What is the approach to managing peripheral neuropathy?

Approach to Peripheral Neuropathy

Initial Diagnostic Evaluation

Begin by identifying the clinical pattern through focused history and examination: assess the distribution (distal symmetric "stocking-glove" vs. asymmetric), time course (acute vs. chronic), fiber type involvement (large fiber with numbness/weakness vs. small fiber with burning pain), and whether symptoms are primarily sensory, motor, or mixed. 1, 2

Key History Elements

• Characterize pain using a 0-10 numerical rating scale, as baseline pain ≥4 is clinically significant and guides treatment decisions 3, 2
• Screen specifically for diabetes mellitus, alcohol use, chemotherapy exposure, vitamin B12 deficiency, thyroid disease, and family history of neuropathy 4, 5
• Document medication history including chemotherapeutic agents (bortezomib, thalidomide), as dose adjustment may be the primary intervention 1, 6
• Assess functional impact on walking, balance, and activities of daily living 3

Physical Examination Priorities

• Test for distal sensory loss to light touch, pinprick, vibration (128 Hz tuning fork), and temperature in hands and feet 2, 5
• Examine for distal muscle weakness and atrophy, particularly in foot dorsiflexors and intrinsic hand muscles 5
• Check ankle reflexes (often absent early) and assess gait for steppage or ataxia 5
• Inspect feet for ulcers, calluses, and deformities in diabetic patients 2

Laboratory Workup

Order a focused initial panel: complete blood count, comprehensive metabolic profile, fasting glucose, hemoglobin A1c, vitamin B12, thyroid-stimulating hormone, and serum protein electrophoresis with immunofixation. 2, 4, 5

Additional Testing Based on Clinical Pattern

• Consider hepatitis B, C, and HIV serology if risk factors present 2
• Order nerve conduction studies/electromyography to distinguish axonal from demyelinating neuropathy—this dramatically narrows the differential and identifies treatable causes 4, 7, 8
• Skin biopsy for intraepidermal nerve fiber density if small-fiber neuropathy suspected with normal nerve conduction studies 8
• Lumbar puncture only if Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy suspected 4

Disease-Modifying Management

For diabetic peripheral neuropathy, optimize glycemic control immediately with target HbA1c of 6-7%, as this is the only intervention that prevents progression. 1, 2, 6

• Address cardiovascular risk factors aggressively: control hypertension and hyperlipidemia, as these contribute to neuropathy progression 1, 2
• Correct vitamin B12 deficiency if identified 2, 9
• For chemotherapy-induced neuropathy, discuss dose delay, dose reduction, or stopping the neurotoxic agent if symptoms are intolerable 1, 6

Pharmacological Treatment for Neuropathic Pain

Start duloxetine 60 mg once daily as first-line treatment for painful diabetic peripheral neuropathy and chemotherapy-induced peripheral neuropathy, as it is FDA-approved for diabetic neuropathy and has the strongest evidence for chemotherapy-induced neuropathy. 1, 2, 6, 10

First-Line Options (Choose One Initially)

• Duloxetine 60 mg once daily, may increase to 120 mg daily if needed after 1-2 weeks; NNT 4.9-5.2 1, 6, 10

  • Avoid in hepatic disease 1
  • Monitor for nausea (often transient), dizziness, and somnolence 1

• Pregabalin 150 mg/day divided twice daily, titrate to 300-600 mg/day over 1 week; NNT 4.04-5.99 1, 6, 11

  • Start at 75 mg twice daily, increase to 150 mg twice daily after 1 week if tolerated 11
  • Monitor for peripheral edema, weight gain, and dizziness 1
  • Benefits may appear as early as week 1 1, 11

• Gabapentin 300 mg at bedtime, titrate to 900-3600 mg/day divided three times daily over 1-2 weeks 1, 6

  • Requires more frequent dosing than pregabalin but similar efficacy 1
  • More gradual titration needed to minimize dizziness 1

Second-Line Options (If First-Line Fails or Not Tolerated)

• Tricyclic antidepressants (amitriptyline 10-25 mg at bedtime), titrate slowly to 75 mg/day; NNT 1.5-3.5 3, 1, 6

  • Critical caveat: Obtain ECG before starting in patients >40 years or with any cardiovascular history 1
  • Contraindicated in glaucoma, orthostatic hypotension, cardiovascular disease, or fall risk 1
  • Start at 10 mg in elderly patients 1
  • Significant anticholinergic effects (dry mouth, constipation, urinary retention, confusion) limit use 3, 1

• Venlafaxine 37.5-75 mg twice daily, titrate to 150-225 mg/day if duloxetine not tolerated 1, 6

• Tramadol 50 mg twice daily, titrate to 200-400 mg/day divided—use cautiously as second-line only 1, 6

Combination Therapy

• If partial response to one first-line agent, add a second first-line medication with different mechanism (e.g., duloxetine + pregabalin) 1, 2
• If inadequate response after optimizing one agent, consider switching to another first-line option before combining 1

Critical Pitfalls

• Avoid strong opioids for long-term management due to addiction risk, constipation, and lack of long-term efficacy data 1, 6
• In elderly patients: start all medications at half the usual dose, titrate more slowly, and monitor closely for orthostatic hypotension, confusion, and falls 1, 6
• None of these medications restore sensation or modify disease progression—they are purely symptomatic treatments 3

Non-Pharmacological Interventions

• Recommend regular exercise and functional training to reduce neuropathic symptoms 6
• Advise wearing loose-fitting shoes and cotton socks 1
• Suggest soaking feet in cold water for temporary pain relief 1
• Consider transcutaneous electrical nerve stimulation (TENS) for refractory cases—well tolerated and inexpensive despite modest benefits 1, 9
• Reserve spinal cord stimulation for severe, treatment-resistant cases unresponsive to all pharmacotherapy 1, 2

Monitoring and Follow-Up

• Reassess pain scores and quality of life at each visit using the same 0-10 scale 3, 1
• Monitor objectively for medication response, as patients may not achieve desired pain reduction and adverse effects are common 9
• Screen diabetic patients annually for progression of neuropathy and development of foot ulcers 2
• Assess for autonomic neuropathy (orthostatic hypotension, gastroparesis) in diabetic patients 2