What are the recommended treatment options for small‑fiber neuropathy, including first‑line pharmacologic agents and management of underlying causes?

Treatment of Small Fiber Neuropathy

First-Line Pharmacologic Management

For neuropathic pain in small fiber neuropathy, initiate either pregabalin 75 mg twice daily (titrated to 150–300 mg twice daily, maximum 300 mg/day total) or duloxetine 60 mg once daily (up-titrated to 120 mg if needed), as both are FDA-approved first-line agents with number-needed-to-treat values of approximately 4–6 for achieving ≥50% pain reduction. 1, 2

Selecting Between First-Line Agents

• Choose duloxetine when the patient has comorbid depression (provides dual benefit) or when peripheral edema is present, since pregabalin and gabapentin may worsen edema 1, 2
• Choose pregabalin when renal function is ≥60 mL/min and no clinically significant peripheral edema exists 1
• Avoid duloxetine completely in patients with hepatic disease (absolute contraindication) 1, 2
• Gabapentin 900–3600 mg/day in divided doses (typically 300–1200 mg three times daily) is an alternative first-line option when pregabalin or duloxetine are contraindicated 1, 2, 3

Alternative First-Line Options

• Tricyclic antidepressants (amitriptyline 10–75 mg at bedtime, nortriptyline 25–75 mg at bedtime, or imipramine 25–75 mg at bedtime) are effective first-line agents 1, 3
• Avoid tricyclics in patients ≥65 years old or those with glaucoma, orthostatic hypotension, or cardiovascular disease due to heightened adverse event risk 1

Second-Line and Combination Therapy

• If monotherapy with a first-line agent at therapeutic doses provides inadequate relief after 4–6 weeks, add a second first-line agent (e.g., pregabalin + duloxetine or pregabalin + low-dose tricyclic) rather than simply escalating the dose of a single drug, as combination therapy provides greater pain relief with fewer adverse effects 1
• Sodium channel blockers such as carbamazepine (200–400 mg three times daily) or lamotrigine are second-line options when first-line agents fail 1, 2
• Topical agents including capsaicin cream 0.025–0.075% applied 3–4 times daily or lidocaine patches can be used as adjuncts for focal pain 1, 3

Critical Medication Pitfalls to Avoid

• Do not prescribe opioids (including tramadol, tapentadol, or oxycodone) for chronic small fiber neuropathy pain—this is a strong recommendation against their use due to addiction risk, adverse events, and lack of long-term efficacy data 1
• Do not exceed pregabalin 300 mg/day for neuropathic pain, as higher doses (up to 600 mg/day) provide no additional analgesic benefit and markedly worsen tolerability 1
• Do not use pregabalin or gabapentin in patients with clinically significant peripheral edema 1

Treatment of Underlying Causes (Disease-Modifying Approach)

Metabolic Causes

• For diabetic small fiber neuropathy, target HbA1c of 6–7% to slow neuropathy progression, though this will not reverse existing nerve damage 1, 4
• Screen for vitamin B12 deficiency in all patients with small fiber neuropathy, especially those on metformin, and supplement with cyanocobalamin when deficiency is confirmed 1
• For glucose intolerance, a 12-month program of diet and exercise can increase intraepidermal nerve fiber density, demonstrating potential for nerve regeneration 4

Autoimmune Causes

• For sarcoidosis-related small fiber neuropathy, consider intravenous immunoglobulin (IVIg) either alone or with anti-TNF therapy, as 75% of patients derive symptomatic benefit 4
• Anti-TNF monoclonal antibodies (infliximab or adalimumab) may provide benefit for sarcoidosis-related cases 4
• Screen for autoimmune markers including TS-HDS and FGFR3 antibodies, which are found in up to 20% of patients with small fiber neuropathy 5

Other Treatable Causes

• Exclude and treat hypothyroidism, renal disease, vitamin deficiencies (B1, B6, folate), alcohol toxicity, neurotoxic medications, infections, and malignancies 1, 3, 5
• For hereditary transthyretin amyloidosis with polyneuropathy, TTR silencers such as patisiran, vutrisiran, or inotersen are disease-modifying treatments 2

Management of Autonomic Dysfunction

• For orthostatic hypotension, initiate increased salt/fluid intake first, then add fludrocortisone, midodrine, droxidopa, or pyridostigmine as needed 2
• Antihistamines with serotonin blockade properties and beta blockers may be beneficial in some patients 2
• Screen for cardiovascular autonomic dysfunction, bladder disturbances, and reduced heart rate variability, which occur in approximately 70% of patients 4

Non-Pharmacologic Management

• Engage in usual lifestyle activities and continue exercise and normal daily activities as much as possible while minimizing known triggers, to prevent progression to debilitating chronic pain syndrome 4
• Avoid excessive cooling of extremities for pain relief, as this worsens tissue damage and can lead to ulcerations 2, 4
• Pain rehabilitation programs with physical and occupational therapy should be considered for refractory cases to improve physical reconditioning and activity tolerance 2

Diagnostic Confirmation

• Skin biopsy with quantification of intraepidermal nerve fiber density (IENFD) is the gold standard for diagnosis, with sensitivity of 77–88% and specificity of 80–89%; a cutoff of ≤8.8 fibers/mm at the ankle demonstrates good accuracy 4, 6, 7
• Quantitative sensory testing (QST) for thermal thresholds and quantitative sudomotor axon reflex test (QSART) complement skin biopsy and document small fiber dysfunction with high sensitivity 2, 4, 6
• Conventional nerve conduction studies are typically normal in pure small fiber neuropathy and should not be relied upon for diagnosis, as they only assess large fiber function 2, 4, 7

Referral Criteria

• Refer to neurology or a pain specialist when pain remains inadequately controlled after trials of at least two first-line medications at therapeutic doses, when clinical features are atypical, or when the diagnosis is uncertain 1
• Refer to multidisciplinary pain rehabilitation programs for patients with refractory small fiber neuropathy 2

Monitoring Strategy

• Regular reassessment of pain control using validated tools such as the numeric rating scale (0–10) at each visit 1
• Monitor for progression of sensory loss, autonomic symptoms, and development of foot complications 1
• Early diagnosis and treatment is crucial, as patients treated earlier have better outcomes 2