What is the appropriate workup and treatment for peripheral neuropathy?

Workup for Peripheral Neuropathy

Initial Clinical Assessment

Begin by obtaining a detailed symptom history focusing on numbness, tingling, burning pain in hands and/or feet, the distribution pattern (symmetric vs asymmetric), onset (acute vs chronic), and progression. 1, 2 Document pain severity using a numerical pain scale (0-10) and assess for motor weakness, gait disturbances, and autonomic symptoms including orthostatic hypotension, gastroparesis, constipation, and bladder dysfunction. 3, 2

Essential Laboratory Testing

The American College of Physicians recommends a focused initial panel to identify treatable causes, which should include: 1, 2

• Fasting blood glucose and hemoglobin A1c - diabetes is the most common cause, affecting over 50% of peripheral neuropathy cases in Western populations 1, 2, 4
• Vitamin B12 level with metabolites (methylmalonic acid ± homocysteine) - nutritional deficiencies are a common treatable cause 1, 5, 4
• Thyroid-stimulating hormone (TSH) - hypothyroidism is among the most common treatable causes 1, 5
• Serum protein electrophoresis with immunofixation - to screen for monoclonal gammopathies 6, 4
• Complete blood count and comprehensive metabolic profile - to assess for systemic causes 5, 6
• Erythrocyte sedimentation rate - if inflammatory etiology suspected 5

Additional Testing When Clinically Indicated

• Hepatitis B, C, and HIV testing - if risk factors present, as these infections can cause peripheral neuropathy 1
• Electrodiagnostic studies (nerve conduction studies/EMG) - essential to differentiate axonal from demyelinating neuropathy and determine severity 7, 8, 6
• Lumbar puncture with CSF analysis - if Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy suspected 5, 8
• Genetic testing - if hereditary neuropathy (Charcot-Marie-Tooth disease) suspected based on family history 8, 4
• Skin biopsy for intraepidermal nerve fiber density - if small-fiber neuropathy suspected 7

Treatment Approach

Disease-Modifying Management

For diabetic peripheral neuropathy, optimizing glucose control is the foundational intervention and must be prioritized to prevent progression, targeting individualized HbA1c goals. 1, 9, 2 Address cardiovascular risk factors including hypertension and hyperlipidemia aggressively, as these contribute to neuropathy progression. 1, 9

First-Line Pharmacological Treatment for Neuropathic Pain

Duloxetine 60 mg once daily is the first-line pharmacological treatment, with the option to increase to 120 mg daily if needed. 1, 9, 2, 10 This is the only agent with appropriate evidence for both diabetic peripheral neuropathy and chemotherapy-induced peripheral neuropathy, though benefit in the latter is limited. 1, 2

Alternative first-line agents include: 1, 9, 4

• Pregabalin 300-600 mg/day - FDA-approved for diabetic peripheral neuropathy with benefits seen as early as week 1 9, 11
• Gabapentin 300-2400 mg/day - similar efficacy to pregabalin but may require higher doses 9, 4
• Tricyclic antidepressants (amitriptyline 25-75 mg/day) - effective with low number needed to treat (1.5-3.5), but significant anticholinergic side effects limit use 1, 9, 4

Important Prescribing Considerations

Start low and go slow, particularly in elderly patients, titrating gradually to minimize side effects. 9 For duloxetine in diabetic neuropathy, some patients may benefit from starting at 30 mg once daily for 1 week before increasing to 60 mg. 10 Since diabetes is frequently complicated by renal disease, consider lower starting doses in patients with renal impairment. 10

Contraindications and monitoring: 9

• Avoid tricyclic antidepressants in patients with glaucoma, orthostatic hypotension, cardiovascular disease, or fall risk; obtain ECG before starting, especially in older patients
• Avoid duloxetine in hepatic disease
• Monitor for edema and weight gain with pregabalin and gabapentin

Non-Pharmacological Interventions

Physical activity has been demonstrated to improve neuropathic pain and should be offered to all patients. 3, 2 Acupuncture has shown efficacy in meta-analyses of RCTs for pain reduction, though evidence is lacking specifically for chemotherapy-induced peripheral neuropathy. 3

Second-Line and Combination Therapy

If first-line monotherapy provides inadequate relief after optimization, consider switching to another first-line agent with a different mechanism of action or adding a second agent. 9, 4 Topical agents (capsaicin cream or lidocaine patches) may be used for localized pain. 9 Tramadol can be considered as combination therapy, though long-term opioid use should generally be avoided. 9

Ongoing Monitoring

For diabetic patients, annual screening for peripheral neuropathy is mandatory at diagnosis for type 2 diabetes and starting 5 years after diagnosis for type 1 diabetes. 1, 2 Monitor for development of foot ulcers in patients with diabetic neuropathy. 1 Periodically reassess pain severity and quality of life to guide treatment adjustments. 9

Common Pitfalls to Avoid

• Do not delay glucose optimization in diabetic neuropathy - this is the only disease-modifying intervention with high-quality evidence 1, 2
• Do not use doses of duloxetine higher than 60 mg/day for diabetic neuropathy without clear indication - there is no evidence that higher doses confer additional benefit and they are less well tolerated 10
• Do not overlook treatable causes - up to 27% of neuropathy cases remain idiopathic, but systematic testing identifies reversible etiologies in the majority 4
• Do not prescribe tricyclic antidepressants without cardiac screening in older adults - obtain ECG first to avoid serious cardiac complications 9