Initial Approach to Peripheral Neuropathy
Begin with a focused diagnostic workup to identify treatable causes while simultaneously initiating first-line pharmacological therapy with duloxetine, pregabalin, or gabapentin for symptomatic neuropathic pain. 1
Immediate Diagnostic Evaluation
The initial laboratory panel should be focused and cost-effective, targeting the most common treatable etiologies:
- Order fasting blood glucose and hemoglobin A1c to diagnose diabetes mellitus, which accounts for the majority of peripheral neuropathy cases 1, 2
- Measure vitamin B12 levels as deficiency is a readily reversible cause 3, 2
- Check thyroid-stimulating hormone (TSH) to identify hypothyroidism 3, 2
- Obtain complete blood count and comprehensive metabolic profile to screen for systemic causes 2
- Perform serum protein electrophoresis with immunofixation to detect paraproteinemias 2
Additional testing should only be pursued if the initial panel is unrevealing and clinical suspicion warrants further investigation 2.
Clinical Assessment
History and Pattern Recognition
Document the specific characteristics that narrow the differential diagnosis:
- Determine onset timing: acute presentations (days to weeks) suggest Guillain-Barré syndrome, vasculitis, or toxic exposure, while chronic presentations (months to years) suggest metabolic, hereditary, or idiopathic causes 4, 5
- Identify distribution pattern: symmetric "stocking-glove" distribution indicates length-dependent polyneuropathy (diabetes, toxins, nutritional deficiencies), while asymmetric or multifocal patterns suggest mononeuropathy multiplex (vasculitis, leprosy) 2, 6
- Assess symptom quality: burning pain and dysesthesias indicate small-fiber involvement, while numbness and sensory ataxia indicate large-fiber involvement 7, 6
- Elicit occupational and toxic exposures: alcohol use, chemotherapy agents, and industrial toxins are common reversible causes 3, 2
Physical Examination
Perform targeted bedside tests to characterize fiber involvement:
- Test small-fiber function with pinprick and temperature sensation 7, 1
- Test large-fiber function with vibration perception using a 128-Hz tuning fork 7, 1
- Perform 10-g monofilament testing to identify loss of protective sensation and risk for foot ulceration 7, 1
- Assess for autonomic dysfunction: orthostatic blood pressure changes, resting tachycardia, gastroparesis symptoms, bladder dysfunction, and sudomotor abnormalities 7, 8
Electrodiagnostic Studies
Refer for nerve conduction studies and electromyography only when the diagnosis remains unclear after initial evaluation or when clinical features are atypical 7, 4. These studies differentiate axonal from demyelinating neuropathy, which dramatically narrows the differential diagnosis 4, 5.
Primary demyelinating patterns (prolonged latencies, slowed conduction velocity, conduction block) suggest acquired inflammatory conditions like chronic inflammatory demyelinating polyneuropathy or hereditary conditions like Charcot-Marie-Tooth disease 6.
First-Line Pharmacological Management
For Diabetic Peripheral Neuropathy
Initiate duloxetine 60 mg once daily as first-line therapy for neuropathic pain, as it has the strongest evidence base and is specifically FDA-approved for diabetic peripheral neuropathic pain 1, 9. Duloxetine demonstrated superiority over placebo in reducing pain scores by 4.9 points on the HAMD-17 scale in controlled trials 9.
Alternative first-line options include:
- Pregabalin 100-300 mg three times daily (FDA-approved for diabetic peripheral neuropathy) 1, 10, 11
- Gabapentin 300-1,200 mg three times daily, starting at 100-300 mg daily in elderly patients with slow titration 1, 10
For Non-Diabetic Neuropathy
The same three agents (duloxetine, pregabalin, gabapentin) remain first-line choices 1, 10. Tricyclic antidepressants (amitriptyline, nortriptyline 10-75 mg at bedtime) are alternatives but should be used cautiously in elderly patients due to anticholinergic effects, sedation, and cardiac risks 8, 10.
Disease-Modifying Treatment
For diabetic peripheral neuropathy, optimize glucose control immediately as the foundational disease-modifying intervention 7, 1. Tight glycemic control prevents neuropathy development in type 1 diabetes and slows progression in type 2 diabetes 7.
Set realistic HbA1c targets based on individual patient factors rather than pursuing overly aggressive goals that may worsen compliance 8.
Screening and Monitoring Schedule
Screen all patients with type 2 diabetes at diagnosis and those with type 1 diabetes starting 5 years after diagnosis, then annually thereafter 7, 1, 8. Up to 50% of diabetic peripheral neuropathy cases are asymptomatic but still carry significant risk for foot ulceration and amputation 7, 8.
Annual screening should include:
- Medical history focused on neuropathic symptoms 7
- Small-fiber and large-fiber function testing 7, 1
- 10-g monofilament testing for protective sensation 7, 1
- Assessment for autonomic neuropathy manifestations 1, 8
Common Pitfalls
Avoid opioids for chronic neuropathic pain due to addiction risk and lack of evidence for long-term efficacy 8.
Do not overlook alternative causes in diabetic patients—alcohol toxicity, vitamin B12 deficiency (especially in metformin users), hypothyroidism, and paraproteinemias can coexist with or mimic diabetic neuropathy 8, 3.
Start medications at lower doses in elderly patients and titrate slowly to minimize adverse effects, particularly with gabapentin and tricyclic antidepressants 10.
Monitor duloxetine for potential worsening of glycemic control in some diabetic patients 8.
Foot Care Education
Provide explicit foot care instructions emphasizing daily inspection and proper footwear to prevent ulceration in patients with loss of protective sensation 8. The direct connection between preventive foot care and amputation avoidance should be emphasized 8.