usual 1.8 to 3.6 g daily in 3 divided doses; maximum 3.6 g daily.
• Gabapentin renal dosing: creatinine clearance 30 to 59 mL/min: 400 to 1,400 mg daily in 2 doses; 15 to 29: 200 to 700 mg once daily; under 15: 100 to 300 mg once daily.
• Gabapentin warnings: sedation, dizziness, oedema, respiratory depression with opioids and in chronic lung disease, misuse.
• Pregabalin 75 mg orally twice daily (25 to 50 mg twice daily in older adults), increased after 1 week to 150 mg twice daily, then to a maximum of 300 mg twice daily.
• Pregabalin renal dosing: creatinine clearance 30 to 59 mL/min: 75 to 300 mg daily in 2 or 3 doses; 15 to 29: 25 to 150 mg daily in 1 or 2 doses; under 15: 25 to 75 mg once daily. Same warnings as gabapentin.
• Topical lidocaine 5 percent plaster for localised allodynic pain: up to 3 plasters applied to intact skin for up to 12 hours in each 24 hours. Review at 4 weeks and stop if there is no benefit.
• Capsaicin 8 percent patch (specialist): applied for 30 minutes to the feet or 60 minutes to other sites after local anaesthetic, repeated no more often than every 90 days.
• Tramadol 50 mg orally at night, increased to a maximum of 400 mg daily (maximum 300 mg daily over age 75; creatinine clearance under 30 mL/min: every 12 hours with a maximum of 200 mg daily), for short term use as a rescue drug only.
• Tramadol risks: seizures, serotonin syndrome with antidepressants, dependence. Strong opioids are not used for chronic neuropathic pain except under specialist care.

Condition specific points

• Diabetic painful neuropathy: duloxetine, pregabalin or amitriptyline are equally acceptable first drugs. Choose by comorbidity (avoid amitriptyline with heart disease, avoid duloxetine with severe renal impairment).
• Post-herpetic neuralgia: amitriptyline or gabapentin or pregabalin first, lidocaine plaster for focal pain.
• Prevention of acute zoster: valaciclovir 1 g orally three times daily for 7 days within 72 hours of rash, adjusted for kidney function (creatinine clearance 30 to 49 mL/min: 1 g every 12 hours; 15 to 29: 1 g daily; under 15: 500 mg daily).
• Recombinant zoster vaccine in adults over 50, 2 doses 2 to 6 months apart, reduces zoster and its neuralgia.
• Trigeminal neuralgia: carbamazepine 100 mg orally twice daily, increased by 100 to 200 mg every 2 to 3 days to a usual 400 to 800 mg daily; maximum 1.6 g daily.
• For carbamazepine, check sodium, blood count and liver function, and HLA-B*1502 testing in people of Han Chinese, Thai or other South East Asian ancestry.
• Central post-stroke and spinal cord injury pain: pregabalin or amitriptyline first.
• Lamotrigine is an alternative where evidence is limited: 25 mg orally daily for 2 weeks, then 50 mg daily for 2 weeks, then increased by 50 mg every 1 to 2 weeks to 200 mg daily (maximum 400 mg daily). Stop at first rash; halve the schedule with valproate.
• Radiculopathy: the neuropathic drugs listed in this section, early activity and physiotherapy. Epidural steroid injection or surgery by specialist decision for refractory pain or progressive weakness.
• Complex regional pain syndrome: early physiotherapy and occupational therapy, specialist pain referral. Prednisolone 30 to 40 mg orally daily for 2 to 4 weeks may be used early where evidence is limited.
• Phantom limb and post-surgical pain: early specialist referral.

Non-drug care. Explanation, graded activity, physiotherapy, cognitive behavioural therapy, sleep care, treatment of depression, and transcutaneous electrical nerve stimulation for selected patients. Refractory pain after at least 2 to 3 adequate drug courses: specialist pain service for spinal cord stimulation or other interventions.

Monitoring. Pain score and function at 2 to 4 weeks, then every 3 months; sodium, renal function and blood pressure on duloxetine and gabapentinoids; ECG and sedation on tricyclics; mood and suicidality.

Referral and escalation. Immediate: cord compression, vasculitis with ischaemia, ophthalmic zoster, acute limb ischaemia, compartment syndrome. Neurology for atypical, asymmetric, rapidly progressive or severe neuropathy. Specialist pain service after 2 to 3 failed drugs or for complex regional pain syndrome.

Admission criteria. Red flag causes, uncontrolled pain with inability to eat or sleep, or severe mood disturbance with suicidal thoughts.

Discharge and safety netting. Review in 2 to 4 weeks. Return for new weakness, sensory level, bladder or bowel change, fever, cold or discoloured limb, spreading rash, or worsening mood.