Chronic Pain & Neuropathic Pain

Chronic pain persists beyond the expected period of tissue healing (conventionally >3 months) and is itself a disease state rather than a mere symptom. Neuropathic pain arises from a lesion or disease of the somatosensory nervous system, behaves very differently from nociceptive pain, and responds to a distinct pharmacological toolkit. This is a favourite Anaesthesia/pain-medicine area for sensitisation physiology, drug-of-choice questions, and CRPS differentiation.

Definitions & classification

Pain (IASP, revised 2020) is "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage." The revision deliberately removed the requirement that pain be reported in words, so non-verbal patients and neonates are covered.

Pain is broadly classified by mechanism:

Type	Mechanism	Typical descriptors	Example
Nociceptive	Activation of nociceptors by actual/threatened tissue damage	Aching, throbbing, well-localised (somatic) or dull/cramping (visceral)	Fracture, post-operative pain, OA
Neuropathic	Lesion/disease of somatosensory system	Burning, shooting, electric, pins-and-needles	Diabetic neuropathy, post-herpetic neuralgia, sciatica
Nociplastic	Altered nociception without clear tissue/nerve damage	Diffuse, fluctuating, with fatigue/sleep disturbance	Fibromyalgia, IBS, non-specific LBP

High-yield: Nociplastic pain is the newest IASP category (third mechanistic descriptor). Fibromyalgia is the prototype — central sensitisation without demonstrable nociceptive input or nerve lesion.

Neuropathic pain is further split by site of lesion:

• Peripheral — diabetic painful neuropathy, post-herpetic neuralgia, trigeminal neuralgia, post-amputation/phantom limb, chemotherapy-induced (vincristine, cisplatin, taxanes), entrapment (carpal tunnel), HIV neuropathy.
• Central — central post-stroke pain (Dejerine–Roussy, thalamic), spinal cord injury pain, multiple sclerosis pain, syringomyelia.

Grading of neuropathic pain (IASP): pain in a neuroanatomically plausible distribution + history of a relevant lesion → possible; add confirmatory sensory signs in that territory → probable; add a confirmatory test (imaging, EMG/NCS, skin biopsy) → definite.

Pathophysiology — peripheral & central sensitisation

This is the conceptual core and the most examined sub-topic. After injury, the nociceptive system becomes pathologically hyperexcitable at multiple levels.

Peripheral sensitisation occurs at the nociceptor terminal. The "inflammatory soup" — bradykinin, prostaglandins (PGE2), serotonin, histamine, H⁺, ATP, substance P, NGF — lowers the threshold and increases responsiveness of peripheral nociceptors (notably TRPV1 channels). PGE2 phosphorylates Na_v1.7/1.8 sodium channels, increasing firing. Clinically this produces primary hyperalgesia — exaggerated pain at the site of injury.

Central sensitisation is an activity-dependent increase in excitability of dorsal-horn (and higher) neurons. Mechanism:

1. Repetitive C-fibre input releases glutamate and substance P / CGRP at the dorsal horn.
2. Glutamate acts on AMPA receptors initially; sustained input expels the Mg²⁺ block from the NMDA receptor.
3. NMDA activation → Ca²⁺ influx → activation of PKC, nitric oxide synthase, and gene transcription → long-lasting facilitation.
4. Result: enlarged receptive fields, reduced thresholds, and pain spreading to uninjured tissue → secondary hyperalgesia.

High-yield: The NMDA receptor is the molecular linchpin of central sensitisation and "wind-up." NMDA antagonists (ketamine, methadone — also an NMDA blocker) attenuate it. This is why pre-emptive/preventive analgesia and ketamine reduce chronic post-surgical pain.

Wind-up is the progressive increase in the magnitude of dorsal-horn neuron response to repetitive, constant-intensity C-fibre stimulation (≈0.5–1 Hz). It is a short-term, NMDA-dependent phenomenon and a precursor/component of central sensitisation — distinguish it in MCQs from long-term potentiation (a longer-lasting form).

Additional contributors to neuropathic pain:

• Ectopic discharge from injured axons and dorsal root ganglion due to up-regulation/redistribution of voltage-gated sodium channels (Na_v1.3, 1.7, 1.8).
• Loss of descending inhibition (noradrenergic/serotonergic pathways from PAG–RVM) and gain of descending facilitation — rationale for TCAs/SNRIs.
• Reduced GABA/glycine inhibition ("disinhibition") in the dorsal horn → tactile Aβ fibres gain access to pain-signalling neurons → allodynia.
• Microglial and astrocyte activation (neuroinflammation) maintaining the sensitised state.
• Phenotypic switch: Aβ touch fibres begin expressing substance P.

Key terms (definitions are frequently asked verbatim)

Term	Definition
Allodynia	Pain due to a stimulus that does not normally provoke pain (e.g., light touch)
Hyperalgesia	Increased pain from a stimulus that normally provokes pain
Hyperpathia	Explosive, prolonged pain after repetitive/threshold stimulus, often with after-sensation
Hyperaesthesia	Increased sensitivity to stimulation (excludes special senses)
Dysaesthesia	Unpleasant abnormal sensation, spontaneous or evoked
Paraesthesia	Abnormal sensation, not unpleasant (pins-and-needles)
Hypoalgesia	Diminished pain to a normally painful stimulus

High-yield: Allodynia = pain from a non-painful stimulus; hyperalgesia = more pain from a painful stimulus. The "non-painful → painful" conversion is mediated by Aβ-fibre input gaining access to central pain circuits.

Clinical features

Neuropathic pain is suggested by quality (burning, electric-shock, shooting, lancinating), the presence of negative sensory signs (numbness, sensory loss) alongside positive signs (allodynia, hyperalgesia, paraesthesia), a neuroanatomically plausible distribution, and poor response to conventional NSAIDs/opioids.

Screening tools: LANSS, DN4 (Douleur Neuropathique 4 — 4 questions, cut-off ≥4/10 suggests neuropathic pain), painDETECT, and the Neuropathic Pain Questionnaire. These distinguish neuropathic from nociceptive pain at the bedside.

Disease-specific pearls:

• Trigeminal neuralgia: paroxysmal, unilateral, electric-shock-like pain in V2/V3, triggered by chewing/touch; consider MS in the young/bilateral.
• Post-herpetic neuralgia: pain persisting >3 months after the herpes zoster rash; dermatomal; the commonest complication of zoster in the elderly.
• Diabetic peripheral neuropathy: symmetrical, distal, "stocking-glove," burning, worse at night.

Diagnosis & investigations

The diagnosis is primarily clinical (history + neurological examination demonstrating sensory signs in a relevant distribution). Confirmatory tests upgrade certainty:

• Nerve conduction studies / EMG — assess large-fibre function (does not detect small-fibre neuropathy).
• Skin punch biopsy with intra-epidermal nerve fibre density — investigation of choice for small-fibre neuropathy (where NCS is normal).
• Quantitative sensory testing (QST) — graded thermal/mechanical thresholds.
• MRI — for central lesions (stroke, MS, syrinx, cord compression) and for trigeminal neuralgia (neurovascular conflict, MS plaques).
• Quantitative sudomotor axon reflex test (QSART) — autonomic small-fibre function; used in CRPS/autonomic neuropathy.

High-yield: A patient with burning feet, normal NCS → think small-fibre neuropathy → confirm with skin biopsy (reduced intra-epidermal nerve fibre density).

Management & drug of choice

Treat the underlying cause (glycaemic control, decompression, antivirals early in zoster) plus a biopsychosocial, multimodal strategy: pharmacotherapy + physiotherapy + psychological therapy (CBT) + interventional procedures.

Pharmacological ladder for neuropathic pain (NeuPSIG / NICE CG173)

First line: gabapentinoids (gabapentin, pregabalin), TCAs (amitriptyline, nortriptyline), and SNRIs (duloxetine, venlafaxine). Second line: tramadol, topical agents (lidocaine 5% patch, capsaicin 8% patch). Third line: strong opioids (oxycodone, morphine — limited role), botulinum toxin A (focal peripheral).

Approach flow: Confirm neuropathic pain (DN4 ≥4) → choose a first-line agent matched to comorbidity → titrate to effect/max tolerated dose over weeks → if inadequate, switch within first-line or combine (e.g., gabapentinoid + TCA/duloxetine) → add topical/tramadol → refer to pain specialist for interventions.

Drug class	Examples	Mechanism	Key adverse effects / notes
Gabapentinoids	Gabapentin, Pregabalin	Bind α2δ subunit of voltage-gated Ca²⁺ channels → ↓ glutamate/substance P release	Sedation, dizziness, oedema, weight gain. Pregabalin has linear, dose-proportional kinetics & higher bioavailability; abuse potential
TCAs	Amitriptyline, nortriptyline	Inhibit NA & 5-HT reuptake → boost descending inhibition; Na-channel & NMDA block	Anticholinergic, sedation, arrhythmia; caution in IHD/elderly. Nortriptyline better tolerated
SNRIs	Duloxetine, venlafaxine	NA + 5-HT reuptake inhibition	Nausea, ↑BP (venlafaxine). Duloxetine = DOC for painful diabetic neuropathy
Topical	Lidocaine 5% patch, Capsaicin 8% patch	Na-channel block / TRPV1 defunctionalisation	Localised PHN; minimal systemic effect
Others	Carbamazepine, tramadol, ketamine	Na-channel block / opioid+SNRI / NMDA antagonism	—

Condition-specific drugs of choice (commonly tested):

• Trigeminal neuralgia → carbamazepine (DOC; oxcarbazepine alternative). Refractory → microvascular decompression (best long-term surgical result) or percutaneous/gamma-knife.
• Painful diabetic neuropathy → duloxetine or pregabalin (both FDA-approved; pregabalin, duloxetine, tapentadol are the FDA-approved trio).
• Post-herpetic neuralgia → gabapentin/pregabalin, lidocaine 5% patch, TCA; prevent with recombinant zoster vaccine.
• Fibromyalgia → duloxetine, milnacipran, pregabalin (FDA-approved); avoid opioids.

High-yield: Gabapentinoids act on the α2δ subunit of voltage-gated calcium channels — a near-guaranteed pharmacology MCQ. They do not act on GABA receptors despite the name.

High-yield: Conventional NSAIDs and pure opioids are relatively ineffective for neuropathic pain; this poor opioid responsiveness is a classic differentiating feature.

WHO analgesic ladder (for cancer/nociceptive pain, contrast with above): Step 1 non-opioid ± adjuvant → Step 2 weak opioid (codeine/tramadol) ± non-opioid ± adjuvant → Step 3 strong opioid (morphine) ± non-opioid ± adjuvant. A fourth step (interventional — neuraxial, blocks, neurolysis) is now often added.

Complex Regional Pain Syndrome (CRPS)

A high-yield, frequently-confused topic. CRPS is a regional pain syndrome usually following trauma/surgery to a limb, with pain disproportionate to the inciting event plus sensory, vasomotor, sudomotor/oedema, and motor/trophic changes.

Feature	CRPS Type I	CRPS Type II
Old name	Reflex Sympathetic Dystrophy (RSD)	Causalgia
Nerve lesion	No definable nerve injury	Definite nerve injury present
Trigger	Minor trauma, fracture, immobilisation	Major nerve trauma (e.g., gunshot)
Distribution	Regional, not nerve-territory	Initially the injured nerve's territory
Diagnostic criteria	Budapest criteria apply to both types

High-yield: The ONLY essential difference between CRPS I and II is the presence of an identifiable nerve injury (present in Type II/causalgia, absent in Type I/RSD). Both share identical clinical features and the Budapest diagnostic criteria.

Budapest (IASP) clinical criteria require:

1. Continuing pain disproportionate to the inciting event.
2. ≥1 symptom in 3 of 4 categories: Sensory (hyperalgesia/allodynia), Vasomotor (temperature/colour asymmetry), Sudomotor/oedema (sweating/swelling), Motor/trophic (weakness, tremor, dystonia; nail/hair/skin changes).
3. ≥1 sign at evaluation in 2 of 4 of the same categories.
4. No better explanation.

Investigations: largely clinical; three-phase bone scan (periarticular uptake) supports it; plain films may show patchy Sudeck atrophy (osteopenia). Management: early physiotherapy/mobilisation is the cornerstone, graded motor imagery/mirror therapy, neuropathic-pain drugs, short steroid course in acute/inflammatory phase, bisphosphonates, and sympathetic blocks (stellate ganglion for upper limb, lumbar sympathetic for lower limb); spinal cord stimulation for refractory cases.

Interventional & non-pharmacological options

• Nerve blocks / neurolysis (e.g., coeliac plexus block for pancreatic cancer pain, stellate ganglion block).
• Epidural/intrathecal analgesia; intrathecal drug delivery pumps (morphine, ziconotide, baclofen).
• Spinal cord stimulation — strongest evidence in CRPS and failed back surgery syndrome (FBSS).
• Radiofrequency ablation (e.g., medial branch for facet pain), pulsed RF.
• TENS, acupuncture, CBT, graded exercise, mirror therapy for phantom limb.

Complications

• Disability, deconditioning, joint contractures (especially CRPS).
• Opioid-related: tolerance, dependence, opioid-induced hyperalgesia (paradoxically lowered pain threshold — NMDA-mediated), constipation, hypogonadism.
• Depression, anxiety, sleep disturbance, suicidality — bidirectional with chronic pain.
• Gabapentinoid misuse and respiratory depression when combined with opioids.
• Chronic post-surgical pain (CPSP) — risk factors: severe acute post-op pain, pre-existing pain, psychological vulnerability, nerve-injuring surgery (thoracotomy, mastectomy, amputation, hernia).

Key differentials

• Nociceptive vs neuropathic vs nociplastic — distinguish by descriptors, distribution, sensory signs, and treatment response (table above).
• Trigeminal neuralgia vs atypical facial pain / dental pain / cluster headache — paroxysmal vs continuous; trigger zones; autonomic features in cluster.
• CRPS vs cellulitis / DVT / lymphoedema / inflammatory arthritis — CRPS pain is disproportionate with vasomotor/sudomotor change but no infection markers.
• Diabetic neuropathy vs B12 deficiency, alcohol, uraemia, hypothyroid, paraneoplastic, vasculitic neuropathy — screen reversible causes.
• Radicular (sciatica) vs referred somatic pain — dermatomal radiation, straight-leg raise, neurological deficit.

Recently asked / exam angle

• Allodynia vs hyperalgesia — definitions are repeatedly asked; "pain from light touch" = allodynia.
• Wind-up phenomenon is NMDA-receptor mediated (single-best-answer staple).
• Gabapentin/pregabalin act on the α2δ subunit of voltage-gated Ca²⁺ channels — pharmacology favourite.
• Causalgia = CRPS Type II (nerve injury present); RSD = Type I. The differentiating feature is nerve injury.
• DOC trigeminal neuralgia = carbamazepine; DOC painful diabetic neuropathy = duloxetine/pregabalin.
• DN4 ≥4 screens neuropathic pain; Budapest criteria diagnose CRPS.
• IASP 2020 pain definition revision and the addition of nociplastic pain as the third descriptor.
• Pre-emptive/preventive analgesia & ketamine reduce central sensitisation and chronic post-surgical pain.
• Skin biopsy (IENFD) = test of choice for small-fibre neuropathy when NCS is normal.
• Methadone and ketamine both possess NMDA-antagonist activity relevant to neuropathic/opioid-refractory pain.

Rapid revision

1. Chronic pain = pain persisting >3 months; a disease in its own right.
2. Central sensitisation is driven by the NMDA receptor; "wind-up" is its short-term, frequency-dependent precursor.
3. Allodynia = pain from non-painful stimulus; hyperalgesia = exaggerated pain from a painful stimulus.
4. Gabapentinoids bind the α2δ subunit of voltage-gated Ca²⁺ channels — not GABA receptors.
5. First-line neuropathic agents: gabapentinoids, TCAs, SNRIs; opioids/NSAIDs are largely ineffective.
6. Duloxetine and pregabalin are DOC for painful diabetic neuropathy; carbamazepine for trigeminal neuralgia.
7. CRPS II = causalgia (nerve injury present); CRPS I = RSD (no nerve injury) — same Budapest criteria.
8. Budapest CRPS criteria: 4 categories — sensory, vasomotor, sudomotor/oedema, motor/trophic.
9. Three-phase bone scan supports CRPS; Sudeck atrophy = patchy osteopenia on X-ray.
10. Skin punch biopsy (reduced IENFD) confirms small-fibre neuropathy when NCS is normal.
11. DN4 ≥4 flags neuropathic pain; LANSS/painDETECT are alternatives.
12. Early mobilisation/physiotherapy is the cornerstone of CRPS management; SCS for refractory CRPS and FBSS.