What is the recommended workup and treatment for a patient presenting with symptoms of neuropathy, such as numbness, tingling, or pain in the hands and feet, with potential underlying causes including diabetes, vitamin deficiencies, autoimmune disorders, and exposure to toxins?

Neuropathy Workup and Treatment

Initial Clinical Assessment

Begin by determining fiber type involvement: ask specifically about burning pain and tingling (small fiber) versus numbness with loss of balance (large fiber), as this guides both workup and treatment. 1

• Assess the distribution pattern: distal symmetric distribution suggests metabolic or toxic causes (diabetes, alcohol, medications), while patchy or asymmetric patterns suggest mononeuropathy multiplex from vasculitis 1
• Review medications focusing on metformin (especially ≥2g daily), chemotherapy agents (cisplatin, paclitaxel, vincristine), and statins as common culprits 1, 2
• Identify red flags: hemibody sensory loss without motor weakness requires stroke evaluation within 48 hours 1

Physical Examination

Perform targeted testing based on fiber type:

• Small fiber testing: pinprick sensation and temperature perception 1
• Large fiber testing: vibration perception with 128-Hz tuning fork, 10-g monofilament testing, and ankle reflexes 1
• Autonomic signs: check for orthostatic hypotension, resting tachycardia, and skin dryness/cracking 1

Initial Laboratory Workup

Order the following tests as they identify the most common treatable causes:

• Complete blood count (screens for anemia, infection, malignancy) 1
• Fasting blood glucose and HbA1c (diabetes is the most common treatable cause, affecting 50% of neuropathy cases) 1, 2, 3
• Vitamin B12 level (critical, especially in metformin users) 1, 4, 3
• Thyroid-stimulating hormone (hypothyroidism is a well-established treatable cause) 4, 3
• Serum protein electrophoresis with immunofixation (screens for monoclonal gammopathy and multiple myeloma) 4, 2, 3
• Hepatitis C serology if risk factors present (up to 50% of HCV patients develop neuropathy) 1

Treatment Approach

Address Underlying Causes

Optimize glycemic control if diabetic with HbA1c target of 6-7%—this is the only proven strategy to prevent or delay diabetic neuropathy progression. 5, 6, 7

• Supplement vitamin B12 at 2500 mcg daily if deficient, particularly in metformin users 1
• Avoid aggressive glycemic control in elderly patients with significant comorbidities 6

Pharmacologic Management for Neuropathic Pain

First-line options (all have Level A evidence):

• Duloxetine 60 mg once daily 5, 1, 4, 7
• Pregabalin: Start 50 mg three times daily (150 mg/day), may increase to 100 mg three times daily (300 mg/day) within 1 week based on tolerability 1, 8, 7
• Gabapentin: Titrate to 1200 mg daily (38% of patients achieve ≥50% pain reduction at this dose) 1, 2, 7

Second-line options if first-line agents fail:

• Tricyclic antidepressants (amitriptyline, nortriptyline) 1, 2, 7
• Topical capsaicin (8% patch or 0.075% cream) 1
• Venlafaxine, carbamazepine, oxcarbazepine, topical lidocaine 7

Non-Pharmacologic Interventions

• Physical activity is recommended for both chemotherapy-induced and diabetic neuropathy 5, 1
• Acupuncture may be offered for musculoskeletal-related neuropathic symptoms 5, 1

Monitoring and Follow-Up

• Quantify pain using numeric rating scale (0-10) at each visit to objectively assess medication response 6
• Repeat HbA1c every 3 months to assess glycemic control 6
• Perform annual foot examinations with 10-g monofilament testing once loss of protective sensation is documented to prevent ulceration 1, 6

Referral Indications

• Refer to neurology when clinical features are atypical, diagnosis remains unclear after initial workup, or adequate pain management is not achieved with first and second-line therapies 4, 6
• Refer to podiatry for comprehensive foot care in all diabetic patients with neuropathy to prevent ulceration and amputation 6
• Refer for vascular assessment if significant claudication or abnormal ankle-brachial index is present 6

Critical Pitfalls to Avoid

• Do NOT use acetyl-L-carnitine for prevention of chemotherapy-induced peripheral neuropathy (harms outweigh benefits) 1
• Avoid opioids (tapentadol, tramadol) for chronic neuropathic pain due to addiction risk 1
• Do not escalate pregabalin above 300 mg/day for diabetic neuropathy—there is no evidence of additional benefit and significantly worse tolerability 8
• Start medications at lower doses in older patients and titrate slowly to minimize adverse events (dizziness, somnolence, peripheral edema are dose-dependent) 8
• Monitor metformin users closely for B12 deficiency, as long-term use causes neuropathy in a stocking-glove distribution 1
• Taper pregabalin gradually over minimum 1 week when discontinuing to avoid withdrawal symptoms 8