Neuropathic pain

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Neuropathic pain is caused by a lesion or disease of the somatosensory nervous system. Descriptors such as burning, shooting, electric shocks, pins and needles, painful cold, allodynia and numbness raise probability but are not diagnostic alone. Symptoms should follow a neuroanatomically plausible peripheral nerve, root, plexus, stocking, hemibody or below-lesion distribution and be supported by sensory change on examination where possible.

Cancer-related neuropathic pain may result from direct invasion, spinal or foraminal compression, plexopathy, surgery, radiotherapy or chemotherapy. A new painful neuropathy is not automatically a late effect: rapid progression, motor loss, cranial neuropathy, sphincter change or asymmetry may indicate active tumour, inflammation or infection. Cause-directed imaging and specialist assessment can prevent irreversible disability.

NICE offers amitriptyline, duloxetine, gabapentin or pregabalin as initial choices for non-trigeminal neuropathic pain. Selection matters more than a generic hierarchy. Amitriptyline may help sleep but worsens anticholinergic burden and postural hypotension. Duloxetine may suit diabetic neuropathy and low mood but has serotonergic, blood-pressure and hepatic considerations. Gabapentinoids require renal dosing and increase sedation, oedema, misuse and respiratory risk with opioids.

Titration should be slow enough to interpret benefit. Establish baseline sleep and function, start one drug at a low dose and increase according to the BNF, renal function and local pathway. Review after each change. If there is no useful response at a tolerated therapeutic dose for an adequate duration, taper and switch. Partial benefit may justify cautious continuation, but combination therapy should be specialist-led when sedative burden or evidence uncertainty is material.

Non-drug and rehabilitative care remains essential. Desensitisation, protective footwear, pressure care, splints, graded movement, sleep support and psychological strategies can reduce disability and injury. Explain that complete pain abolition is uncommon and that numbness may persist even when painful firing falls. The goal may be tolerating clothing, sleeping four uninterrupted hours or walking safely with an aid.

In advanced illness, time to benefit and tablet burden shape choices. A dying patient unable to swallow may not benefit from a newly initiated oral medicine requiring weeks of titration. Existing gabapentinoids should not be stopped abruptly if avoidable; discuss alternative routes and withdrawal risk with specialist pharmacy. An opioid can treat a mixed nociceptive component, but escalating it alone often fails neuropathic pain and increases toxicity.

Key points

Diagnose neuropathic pain only when characteristic symptoms and sensory signs fit a plausible lesion or disease of the somatosensory system.
First-line examination maps light touch, pinprick, temperature, allodynia, reflexes, power and gait and checks urgently for cord, root or plexus compromise.
Treat the cause when possible: decompression, radiotherapy, diabetes control, vitamin replacement, antiviral treatment or modification of a neurotoxic medicine may preserve function.
NICE initial non-trigeminal options are amitriptyline, duloxetine, gabapentin or pregabalin, selected by comorbidity, interactions, renal function, misuse risk and patient preference.
Start one medicine low, titrate gradually, set a functional goal and allow an adequate trial at a tolerated dose before switching.
If the first option fails or is not tolerated, offer one of the remaining choices rather than layering multiple sedatives immediately.
Capsaicin cream is an option for localised neuropathic pain when oral medicines are unsuitable or not wanted; high-concentration patch use is specialist.
Tramadol should be considered only as short-term rescue in this pathway, not routine long-term treatment, because of dependence, seizure and serotonin risks.
There is no single gold-standard medicine. The benchmark is improved sleep or function with tolerable harm, reviewed alongside cause and rehabilitation.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Cancer-related nerve injury

Tumour can compress or infiltrate roots, plexus, peripheral nerve, spinal cord or brain, and painful neuropathy may precede objective weakness.

Treatment-related damage

Chemotherapy, radiotherapy, surgery and positioning can injure axons, roots or plexuses, with symptoms appearing during treatment or months later.

Systemic peripheral neuropathy

Diabetes, alcohol, vitamin deficiency, renal disease, paraproteinaemia, infection and immune disease cause length-dependent or multifocal somatosensory damage.

Central nervous system lesion

Stroke, multiple sclerosis, spinal injury and central tumour can generate pain in a region of altered sensation below or contralateral to the lesion.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Ectopic nerve discharge
Damaged axons and dorsal-root ganglia develop abnormal ion-channel activity, producing spontaneous burning, shooting pain and paroxysmal electric shocks.
2
Peripheral sensitisation
Inflammatory mediators lower nociceptor thresholds around injured neural tissue, making touch, movement and temperature abnormally painful.
3
Central sensitisation
Sustained afferent input increases spinal excitability and reduces inhibition, expanding receptive fields and maintaining allodynia after peripheral input lessens.
4
Deafferentation
Loss of normal sensory input reorganises central processing so numb areas can paradoxically contain severe spontaneous or evoked pain.
5
Descending modulation change
Mood, sleep, attention and monoaminergic pathways alter inhibitory control, explaining why psychological and pharmacological interventions can change pain without denying neural injury.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Positive sensory symptoms

Burning, electric shocks, painful cold, pins and needles, allodynia and hyperalgesia in a plausible distribution support neuropathic pain.

Negative sensory signs

Reduced pinprick, temperature, vibration or proprioception and absent reflexes identify nerve dysfunction and injury risk.

Radicular pattern

Shooting pain and sensory change along a dermatome with reflex or myotomal weakness suggests nerve-root involvement.

Length-dependent neuropathy

Symmetrical distal feet symptoms progressing proximally and later affecting hands suggests a systemic axonal neuropathy.

Central pain

Pain within a region of altered sensation after stroke, cord injury or demyelination may be diffuse, cold-sensitive and difficult to localise.

Compressive emergencyRed flag

Pain with new weakness, gait decline, saddle loss or sphincter dysfunction requires urgent structural imaging and specialist care.

Red flags requiring action

Back or radicular pain with new motor, sensory, gait or bladder or bowel change requires emergency MSCC or cauda-equina assessment.
Rapidly progressive, asymmetric or proximal neuropathy may indicate plexopathy, vasculitis, infection, leptomeningeal disease or treatment toxicity needing specialist investigation.
A hot, swollen, colour-changing limb with allodynia after procedure requires evaluation for infection, thrombosis and complex regional pain syndrome.
New confusion, falls or respiratory slowing after gabapentinoid addition to an opioid is medication toxicity until reviewed.
Gabapentin and pregabalin require renal adjustment and gradual withdrawal; abrupt cessation after sustained use can cause severe symptoms or seizures.
Active suicidal thinking, marked mood change, misuse or escalating unsanctioned doses requires same-day mental-health and medicine-safety assessment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line neurological pain historyFirst stepFirst line
Why
Map distribution, positive and negative symptoms, onset, progression, triggers, functional loss and temporal relation to cancer or treatment.
Interpretation and limitations
Neuropathic descriptors plus a plausible lesion increase diagnostic confidence; rapid progression or motor and sphincter change determines urgency.
02
Focused neurological examination
Why
Test modality-specific sensation, allodynia, reflexes, power, tone, coordination, gait, cranial nerves and spinal signs as indicated.
Interpretation and limitations
Objective distribution helps localise central, root, plexus or peripheral injury and identifies weakness requiring urgent imaging.
03
PainDETECT or DN4 screening tool
Why
Structure symptoms and signs when a neuropathic component is uncertain or several pain types coexist.
Interpretation and limitations
A score supports but does not establish diagnosis and must not override anatomical inconsistency or emergency findings.
04
Cause-directed blood tests
Why
Assess glucose or HbA1c, B12, folate, thyroid, renal and liver function, paraprotein and other tests guided by phenotype.
Interpretation and limitations
Correct reversible systemic causes and use renal or hepatic results to choose and titrate adjuvants safely.
05
MRI or other targeted imaging
Why
Investigate suspected cord, root, plexus, brain or local tumour compression and structural treatment complications.
Interpretation and limitations
Urgent MRI is the reference investigation for suspected MSCC; routine imaging is not required for every stable distal neuropathy.
06
Neurophysiology or specialist testing
Why
Characterise uncertain, progressive, asymmetric or motor neuropathy and distinguish axonal, demyelinating, root and entrapment patterns.
Interpretation and limitations
Normal routine studies do not exclude small-fibre neuropathy; specialist interpretation should be integrated with clinical localisation.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Nociceptive pain

Local aching, tenderness and movement provocation without sensory change may arise from bone, joint or soft tissue and often coexists with neuropathy.

Metastatic cord compression

Progressive back or radicular pain with weakness, gait or sphincter change is an emergency diagnosis rather than routine peripheral neuropathy.

Vascular or inflammatory limb disease

Ischaemia, thrombosis, cellulitis, gout and lymphoedema can produce burning pain, colour change and tenderness but have different examination findings.

Opioid-induced hyperalgesia

Diffuse pain sensitivity and allodynia emerging with high-dose escalation may reflect opioid neurotoxicity rather than progressive neural injury.

Chronic primary pain

Widespread pain without a plausible somatosensory lesion may reflect central nociplastic processing and should not be labelled neuropathic from adjectives alone.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Initial treatmentChoose one adjuvant by patient riskFirst stepNon-trigeminal neuropathic pain is diagnosed and no neurological emergency requires immediate intervention.

1Identify and treat the cause, define a sleep or function goal and review renal, hepatic, cardiac, falls, mood, interaction and misuse risks.
2Choose amitriptyline, duloxetine, gabapentin or pregabalin, start at a tolerable dose and provide titration, driving and withdrawal information.
3Review after each increase and after an adequate trial; continue for meaningful benefit, taper and switch for failure or harm and avoid abrupt gabapentinoid cessation.

02Neurological emergencyImage and treat compression urgentlyNeuropathic pain is accompanied by new weakness, gait change, sphincter disturbance, saddle loss or other progressive central signs.

1Perform and document a full neurological examination, protect a potentially unstable spine and contact the acute oncology, spinal or neurological service immediately.
2Obtain urgent MRI or other pathway imaging and start condition-specific emergency treatment, including dexamethasone for neurological MSCC when indicated.
3Coordinate surgery or radiotherapy decisions, thromboprophylaxis and rehabilitation while providing analgesia that does not delay reassessment.

03Localised painReduce systemic sedative burdenA small painful area is superficial and oral agents are unsuitable, unwanted or causing systemic adverse effects.

1Confirm intact skin and a peripheral localised mechanism and explain that burning can occur during topical treatment.
2Offer capsaicin cream according to the BNF, using gloves and avoiding eyes, mucosa, broken skin and heat immediately after application.
3Review adherence and benefit after an adequate trial and refer for specialist topical patch or interventional options when disability persists.

04Refractory complexityReformulate before combining medicinesTwo appropriate monotherapy trials fail, toxicity prevents dosing or mixed cancer pain remains disabling.

1Recheck lesion, progression, adherence, opioid neurotoxicity, mood, sleep and whether the functional target remains realistic.
2Refer to specialist pain, palliative, neurology or oncology services for combination therapy, nerve procedure, radiotherapy or advanced topical treatment.
3Use one coordinated taper and initiation schedule, monitor interaction and falls risk and retain rehabilitation and psychological support.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

One NICE initial option that may particularly help nocturnal pain and sleep when anticholinergic burden is acceptable.

Amitriptyline for neuropathic pain

Start 10 mg orally at night, or 10 to 25 mg in a younger robust adult, and titrate slowly every one to two weeks according to response and the BNF, usually not exceeding 75 mg nightly for pain.

Avoid or use specialist caution with arrhythmia, glaucoma, urinary retention, severe constipation, cognitive impairment, falls and overdose risk; sedation and postural hypotension are common.

One NICE initial option, with evidence in painful diabetic neuropathy and possible concurrent benefit for depression or anxiety.

Duloxetine for neuropathic pain

A common regimen is 60 mg orally once daily, with 30 mg once daily initially when tolerability is a concern before increasing under the BNF and local pathway.

Review liver disease, renal impairment, blood pressure, hyponatraemia, bleeding and serotonergic interactions; nausea and withdrawal occur, so taper rather than stop abruptly.

One NICE initial option for peripheral or central neuropathic pain when a gradual trial is feasible.

Gabapentin for neuropathic pain

Start low, often 100 to 300 mg orally at night in frailty or 300 mg once daily in a robust adult, then titrate in divided doses according to the BNF, response and mandatory renal adjustment.

Dizziness, somnolence, oedema, falls, misuse, dependence and respiratory depression with opioids occur; reduce in renal impairment and taper after sustained use.

One NICE initial option with simpler pharmacokinetics than gabapentin but similar sedative and dependence concerns.

Pregabalin for neuropathic pain

A common adult starting regimen is 75 mg orally twice daily, or lower in frailty or renal impairment, with gradual BNF-guided titration no more frequently than clinically appropriate.

Adjust to creatinine clearance, monitor dizziness, oedema, weight, falls, misuse and breathing with opioids and taper gradually to avoid withdrawal.

A NICE option when localised peripheral neuropathic pain is suitable and oral treatment is avoided or poorly tolerated.

Capsaicin cream for localised neuropathic pain

Apply a small amount of 0.075% capsaicin cream to the affected intact skin three or four times daily according to the product and BNF instructions for an adequate trial.

Transient burning is common; use gloves, wash hands, avoid broken skin, eyes and mucosa and do not apply immediately before or after hot bathing.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Sleep and mood disturbance

Paroxysms, allodynia and fear of touch disrupt sleep, self-care, intimacy and mood, increasing disability beyond average pain intensity.

Falls and unnoticed injury

Sensory loss, weakness and sedating adjuvants combine to cause gait instability, burns, foot ulcers and pressure injury.

Treatment toxicity

Anticholinergic burden, postural hypotension, hyponatraemia, oedema, sedation, respiratory depression and dependence can outweigh modest analgesic benefit.

Progressive neurological loss

Failure to investigate compression, plexopathy or toxic neuropathy can permit irreversible weakness, sphincter dysfunction and loss of independence.

Polypharmacy without benefit

Adding several adjuvants before adequate single-drug trials obscures response, compounds sedation and makes safe tapering difficult.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track the agreed goal such as sleep, clothing tolerance, walking or self-care and do not rely on pain intensity alone.
Review sedation, dizziness, postural symptoms, falls, cognition, oedema, weight and respiratory effect after each titration.
Repeat renal assessment and adjust gabapentin or pregabalin during dehydration, acute kidney injury or declining function.
Ask about mood, suicidal thinking, misuse, dose escalation and withdrawal symptoms during dependence-forming medicine use.
Map power, gait and sphincter symptoms again when pain progresses because neurological compromise can emerge after an initially sensory presentation.
Taper ineffective treatment gradually, document the outcome of each adequate trial and avoid indefinite low-dose polypharmacy with no measurable benefit.
Inspect insensate skin and feet and reinforce pressure, heat and footwear protection even when painful symptoms improve.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Descriptors need anatomy

Burning language alone is insufficient; distribution and sensory examination should point to a credible somatosensory lesion.

Numbness can hurt

Deafferented areas may contain severe spontaneous pain, so reduced sensation does not contradict neuropathic suffering.

Analgesia may precede numbness change

Adjuvants can reduce painful firing without restoring lost axons or protective sensation, leaving injury prevention essential.

Time horizon changes prescribing

A medicine taking weeks to titrate may offer little value in the last days unless it is continuing an effective established regimen.

Gabapentinoids are not benign

Controlled-drug status, dependence, renal accumulation and respiratory interaction require the same precision applied to opioids.

Combination is a specialist decision

Partial monotherapy responses may support combination, but compounded sedation and uncertain incremental benefit require explicit review.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing neuropathic pain from the word burning without anatomical evidence.
02
Starting an adjuvant while delaying urgent MRI for progressive neurological signs.
03
Offering every first-line drug simultaneously rather than one interpretable trial.
04
Using standard gabapentinoid doses despite severe renal impairment.
05
Combining gabapentinoids, opioids and benzodiazepines without respiratory review.
06
Stopping pregabalin or gabapentin abruptly after sustained treatment.
07
Continuing ineffective low doses indefinitely without titration or taper.
08
Choosing amitriptyline without checking falls, urinary retention and anticholinergic burden.
09
Promising complete pain abolition and neglecting functional rehabilitation.
10
Forgetting skin and foot protection when sensory loss persists.