Pain after Traumatic Peripheral Nerve Injury
This topic possibly falls outside the purview of the exam, based on a lack of robust curriculum item supporting its inclusion.
It is included based on a recent BJA Education article and relevance to pain medicine.
Traumatic peripheral nerve injury (TPNI) is a well-recognised cause of chronic neuropathic pain
Aetiology
Sharp laceration e.g. glass, blades: the most common cause
High-energy blunt trauma causing traction or acute compression; often associated with fracture or dislocation
Digit or limb amputation: necessitates nerve division and carries a particularly high risk of neuropathic pain
Iatrogenic: 8 - 25% of peripheral nerve injuries
Nerve interventions e.g. decompression, nerve blocks, nerve graft harvest, radiofrequency ablation
Unrelated surgery e.g. cancer resection, orthopaedic surgery, inguinal hernia repair
Poor perioperative positioning
Tourniquet use
Nerve injury specifically following regional or neuraxial anaesthesia is covered on the nerve injury page
Often affects younger adults and is associated with persistent pain, functional impairment and considerable socioeconomic and medicolegal impact
ICD-11 lists chronic peripheral neuropathic pain as a primary category, with pain after peripheral nerve injury a distinct entity
Diagnosis requires:
A documented or plausible history of nerve injury
A temporal relationship between injury and symptom onset
A neuroanatomically plausible distribution of pain and sensory change
Clinical signs of nerve dysfunction within that same distribution: sensory loss, allodynia or hyperalgesia
It is also cross-referenced under chronic post-traumatic and post-surgical pain, reflecting its frequent association with procedures
Nerve Structure
The connective tissue 'scaffold'
Axons sit within a hierarchical connective tissue framework which provides mechanical protection and an environment permissive to regeneration
From innermost to outermost:
Basal lamina: extracellular matrix secreted by Schwann cells, which maintains alignment of the axon-Schwann cell unit
Endoneurium: loose connective tissue around each axon, which supports axonal homeostasis and guides longitudinal regrowth
Perineurium: multilayered sheath surrounding each fascicle, with tight junctions to provide compartmentalisation and resilience
Epineurium: outermost layer enclosing multiple fascicles, which provides tensile strength
The predominant glial cell of the peripheral nervous system
Myelinate fast-conducting motor and sensory axons, and support unmyelinated axons including those subserving pain
Essential for axonal regeneration after injury
If reinnervation is delayed beyond 6 - 12 weeks they progressively lose their repair phenotype - trophic support falls and some undergo apoptosis
Axons rely on aerobic metabolism
Segmental pedicles feed longitudinal vascular plexi within the endoneurium and intraneural connective tissue
Focal hypoperfusion ± intraneural oedema is the most common cause of physiological conduction block, and is rapidly reversible (minutes to hours)
Classification
The Seddon classification is covered on the nerve injury page
Sunderland expanded this into five grades of ultrastructural disruption:
Sunderland
Seddon
Structures disrupted
Grade I
Neurapraxia
Myelin only
Grade II
Axonotmesis
Axon; scaffold preserved
Grade III
Axonotmesis
Axon and endoneurium
Grade IV
Axonotmesis
Axon, endoneurium and perineurium; epineurium preserved
Grade V
Neurotmesis
Complete disruption of axon and scaffold
Grades III - V involve progressive scaffold disruption, with:
↓ potential for spontaneous recovery
↑ need for surgical reconstruction
Degeneration and Regeneration
The response to injury occurs in four sequential phases: degeneration, regeneration, remyelination and reinnervation
Neurapraxia
Focal demyelination with axons in continuity
No Wallerian degeneration
Schwann cell-mediated remyelination
Recovery typically rapid (3 - 6 weeks) and almost complete
Axonotmesis and neurotmesis
Distal axon loses connection to the cell body and degenerates
Ca2+ influx activates calpain proteases, breaking down the cytoskeleton and causing irreversible conduction failure distally
The proximal axon dies back by around one node of Ranvier before sealing off
Wallerian degeneration
Begins within days and is well established by 1 - 2 weeks
Active process which clears the degenerating axon and the endoneurial tube
Macrophages are recruited to clear myelin debris
Schwann cells switch to a repair phenotype:
Proliferate and migrate along the nerve
↓ myelin-associated proteins which inhibit axonal growth
Secrete neurotrophic factors e.g. nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF)
Bands of Büngner - Schwann cells align within basal lamina tubes, guiding axons back along their original path
Regenerating axons grow at approximately 1mm per day
Success depends on scaffold integrity:
Regeneration may occur spontaneously after axonotmesis
Does not occur after neurotmesis unless surgery restores scaffold continuity
Disorganised axonal sprouting within fibrotic stroma
Hyperexcitable and non-conductive, and frequently associated with neuropathic pain
Two subtypes:
Neuroma-in-continuity, which is almost inevitable after scaffold disruption or surgical repair with up to half of axons failing to exit the lesion
Terminal neuroma, which follows unreconstructed grade V injury or amputation
Motor
The neuromuscular junction remains structurally intact for several months
Failure to reinnervate within 12 months leads to irreversible motor endplate degeneration and permanent denervation atrophy
Sensory
Receptors (e.g. Merkel cells, Meissner corpuscles) persist for 2 - 3 years
Explains better outcomes with delayed sensory reinnervation
Both lesion-to-target distance and delays before surgery therefore determine outcome
Urgent diagnosis, grading and early referral to a peripheral nerve service are essential
Pain Mechanisms
Peripheral changes at the injured axon
Ionic instability: Ca2+ influx and Na+ /K+ ATPase dysfunction impair repolarisation
↑ voltage-gated Na+ channels: spontaneous (ectopic) action potentials
↓ K+ channels and ↑ N-type Ca2+ channels: prolonged depolarisation and ↑ neurotransmitter release
↑ transducer channels (TRP, P2X, acid-sensing ion channels, Piezo): axon becomes hyper-responsive to thermal, chemical and mechanical stimuli
Schwann cells and macrophages release proinflammatory cytokines (TNF-α, IL-1β, IL-6) and neurotrophic factors (NGF, BDNF, GDNF)
These lower nociceptor thresholds and drive maladaptive regeneration
NGF in denervated skin ↑ nociceptive innervation in areas of overlap from neighbouring nerves: primary allodynia
↑ density of Na+ channels and mechanosensitive channels: spontaneous and mechanically evoked firing
Clinically: focal mechanical hypersensitivity, positive Tinel's sign, allodynia or hyperalgesia
The presence of a neuroma does not by itself predict pain; many are asymptomatic
Local mechanical irritation is important e.g. a prosthetic socket after amputation
Sympathetically maintained pain
Aberrant sympathetic sprouting ↑ α1 -adrenoceptor expression on nociceptors
Features: cold allodynia, colour change, pain worsened by emotional or autonomic arousal
Hyperexcitable afferents release glutamate and substance P in laminae I - II of the dorsal horn
AMPA and NMDA receptor activation on second-order neurones: wind-up and long-term potentiation
↓ inhibitory GABAergic and glycinergic tone
Activated microglia and astrocytes further amplify dorsal horn excitability
Descending modulation is disrupted:
↓ noradrenergic tone from the locus coeruleus
Serotonergic signalling may shift from inhibition to facilitation
Supraspinal structural and functional changes integrate sensory, emotional and cognitive aspects of pain
Psychological and social factors can reinforce pain behaviours
Principles of Management
Prevention, early recognition and timely mitigation remain the primary goals
Interventions are most effective within a multidisciplinary, biopsychosocial framework and follow optimisation of:
Pharmacological therapy
Physical rehabilitation
Psychological support
Specialist management of motor deficits
There is no universal treatment algorithm; decisions are individualised
Patient goals should guide treatment e.g. restoring tolerance to footwear, orthoses or a prosthetic socket
Considerations before intervention
Adjacent surgical metalwork carries infection risk and imaging artefact
Depth of the affected nerve
Nerve composition: sensory vs mixed (risk of motor deficit)
Isolated nerve vs multiple nerves with overlapping distal innervation
Step
Approach
1
Early specialist peripheral nerve surgical assessment
2
Non-surgical targeted interventions, escalating from non-invasive to invasive
3
Implantable neuromodulation
Refer for a specialist peripheral nerve surgical opinion if any of the following are present:
Symptomatic neuroma
Nerve tethering, entrapment or compression
Irritation from adjacent metalwork or scar
Pain which is clearly mechanically provoked (pressure, movement, contact)
Non-Surgical Interventions
TENS: inexpensive and safe, but variable efficacy and limited evidence of long-term benefit
Topical therapies for superficial allodynia:
High-dose capsaicin 8% patch; can be delivered in outpatients
Lidocaine 5% plaster
Perineural local anaesthetic ± corticosteroid
Ultrasound-guided; usually provides only transient analgesia
Mainly diagnostic: combined with nerve stimulation, reproduction of the patient's typical pain confirms which nerve is responsible
Particularly useful where territories overlap or there are multiple sensory branches
Relief outlasting the expected duration of the local anaesthetic may predict benefit from neuromodulation
Third-line option in recent IASP neuropathic pain guidance
Mechanism: inhibits SNAP-25-dependent neurotransmitter release, ↓ voltage-gated Na+ channel activity and modulates TRPV1 expression
Given perineurally (superficial sensory nerves) or intradermally (focal cutaneous allodynia)
Benefit usually lasts several weeks; can be repeated at 10 - 12 week intervals
Ultrasound-guided injection of fluid to separate the nerve from scar, fascia or fibrotic tissue
Aims to restore nerve gliding, improve perfusion and ↓ mechanical sensitisation
Saline 0.9% (inert mechanical separation) or 5% dextrose (possible additional antinociceptive effect via TRPV1); neither is neurotoxic
Used where scarring, entrapment or tethering is suspected e.g. persistent symptoms after carpal tunnel surgery; often repeated over 3 - 4 sessions
The least invasive needle-based neuromodulation technique
Evidence less robust than for implantable devices, but emerging data support its use in post-surgical and post-traumatic neuropathic pain
Joule-Thomson effect: pressurised gas (N2 O or CO2 ) expands within the probe, forming an ice ball at around -70°C
Produces a cold-induced axonotmesis causing Wallerian-like degeneration but with the scaffold preserved, allowing later regeneration
Unlike radiofrequency ablation, which disrupts the scaffold
Best suited to sensory nerves (e.g. saphenous) or mixed nerves with limited motor function (e.g. intercostal)
Mixed nerves with a substantial motor component only where motor deficit is pre-existing or acceptable
Advantages
Disadvantages
Reversible conduction block
Temporary: function returns over weeks to months
Scaffold preserved, so regeneration possible
Motor block if mixed nerve targeted
Relief of 2 - 6 months in over half of patients
Limited evidence base
Implantable Neuromodulation
A non-destructive, reversible strategy for refractory neuropathic pain
Each modality targets a different level of the somatosensory pathway:
Modality
Target
Best suited to
Peripheral nerve stimulation
Lead placed percutaneously next to the affected nerve
Single-nerve injury with focal pain
Dorsal root ganglion stimulation
DRG of the affected spinal segment
Focal dermatomal pain, or where peripheral targeting is not feasible
Spinal cord stimulation Dorsal columns
Diffuse or multi-nerve involvement
Spinal cord stimulation is the most established technique; NICE supports its use in chronic neuropathic pain
Dorsal root ganglion stimulation allows precise dermatomal targeting with fewer off-target effects, and has been shown to outperform spinal cord stimulation for focal neuropathic pain
Surgical Interventions
Surgical approach is guided by whether the affected nerve is still functioning
Pain arises from anatomically restricted trigger areas which can be improved surgically
Neurolysis: release from compression, traction or tethering
External: microsurgical dissection from surrounding scar
Internal: epineurotomy and selective intraneural dissection where fascicles are variably affected
Removal of metalwork irritating or compressing the nerve
Aims to restore gliding, improve perfusion and ↓ mechanical sensitisation
The focus is management of the neuroma
Simple neurectomy is considered obsolete
Instead: excise the neuroma, move the nerve away from sites of mechanical triggering and allow it to regenerate into a quiescent target
Neuroma-in-continuity: excision then direct repair, or gap repair with autograft, processed allograft or synthetic conduit
Terminal neuroma: excision then reconstruction
Side-to-end repair into an adjacent healthy sensory nerve
Targeted muscle reinnervation (TMR): nerve joined to a redundant motor nerve branch
Regenerative peripheral nerve interface (RPNI): nerve implanted into a free muscle graft
TMR and RPNI create a physiological 'sink' which dampens ectopic discharge and aberrant sprouting
Surgery achieves meaningful pain relief in around 70% of neuromas, with TMR giving the best results
Fat grafting: mechanical protection and anti-inflammatory effects
Pedicled or free flaps: well-vascularised tissue which improves gliding and supports nerve repair
Surgery should sit within the wider multidisciplinary pathway:
Perioperative analgesia including regional anaesthesia
Physiotherapy for mobilisation and desensitisation
Psychological support