A patient develops peripheral neuropathy after initiating high‑dose B‑vitamin (especially pyridoxine) supplementation; what is the likely etiology and how should it be managed?

Pyridoxine-Induced Peripheral Neuropathy: Etiology and Management

Immediately discontinue all vitamin B6 (pyridoxine) supplements and initiate pregabalin 150-600 mg/day for at least three months as first-line neuropathic pain management. 1, 2

Etiology: The Pyridoxine Paradox

High-dose pyridoxine causes peripheral neuropathy through competitive inhibition of the active form (pyridoxal-5'-phosphate), creating a functional vitamin B6 deficiency despite supraphysiologic intake. 3

Mechanism of Toxicity

• Pyridoxine at high concentrations competitively inhibits pyridoxal-5'-phosphate-dependent enzymes, paradoxically producing symptoms identical to B6 deficiency 3
• The likely mechanism involves inhibition of pyridoxal kinase (PDXK) in peripheral tissues, disrupting GABA neurotransmission within sensory neurons and leading to excitotoxicity and neurodegeneration 4
• Pathological changes include axonal degeneration similar to Wallerian degeneration, with swelling of axonal mitochondria, disruption of axoplasmic ground substance, and accumulation of dense bodies within neurons 5
• Motor neurons feeding distal muscles are preferentially affected, leading to progressive denervation of muscle fibers 5

Dose-Toxicity Relationship

• Chronic intake ≥100 mg/day consistently causes sensory neuropathy, ataxia, and loss of deep-tendon reflexes 1
• Even doses as low as 6-40 mg/day have caused documented neuropathic toxicity in susceptible individuals 1, 6
• The most severe reported case involved 9.6 grams/day, resulting in severe sensorimotor neuropathy with both sensory and motor involvement 7

Clinical Presentation

• Predominantly sensory neuropathy affecting distal extremities with numbness, paresthesias, and loss of distal sensation 2, 8
• Loss of deep tendon reflexes and sensory ataxia are characteristic 8
• Motor weakness can occur in severe cases, though less common 7
• Central nervous system is typically spared because pyridoxine poorly crosses the blood-brain barrier 4

Immediate Management Algorithm

Step 1: Discontinue All B6 Sources

• Stop all vitamin B6 supplements immediately 2
• Review and eliminate all multivitamins, B-complex preparations, fortified foods, and energy drinks that may contain hidden pyridoxine 9
• For severe cases with significant motor involvement, consider inpatient admission for monitoring 2

Step 2: Baseline Neurological Documentation

• Document extent of sensory loss in distal extremities (pinprick, light touch, vibration, proprioception) 2
• Test deep tendon reflexes (typically absent or diminished) 8
• Assess motor strength in distal muscles if weakness is present 7
• Evaluate gait and coordination for ataxia 8

Step 3: Pharmacological Pain Management

First-line therapy (choose one):

• Pregabalin 150-600 mg/day for at least 3 months 5, 1, 2
• Gabapentin 300-2,400 mg/day, titrated to highest tolerated dose 5, 1, 2

Second-line therapy if first-line fails:

• Duloxetine 30-60 mg/day 5, 1, 2

Adjunctive therapy for breakthrough pain:

• Tramadol for chronic pain management 5, 2

Step 4: Non-Pharmacological Supportive Measures

• Wear loose-fitting shoes, roomy cotton socks, and padded slippers 5, 2
• Keep feet uncovered in bed to prevent pressure-related discomfort from bedding 5, 2
• Engage in moderate walking to improve circulation, but avoid excessive walking or prolonged standing 5, 2
• Soak feet in cold water and massage for temporary pain relief 5, 2

Monitoring and Prognosis

Recovery Timeline

• Symptoms typically improve over weeks to months after pyridoxine discontinuation 2, 6
• Subjective improvement is commonly reported, though objective recovery may be incomplete 6
• Grade 3-4 impairments require longer recovery periods than grade 1-2 impairments 5
• Some morphological nerve damage may persist even after clinical improvement 5

Follow-Up Schedule

• Monitor neurological symptoms regularly to assess improvement trajectory 2
• Re-examine sensory function, reflexes, and motor strength at 4-week intervals initially 2
• Consider measuring plasma pyridoxal-5'-phosphate levels to confirm elevated B6 status if diagnosis is uncertain 2

High-Risk Populations Requiring Extra Caution

• Elderly patients: Age-related metabolic changes increase susceptibility to toxicity 2, 9
• Renal impairment: Reduced clearance dramatically increases toxicity risk; pyridoxine is contraindicated in this population 5, 2, 9
• Low-protein diet: May potentiate sensory neuron lesions from pyridoxine 5

Critical Pitfalls to Avoid

Never use high-dose B6 as treatment for existing neuropathy—it will worsen the condition you are trying to treat. 9

• Do not confuse the prophylactic isoniazid-neuropathy dose (25-50 mg/day) with therapeutic dosing; this specific indication does not apply to other neuropathies 1, 9
• Avoid vitamin C at high doses concurrently if patient has history of bortezomib chemotherapy, as it may interfere with drug metabolism 5
• Do not assume B-complex vitamins are safe; formulations containing 30 mg pyridoxine showed no objective benefit for chemotherapy-induced neuropathy 1
• Never exceed 100 mg/day for any indication in adults, and avoid entirely in elderly or renally impaired patients 1

When B6 Deficiency Is Actually Present

If documented B12 deficiency coexists (not B6), treat with hydroxocobalamin 1 mg intramuscularly on alternate days until neurological improvement plateaus, then 1 mg every 2 months for life. 1

• Exclude alternative etiologies (neurotoxic drugs, hypothyroidism, renal disease, malignancy, infections) before attributing neuropathy to any vitamin deficiency 1
• Low B6 levels may be observed in patients with neuropathy of various etiologies, but no firm causal relationship has been established 6
• B6 supplementation as monotherapy for neuropathy treatment lacks evidence; reported benefits are only from combination treatments with other vitamins 6