Top 10 Evidence-Based Recommendations

ALA is a mitochondrial antioxidant that improves glucose-induced oxidative stress and microvascular blood flow to nerves, reducing burning and pins-and-needles sensations.^[1][2][4]

Meta-analyses show ALA reduces total symptom scores in diabetic sensorimotor polyneuropathy; dose-response seen for oral 600–1800 mg/day. IV 600 mg/day for 3 weeks yields clinically meaningful pain reduction.^[2][4]

PEA downshifts neuroinflammation via the endocannabinoid-related ALIA mechanism (PPAR-α), calming hyperactive mast cells and glia—key drivers of neuropathic pain.^[7][9]

A quadruple-blinded RCT (n=70) in diabetic neuropathy showed significant reductions in pain scores and sleep problems vs placebo after 8 weeks; meta-analysis across pain syndromes supports analgesic benefit.^[7][9]

B12 supports myelin synthesis and nerve regeneration; metformin use and low-normal B12 are common in diabetics with neuropathy.^[6][15]

Meta-analysis of RCTs shows B12 reduces neuropathic symptoms and pain vs controls; a 1-year RCT in metformin-treated type 2 diabetes improved electrophysiology and sudomotor measures.^[6][15]

Lipid-soluble thiamine analog that activates transketolase, diverting toxic advanced glycation flux in nerves and microvessels.^[10][12][13]

Placebo-controlled trials show symptom score improvements in diabetic polyneuropathy (greater at 600 mg/day). Larger/longer trials still needed for hard endpoints.^[10][13]

Replenishes glutathione and activates NRF2, lowering neuro-inflammation (TNF-α) and oxidative stress linked to neuropathic pain.^[3][5]

An RCT (n=90) adding 2400 mg/day NAC to standard care for 12 weeks improved neuropathy and pain scores vs control; a double-blind RCT found 1200 mg/day had similar pain relief to pregabalin over 8 weeks.^[3][5]

Incorporates into neuronal membranes and dampens pro-inflammatory cytokines driving axonal injury from taxanes/platinums.^[18][19][21]

Randomized trials show lower incidence of paclitaxel-induced neuropathy with omega-3 vs placebo; data for treatment (not prevention) are limited.^[18][21]

Downregulates NF-κB and oxidative pathways implicated in diabetic nerve injury; may also reduce depression/anxiety that amplify pain.^[22][17]

Small RCTs in diabetic neuropathy show reduced neuropathy severity and improved glycemic indices; additional RCT reduced depression/anxiety in DPN. Evidence is promising but not yet robust.^[22][17]

Supports mitochondrial energy and nerve regeneration; may improve small fiber function.^[14][11]

Older RCTs suggest improved pain and vibration perception in diabetic neuropathy, but Cochrane rates certainty low. Importantly, a large oncology trial found ALC worsened taxane-induced neuropathy over 2 years when used preventively.^[11][16]

GLA can correct impaired nerve membrane fatty acid composition in diabetes, potentially improving conduction and pain.^[23][20]

A recent randomized double-blind trial showed VAS and NTSS-6 pain improvements in 4 weeks; legacy small RCTs suggest benefits but evidence remains limited vs first-line picks.^[20][23]

Modulates nociception and neuroinflammation; deficiency is common in diabetes and correlates with neuropathic pain.^[8][24][25]

Systematic review shows vitamin D supplementation reduces neuropathic pain scores in DPN despite limited changes in nerve conduction; strongest effects when correcting deficiency.^[8]