Palmitoylethanolamide/Baicalin Supplementation and Changes in Pain and Sudomotor Function in Type 2 Diabetes: A Retrospective Matched Real-World Cohort Study

Background: Diabetic peripheral neuropathy (DPN) is a progressive complication of type 2 diabetes mellitus (T2DM) for which no approved disease-modifying therapy exists. Palmitoylethanolamide/Baicalin (PEA/Bai; Neuridase^®) is a nutraceutical formulation with anti-neuroinflammatory and antioxidant properties; however, real-world evidence on its associations with objective neuropathy biomarkers remains limited; nutraceutical approaches to DPN remain exploratory and adjunctive in the absence of randomised controlled trial evidence of disease modification. Methods: We conducted a single-centre, retrospective, 1:1 matched-cohort study at an Internal Medicine outpatient clinic. Forty-eight T2DM patients with clinically diagnosed DPN who received PEA/Bai supplementation (Neuridase^® group) were matched to 48 untreated controls drawn from a large institutional database, using age, sex, BMI, and diabetes duration as matching variables. Acknowledged a priori limitations include baseline imbalance in neuropathy severity (VAS and ESC) and SGLT2 inhibitor use, reflecting real-world prescribing patterns (confounding by indication) and constituting potential sources of residual confounding that preclude causal inference. The primary outcome was change in VAS neuropathic pain score from baseline (T0) to 6-month follow-up (T6). Secondary outcomes were changes in electrochemical skin conductance (ESC, µS) in hands, feet, and four-limb sum measured by Sudoscan. Results: At baseline, the Neuridase^® group exhibited significantly greater neuropathic burden: higher VAS scores (median 5.5 [IQR 3.8–7.2] vs. 2.0 [0.0–5.0]; p < 0.001) and lower ESC in both hands (53.0 vs. 72.2 µS; p < 0.001) and feet (74.5 vs. 81.0 µS; p < 0.001), reflecting real-world prescribing patterns. Over 6 months, VAS decreased significantly in the Neuridase^® group (5.5→3.0; p < 0.0001; median Δ = −2.5 points, exceeding the clinically important difference), with no change in controls (2.0→2.0; p = 0.85). Differential Sudoscan trajectories were observed: the Neuridase^® group showed significant improvement in hand ESC (53.0→60.0 µS; p = 0.035) and preservation of foot ESC (p = 0.888), while controls exhibited significant deterioration across all three sudomotor indices (hand p = 0.038; foot p = 0.008; four-limb sum p = 0.004). In a complementary categorical pain trajectory analysis, VAS worsening occurred in 31.3% of controls compared with 0% of Neuridase^®-treated patients (p = 0.00022). Among patients with pathological hand ESC at baseline (<60 µS), 27.8% of Neuridase^® patients (n = 36) transitioned to non-pathological values at T6 versus 0% of controls (n = 32; p = 0.001). Conclusions: In a real-world matched cohort, PEA/Baicalin supplementation was associated with clinically meaningful pain reduction and with differential longitudinal sudomotor trajectories compared to matched untreated controls. These exploratory, hypothesis-generating findings from a retrospective non-randomised design are consistent with possible modulatory effects of PEA/Baicalin on objective sudomotor autonomic biomarkers in DPN. Confounding by indication, baseline severity imbalance, and residual confounders including SGLT2 inhibitor use preclude causal interpretation. These observations provide a rationale for adequately powered, prospective, randomised placebo-controlled trials with extended follow-up and structural neuropathy endpoints.