Neuropathic Pain - Mechanisms and Management

Quick Answer

What is neuropathic pain?

Neuropathic pain is defined by the International Association for the Study of Pain (IASP) as "pain caused by a lesion or disease of the somatosensory nervous system." It affects 6-10% of the general population, with higher prevalence in diabetes (25-50%), HIV/AIDS (30%), multiple sclerosis (50%), and following herpes zoster (30-50% of patients aged >60). [1,2,3]

Key distinguishing features:

• Positive symptoms: Burning, shooting, electric shock-like, lancinating pain; allodynia (pain from non-painful stimuli); hyperalgesia (exaggerated pain response)
• Negative symptoms: Numbness, reduced sensation, sensory loss
• Characteristic qualities: Pain in an area of sensory abnormality; often worse at night

Mechanisms:

Evidence-based pharmacological management (NeuPSIG 2019):

Second-line agents:

• Tramadol (opioid + SNRI properties)
• Capsaicin 8% patch (post-herpetic neuralgia)
• Lidocaine 5% patch (localized neuropathic pain)
• Botulinum toxin (trigeminal neuralgia, peripheral neuropathy)

Interventional options:

• Spinal cord stimulation (failed back surgery syndrome, CRPS, peripheral neuropathy)
• Dorsal root ganglion stimulation
• Peripheral nerve stimulation
• Intrathecal drug delivery (refractory cases)

Key principle: Neuropathic pain responds poorly to conventional analgesics (NSAIDs, simple opioids). Multimodal therapy targeting specific mechanisms is required. Combination therapy (gabapentinoid + TCA/SNRI) may be synergistic.

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Clinical Overview

Definition and Classification

IASP Definition (2017): "Pain caused by a lesion or disease of the somatosensory nervous system."

Classification by Location:

Classification by Etiology:

Diagnostic Criteria (NeuPSIG 2016):

Definite neuropathic pain:

1. Pain with distinct neuroanatomically plausible distribution
2. History suggestive of relevant lesion/disease affecting peripheral or central somatosensory system
3. Demonstration of distinct neuroanatomically plausible distribution by at least one confirmatory test:
   • Demonstration of the lesion/disease by imaging or neurophysiology
   • Demonstration of pain or sensory abnormalities within neuroanatomically plausible distribution

Probable neuropathic pain:

• Criteria 1 and 2 above, but no confirmatory test

Epidemiology

Risk factors:

• Age (increasing prevalence with age)
• Female gender (some conditions)
• Diabetes mellitus
• Vitamin B12 deficiency
• Alcohol abuse
• HIV infection
• Chemotherapy exposure (taxanes, vinca alkaloids, platinum compounds)
• Surgery (amputation, thoracotomy, mastectomy)

Pathophysiology

Peripheral Mechanisms:

1. Ectopic Impulse Generation:

• Damaged neurons generate spontaneous action potentials
• Occurs at sites of injury (neuroma) and along axon (demyelination)
• Mechanisms: Altered sodium channel expression (Nav1.3, Nav1.7, Nav1.8), abnormal ion channel clustering
• Manifests as spontaneous pain, paresthesias

2. Peripheral Sensitization:

• Lowered threshold for nociceptor activation
• Increased responsiveness to noxious stimuli
• Mechanisms: Upregulation of TRPV1 channels, reduced potassium currents, inflammatory mediator release (bradykinin, prostaglandins, NGF)
• Manifests as primary hyperalgesia

3. Cross-Excitation (Ephaptic Transmission):

• Abnormal connections between damaged nerve fibers
• Activity in one fiber triggers activity in adjacent fibers
• Mechanism: Demyelination allows ionic flow between adjacent axons

4. Sympathetic-Sensory Coupling:

• Post-ganglionic sympathetic terminals innervate nociceptors
• Noradrenaline release activates or sensitizes nociceptors
• Mechanism: α-adrenoceptor expression on nociceptors after injury
• Basis of sympathetically maintained pain (CRPS type II)

Central Mechanisms:

1. Central Sensitization:

• Increased responsiveness of spinal cord dorsal horn neurons
• Reduced threshold, increased spontaneous activity, expanded receptive fields
• Mechanisms: NMDA receptor activation, reduced GABA/glycine inhibition, microglial activation, pro-inflammatory cytokine release (IL-1β, IL-6, TNF-α)
• Key neuroplastic change in chronic neuropathic pain

2. Loss of Descending Inhibition:

• Impaired endogenous analgesic pathways
• Reduced 5-HT and NE in spinal cord
• Mechanisms: Serotonergic and noradrenergic pathway dysfunction

3. Reorganization of Somatosensory Cortex:

• Cortical reorganization following deafferentation
• Expansion of cortical representation of adjacent areas into deafferented zones
• May contribute to phantom limb sensations and pain

Molecular Mechanisms:

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Clinical Assessment

History

Pain characteristics:

Associated symptoms:

• Allodynia (pain from normally non-painful stimuli: touch, temperature, pressure)
• Hyperalgesia (increased pain from painful stimuli)
• Dysesthesias (unpleasant abnormal sensations)
• Paresthesias (spontaneous abnormal sensations)
• Sensory loss (numbness, reduced sensation)
• Motor symptoms (weakness, fasciculations if motor nerves involved)
• Autonomic symptoms (color change, temperature change, sweating in CRPS)

Physical Examination

Sensory examination:

Mapping:

• Map area of sensory abnormality
• Compare to dermatome/myotome maps
• Identify peripheral nerve vs. radicular vs. central pattern

Screening Tools and Questionnaires

DN4 (Douleur Neuropathique 4 questions):

• 7 items: 4 sensory descriptors + 3 clinical signs
• Score ≥4/10 suggests neuropathic pain
• Sensitivity 83%, specificity 90%

PainDETECT:

• 9-item screening tool
• Score >18/38 suggests neuropathic pain
• Good sensitivity and specificity

LANSS (Leeds Assessment of Neuropathic Symptoms and Signs):

• 5 symptom items + 2 clinical tests
• Score ≥12/24 suggests neuropathic pain

ID Pain:

• 6-item screening tool
• Score ≥2 suggests neuropathic component

Diagnostic Workup

Investigations:

Imaging:

• MRI spine (radiculopathy, spinal cord pathology)
• CT/MRI brain (central pain, stroke, MS)
• Vascular imaging (vascular claudication vs. neuropathic pain)

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Pharmacological Management

First-Line Agents

Gabapentinoids (Gabapentin, Pregabalin):

Mechanism:

• Bind to α2δ-1 subunit of voltage-gated calcium channels (Cav2.2)
• Reduce calcium influx at presynaptic terminals
• Decrease release of excitatory neurotransmitters (glutamate, substance P, CGRP)
• Do not act on GABA receptors (despite name)

Gabapentin:

• Dosing: Start 300 mg nocte, titrate to 300 mg TID over 1-2 weeks, then increase by 300 mg every 3-7 days
• Max dose: 3600 mg/day (TID dosing; bioavailability decreases with increasing dose)
• Pharmacokinetics: Renal excretion (adjust for renal impairment); not protein bound; no hepatic metabolism
• Side effects: Dizziness, somnolence, peripheral edema, weight gain, cognitive impairment
• Evidence: Effective in diabetic neuropathy, post-herpetic neuralgia, mixed neuropathic pain

Pregabalin:

• Dosing: Start 75 mg BD, titrate to 150 mg BD after 3-7 days, max 300 mg BD
• Pharmacokinetics: Renal excretion; linear kinetics (better bioavailability than gabapentin); Tmax 1 hour
• Side effects: Similar to gabapentin; also dry mouth, blurred vision, euphoria (abuse potential Schedule V)
• Evidence: Effective in diabetic neuropathy, post-herpetic neuralgia, fibromyalgia, spinal cord injury pain

Tricyclic Antidepressants (TCAs):

Mechanism:

• Inhibition of serotonin and norepinephrine reuptake → enhanced descending inhibition
• Sodium channel blockade (local anesthetic-like effect)
• NMDA receptor antagonism (amitriptyline metabolite nortriptyline)
• Anticholinergic, antihistamine effects

Amitriptyline:

• Dosing: Start 10-25 mg nocte, titrate by 10-25 mg weekly, max 150 mg
• Pharmacokinetics: Hepatic metabolism (CYP2D6, CYP3A4); long half-life (10-50 hours)
• Side effects: Sedation, dry mouth, constipation, urinary retention, orthostatic hypotension, weight gain, cardiac conduction abnormalities (avoid in prolonged QT, heart block)
• Evidence: Number needed to treat (NNT) ~2.5 for neuropathic pain; effective in diabetic neuropathy, post-herpetic neuralgia

Nortriptyline:

• Less sedating, fewer anticholinergic effects than amitriptyline
• Better tolerated, especially in elderly
• Similar efficacy to amitriptyline

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):

Duloxetine:

• Dosing: Start 30 mg daily, increase to 60 mg daily after 1 week, max 120 mg
• Mechanism: Balanced SNRI (more potent NE reuptake inhibition at higher doses)
• Pharmacokinetics: Hepatic metabolism (CYP2D6, CYP1A2); avoid in severe hepatic impairment
• Side effects: Nausea, dry mouth, constipation, dizziness, insomnia, sexual dysfunction, hypertension
• Contraindications: Hepatic impairment, concurrent MAOIs
• Evidence: FDA-approved for diabetic peripheral neuropathic pain, fibromyalgia; NNT ~6

Venlafaxine:

• SNRI at higher doses (>150 mg); primarily SSRI at lower doses
• Effective in diabetic neuropathy, painful polyneuropathy
• Side effects: Similar to other SNRIs; withdrawal syndrome if stopped abruptly

Second-Line Agents

Topical Agents:

Lidocaine 5% Patch:

• Mechanism: Sodium channel blockade in peripheral nerves
• Indication: Localized peripheral neuropathic pain (post-herpetic neuralgia)
• Application: Up to 3 patches to painful area, 12 hours on/12 hours off
• Side effects: Minimal systemic absorption; local skin reactions
• Advantage: No systemic side effects, minimal drug interactions

Capsaicin 8% Patch:

• Mechanism: TRPV1 agonist → initial activation then desensitization of nociceptors; defunctionalization
• Indication: Post-herpetic neuralgia, HIV neuropathy
• Application: Single 60-minute application by trained personnel; pain relief lasts 3-6 months
• Side effects: Application site pain (requires pretreatment with topical anesthetic)
• Advantage: Long duration, no systemic side effects

Capsaicin 0.025-0.075% Cream:

• Requires multiple daily applications for 4-6 weeks for effect
• Less effective than high-concentration patch

Botulinum Toxin:

• Mechanism: Inhibits acetylcholine release from presynaptic terminals; may also inhibit substance P, glutamate
• Indication: Trigeminal neuralgia, post-herpetic neuralgia, painful diabetic neuropathy
• Dosing: Subcutaneous or intradermal injection into painful area
• Evidence: Small studies show benefit; not first-line

Opioids:

Tramadol:

• Weak μ-opioid agonist + SNRI (inhibits 5-HT and NE reuptake)
• Dose: 50-100 mg QID (max 400 mg/day; 300 mg if >75 years)
• Side effects: Nausea, dizziness, somnolence, constipation, seizures (lowers seizure threshold)
• Evidence: Effective in diabetic neuropathy, PHN; lower abuse potential than strong opioids

Strong Opioids (Oxycodone, Morphine, Fentanyl):

• Generally third-line for neuropathic pain
• Evidence supports efficacy (CRPS, PHN, phantom limb pain)
• Concerns: Tolerance, dependence, opioid-induced hyperalgesia, endocrinopathy
• Use only when first/second-line agents fail and in carefully selected patients

Other Agents:

Lamotrigine:

• Mechanism: Sodium channel blockade, inhibition of glutamate release
• Evidence: Effective in trigeminal neuralgia (especially if carbamazepine-resistant), HIV neuropathy
• Side effect: Serious rash (Stevens-Johnson syndrome) - slow titration essential

Carbamazepine:

• Mechanism: Sodium channel blockade
• First-line for trigeminal neuralgia (evidence from multiple RCTs)
• Side effects: Dizziness, somnolence, nausea, hyponatremia, rash, blood dyscrasias
• Monitoring: FBC, LFTs, sodium

Oxcarbazepine:

• Similar mechanism to carbamazepine; fewer side effects
• Effective in trigeminal neuralgia

Baclofen:

• GABA-B agonist
• Adjuvant for trigeminal neuralgia (especially if carbamazepine inadequate)

Combination Therapy

Rationale:

• Different mechanisms of action
• Lower doses of individual agents → reduced side effects
• Enhanced efficacy

Evidence-based combinations:

• Gabapentin + Nortriptyline (superior to monotherapy)
• Pregabalin + Duloxetine
• TCA + Opioid

Trial combinations systematically:

• Titrate first agent to adequate dose or side effect limit
• Add second agent; titrate
• Assess benefit vs. side effects

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Non-Pharmacological Management

Interventional Procedures

Spinal Cord Stimulation (SCS):

Mechanism:

• Gate control theory - orthodromic stimulation of large Aβ fibers inhibits transmission of nociceptive signals in dorsal horn
• Supraspinal mechanisms - activation of descending inhibitory pathways
• Neurochemical effects - increased GABA, decreased glutamate and aspartate in dorsal horn

Indications:

• Failed back surgery syndrome (FBSS)
• Complex regional pain syndrome (CRPS) types I and II
• Peripheral neuropathy (diabetic, chemotherapy-induced)
• Refractory angina pectoris
• Phantom limb pain
• Peripheral vascular disease

Technique:

• Trial stimulation (7-10 days) with temporary percutaneous leads
• Permanent implant if >50% pain relief and improved function during trial
• Electrodes placed in epidural space (cervical, thoracic, or lumbar depending on pain location)
• Pulse generator implanted subcutaneously (buttock, abdomen)

Outcomes:

• 50-70% achieve >50% pain relief
• Reduced opioid use
• Improved function and quality of life
• Cost-effective at 2-3 years

Complications:

• Lead migration (most common technical problem)
• Infection (2-5%)
• Hardware failure/fracture
• Dural puncture headache
• Epidural hematoma (rare)
• Loss of efficacy over time (tolerance, electrode encapsulation)

Contraindications:

• Active infection
• Coagulopathy
• Inability to operate device
• Unrealistic expectations
• Untreated psychiatric comorbidity

Dorsal Root Ganglion (DRG) Stimulation:

• Targets DRG (sensory ganglia)
• Advantages: Focal coverage, reduced paraesthesia, effective for CRPS of limbs
• Similar technique to SCS

Peripheral Nerve Stimulation:

• Electrodes placed near specific peripheral nerves
• Indications: Occipital neuralgia, ilioinguinal neuralgia, post-surgical neuralgias

Intrathecal Drug Delivery:

• Indications: Refractory neuropathic pain, cancer pain, spasticity
• Agents: Morphine, hydromorphone, ziconotide (N-type calcium channel blocker), bupivacaine, clonidine
• Implanted pump with catheter into intrathecal space
• Requires specialized pain center

Neuromodulation Techniques

Transcutaneous Electrical Nerve Stimulation (TENS):

• Mechanism: Gate control theory; endogenous opioid release
• Application: Electrodes over painful area or related dermatome
• Evidence: Limited for neuropathic pain; may help some patients
• Safe, inexpensive, patient-controlled

Repetitive Transcranial Magnetic Stimulation (rTMS):

• Motor cortex stimulation
• Evidence: Modest benefit in central pain, neuropathic pain
• Non-invasive; repeated sessions required

Transcranial Direct Current Stimulation (tDCS):

• Weak electrical current modulates cortical excitability
• Emerging evidence in chronic pain

Physical and Psychological Therapies

Physical Therapy:

• Graded motor imagery (for CRPS)
• Desensitization techniques
• Mirror therapy (phantom limb pain)
• Tactile discrimination training

Psychological Therapies:

• Cognitive-behavioral therapy (CBT) - best evidence
• Acceptance and commitment therapy (ACT)
• Mindfulness-based stress reduction
• Biofeedback

Addressing:

• Pain catastrophizing
• Fear-avoidance behavior
• Kinesiophobia (fear of movement)
• Depression and anxiety (common comorbidities)

Complementary Therapies

Acupuncture:

• Variable evidence; may help some patients
• Mechanisms: Gate control, endogenous opioid release, anti-inflammatory effects

Cannabinoids:

• Emerging evidence for neuropathic pain
• Nabiximols (Sativex): THC:CBD oromucosal spray
• Side effects: CNS effects, abuse potential

Supplements:

• Alpha-lipoic acid (diabetic neuropathy)
• Acetyl-L-carnitine (chemotherapy-induced neuropathy)
• Vitamin B12 (if deficient)

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Specific Neuropathic Pain Conditions

Diabetic Neuropathy

Types:

• Distal symmetric polyneuropathy (most common, 75%)
• Autonomic neuropathy
• Focal/multifocal neuropathies (cranial, radiculopathy, plexopathy)
• Small fiber neuropathy

Features:

• Stocking-glove distribution
• Burning, shooting pain, allodynia
• Nocturnal exacerbation
• Sensory loss (vibration, proprioception > pain/temperature)

Management:

• Glycemic control (primary prevention, modest benefit for established pain)
• First-line: Duloxetine, pregabalin, gabapentin, TCAs
• Second-line: Tramadol, high-dose capsaicin patch
• Third-line: Opioids (short-term), spinal cord stimulation (refractory)

Post-Herpetic Neuralgia (PHN)

Features:

• Pain persisting >3 months after herpes zoster rash
• Risk increases with age (>50: 30-50% develop PHN)
• Burning, stabbing pain in affected dermatome
• Allodynia common

Prevention:

• Zoster vaccine (reduces incidence and severity)
• Early antiviral therapy (acyclovir, valacyclovir) within 72 hours of rash
• Early aggressive pain management during acute zoster

Management:

• First-line: Gabapentin, pregabalin, TCAs (nortriptyline), lidocaine 5% patch
• Second-line: Capsaicin 8% patch, strong opioids
• Interventional: Epidural (acute phase), spinal cord stimulation (chronic)

Trigeminal Neuralgia

Features:

• Sudden, severe, electric shock-like facial pain
• Triggers: Light touch, chewing, talking, cold wind
• Maxillary/mandibular divisions most common
• "The suicide disease" - high suicide risk

Classical vs. Secondary:

• Classical: Neurovascular compression of trigeminal nerve root (MRI shows vessel loop)
• Secondary: MS, tumor, arteriovenous malformation

Management:

• First-line: Carbamazepine (evidence-based), oxcarbazepine
• Second-line: Baclofen, lamotrigine, phenytoin
• Interventional:
  • Microvascular decompression (surgical, best long-term outcome)
  • Radiofrequency thermocoagulation
  • Balloon compression
  • Glycerol rhizotomy
  • Stereotactic radiosurgery (Gamma Knife)

Complex Regional Pain Syndrome (CRPS)

Type I (Reflex Sympathetic Dystrophy): No nerve lesion Type II (Causalgia): Nerve lesion identified

Features:

• Severe pain disproportionate to injury
• Sensory: Allodynia, hyperalgesia
• Autonomic: Temperature asymmetry, color change, sweating
• Motor: Weakness, tremor, dystonia
• Trophic: Hair/nail changes, osteoporosis

Management:

• Early mobilization/physical therapy (critical)
• First-line: Gabapentin, pregabalin, TCAs, bisphosphonates
• Interventional: Sympathetic blocks (early), spinal cord stimulation, DRG stimulation
• Refractory cases: Ketamine infusions

Phantom Limb Pain

Features:

• Pain in amputated limb
• Affects 60-80% of amputees; severe in 5-10%
• Often described as crushing, burning, shooting
• May have telescoping sensation (phantom retreats proximally)

Prevention:

• Perioperative epidural analgesia may reduce incidence
• Early postoperative pain control

Management:

• First-line: Gabapentin, pregabalin, TCAs, mirror therapy
• Interventional: TENS, spinal cord stimulation, motor cortex stimulation
• Psychological support essential

Central Neuropathic Pain

Causes:

• Spinal cord injury (40-60% of patients)
• Post-stroke pain (8-10% of stroke survivors)
• Multiple sclerosis (50%)
• Syringomyelia
• Parkinson's disease

Features:

• Often diffuse, burning, dysaesthetic
• Allodynia common (especially in post-stroke pain)
• Below-level pain in spinal cord injury ("at-level" and "below-level")
• Difficult to treat

Management:

• First-line: Gabapentin, pregabalin (good evidence in SCI), TCAs
• Second-line: Cannabinoids, lamotrigine, opioids
• Interventional: Spinal cord stimulation, deep brain stimulation, motor cortex stimulation

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Indigenous Health Considerations

Aboriginal and Torres Strait Islander Populations:

Disparities:

• Higher rates of diabetes (3-4×) → increased diabetic neuropathy
• Higher rates of chronic pain overall
• Lower access to pain specialists and multidisciplinary pain clinics
• Geographic barriers to specialized care (SCS, intrathecal pumps)

Cultural considerations:

• Higher pain tolerance may lead to under-reporting
• Traditional healing practices may be preferred for pain management
• Trust issues with healthcare system due to historical factors
• Need for culturally safe pain assessment tools

Management approaches:

• Culturally appropriate communication about pain
• Involvement of Aboriginal Health Workers in pain management plans
• Address social determinants (housing, nutrition, employment) that impact pain
• Telemedicine for specialist pain consultations in remote areas
• Access to SCS and interventional pain services in major centers with support for travel/accommodation

Māori Populations:

Similar disparities exist with higher rates of chronic pain conditions and barriers to accessing comprehensive pain services.

Whānau-based care:

• Recognition that chronic pain affects entire family
• Support for carers and family members
• Integration of traditional healing (rongoa Māori) with Western medicine where appropriate
• Māori Health Workers facilitating pain management education

Key principle: Management of neuropathic pain in Indigenous populations requires not only pharmacological and interventional options but also culturally safe approaches that address access barriers and integrate traditional healing practices where appropriate.

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ANZCA Exam Focus

High-Yield Topics

Written Examination:

• Pathophysiology of peripheral and central sensitization
• Pharmacology of gabapentinoids (mechanism, kinetics, side effects)
• TCA and SNRI mechanisms and comparison
• Evidence-based treatment algorithms (NeuPSIG guidelines)
• Spinal cord stimulation indications and mechanism

Viva Voce:

• Distinguishing neuropathic from nociceptive pain
• Stepwise pharmacological escalation
• Patient selection for spinal cord stimulation
• Management of trigeminal neuralgia
• Complex case: Failed back surgery syndrome with neuropathic component

Common Exam Scenarios

Scenario 1: Diabetic Neuropathy

• 58-year-old with type 2 diabetes, painful feet for 2 years
• Burning pain, worse at night, allodynia to bedsheets
• Failed on simple analgesics

Key discussion points:

• Confirm diagnosis (examination, monofilament testing)
• First-line options (duloxetine, pregabalin, TCAs)
• Glycemic control optimization
• Foot care education
• Stepwise escalation if first-line fails

Scenario 2: Spinal Cord Stimulation Trial

• 45-year-old with FBSS, persistent leg pain after L4-L5 decompression
• No further surgical options
• On high-dose opioids with poor function

Key discussion points:

• Patient selection criteria
• Trial procedure description
• Mechanism of SCS
• Expected outcomes and complications
• Multidisciplinary assessment (psychology screening)

Scenario 3: Trigeminal Neuralgia

• 62-year-old with severe facial pain, electric shock-like
• Triggered by chewing, talking
• Failed carbamazepine due to side effects

Key discussion points:

• Confirm diagnosis (imaging for neurovascular compression)
• Alternative medications (oxcarbazepine, baclofen, lamotrigine)
• Interventional options (radiofrequency, balloon compression, MVD)
• Urgency (suicide risk)

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Assessment Content

SAQ 1: Neuropathic Pain Management (20 marks)

Question:

A 52-year-old man with type 2 diabetes mellitus (HbA1c 8.2%) presents with a 2-year history of bilateral foot pain. He describes burning pain in a stocking distribution, worse at night, with tingling and numbness. Examination reveals reduced sensation to light touch, pinprick, and vibration in both feet up to the mid-calf level. There is no motor weakness. His current medications are metformin and gliclazide. He has tried paracetamol and ibuprofen without benefit.

a) What features in this history and examination suggest neuropathic rather than nociceptive pain? (5 marks)

b) Outline your stepwise pharmacological approach to managing his pain, including specific drug choices, dosing, and mechanisms of action. (10 marks)

c) He fails to respond to first-line agents and develops severe pain affecting his sleep and mood. What additional pharmacological and non-pharmacological options would you consider? (5 marks)

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Model Answer:

a) Features suggesting neuropathic pain (5 marks):

b) Stepwise pharmacological approach (10 marks):

Step 1: First-line agents (choose one, titrate):

Step 2: If inadequate response after 4-6 weeks:

• Switch to alternative first-line agent from different class, OR
• Add second first-line agent (combination therapy)

Step 3: Second-line agents:

• Tramadol 50-100 mg QID (weak opioid + SNRI)
• Capsaicin 8% patch - single 60-min application to feet (TRPV1 agonist, defunctionalizes nociceptors)

Step 4: Third-line:

• Strong opioids (oxycodone, morphine) - short-term trial only; discuss risks

Non-pharmacological simultaneously:

• Optimize glycemic control (refer endocrinology)
• Foot care education and regular podiatry
• Physical therapy for desensitization

c) Additional options if refractory (5 marks):

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References

1. Finnerup NB, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173. PMID: 25575710

2. Dworkin RH, et al. Recommendations for the pharmacological management of neuropathic pain. Mayo Clin Proc. 2010;85:S3-S14. PMID: 20194146

3. van Hecke O, et al. Neuropathic pain in the general population: a systematic review. Pain. 2014;155:654-662. PMID: 24291734

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