{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:53:43Z","timestamp":1781672023219,"version":"3.54.5"},"reference-count":19,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>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\u00ae) 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\u00ae 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, \u00b5S) in hands, feet, and four-limb sum measured by Sudoscan. Results: At baseline, the Neuridase\u00ae group exhibited significantly greater neuropathic burden: higher VAS scores (median 5.5 [IQR 3.8\u20137.2] vs. 2.0 [0.0\u20135.0]; p &lt; 0.001) and lower ESC in both hands (53.0 vs. 72.2 \u00b5S; p &lt; 0.001) and feet (74.5 vs. 81.0 \u00b5S; p &lt; 0.001), reflecting real-world prescribing patterns. Over 6 months, VAS decreased significantly in the Neuridase\u00ae group (5.5\u21923.0; p &lt; 0.0001; median \u0394 = \u22122.5 points, exceeding the clinically important difference), with no change in controls (2.0\u21922.0; p = 0.85). Differential Sudoscan trajectories were observed: the Neuridase\u00ae group showed significant improvement in hand ESC (53.0\u219260.0 \u00b5S; 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\u00ae-treated patients (p = 0.00022). Among patients with pathological hand ESC at baseline (&lt;60 \u00b5S), 27.8% of Neuridase\u00ae 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.<\/jats:p>","DOI":"10.3390\/nu18121894","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:52:08Z","timestamp":1781229128000},"page":"1894","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Palmitoylethanolamide\/Baicalin Supplementation and Changes in Pain and Sudomotor Function in Type 2 Diabetes: A Retrospective Matched Real-World Cohort Study"],"prefix":"10.3390","volume":"18","author":[{"given":"Salvatore","family":"Scibetta","sequence":"first","affiliation":[{"name":"Internal Medicine Unit with Rheumatology, Dermatology, Diabetology and Tertiary Diabetic Foot Health-Care, Department of Clinical Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy"},{"name":"Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), Via Ugo La Malfa 153, 90146 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Calvo","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit with Rheumatology, Dermatology, Diabetology and Tertiary Diabetic Foot Health-Care, Department of Clinical Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Pinzolo","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit with Rheumatology, Dermatology, Diabetology and Tertiary Diabetic Foot Health-Care, Department of Clinical Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy"},{"name":"Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties [PROMISE], University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Corrao","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Azienda Ospedaliera Universitaria \u201cPoliclinico G. Martino\u201d, 90124 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5621-1374","authenticated-orcid":false,"given":"Salvatore","family":"Corrao","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit with Rheumatology, Dermatology, Diabetology and Tertiary Diabetic Foot Health-Care, Department of Clinical Medicine, National Relevance and High Specialization Hospital Trust ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy"},{"name":"Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical Specialties [PROMISE], University of Palermo, 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.2337\/dc16-2042","article-title":"Diabetic neuropathy: A position statement by the American Diabetes Association","volume":"40","author":"Boulton","year":"2017","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1212\/WNL.43.4.817","article-title":"The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: The Rochester Diabetic Neuropathy Study","volume":"43","author":"Dyck","year":"1993","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41572-019-0092-1","article-title":"Diabetic neuropathy","volume":"5","author":"Feldman","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.2337\/dc10-1303","article-title":"Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments","volume":"33","author":"Tesfaye","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.2337\/diabetes.54.6.1615","article-title":"The pathobiology of diabetic complications: A unifying mechanism","volume":"54","author":"Brownlee","year":"2005","journal-title":"Diabetes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S1474-4422(12)70065-0","article-title":"Diabetic neuropathy: Clinical manifestations and current treatments","volume":"11","author":"Callaghan","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(14)70251-0","article-title":"Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis","volume":"14","author":"Finnerup","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1517\/14656566.2014.972935","article-title":"Efficacy of alpha-lipoic acid in diabetic neuropathy","volume":"15","author":"Papanas","year":"2014","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.36076\/ppj\/2016.19.11","article-title":"Palmitoylethanolamide, a special food for medical purposes, in the treatment of chronic pain: A pooled data meta-analysis","volume":"19","author":"Paladini","year":"2016","journal-title":"Pain Physician"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1124\/mol.104.006353","article-title":"The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of Palmitoylethanolamide","volume":"67","author":"Fu","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"437","DOI":"10.2147\/JPR.S32143","article-title":"Therapeutic utility of Palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: A case series","volume":"5","author":"Hesselink","year":"2012","journal-title":"J. Pain Res."},{"key":"ref_12","first-page":"2774","article-title":"Effects of Baicalin capsules combined with \u03b1-lipoic acid on nerve conduction velocity, oxidative stress and inflammatory injury in patients with diabetic peripheral neuropathy","volume":"13","author":"Tang","year":"2021","journal-title":"Am. J. Transl. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.2147\/DDDT.S319260","article-title":"Baicalin alleviates oxidative stress and inflammation in diabetic nephropathy via Nrf2 and MAPK signaling pathway","volume":"15","author":"Ma","year":"2021","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1111\/j.1526-4637.2012.01432.x","article-title":"Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis","volume":"13","author":"Gatti","year":"2012","journal-title":"Pain Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1089\/dia.2013.0129","article-title":"Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction","volume":"15","author":"Casellini","year":"2013","journal-title":"Diabetes Technol. Ther."},{"key":"ref_16","first-page":"482","article-title":"Sudomotor function assessment as a screening tool for the diagnosis of small fibre neuropathy and autonomic damage in metabolic disorders","volume":"8","author":"Vas","year":"2014","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"103714","DOI":"10.5402\/2012\/103714","article-title":"Quick and simple evaluation of sudomotor function for screening of diabetic neuropathy","volume":"2012","author":"Yajnik","year":"2012","journal-title":"ISRN Endocrinol."},{"key":"ref_18","first-page":"1691","article-title":"SGLT2 inhibitor use is associated with reduced neuropathic pain and improved sudomotor function in patients with type 2 diabetes","volume":"12","author":"Ishibashi","year":"2021","journal-title":"J. Diabetes Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.2337\/dc10-0253","article-title":"Corneal confocal microscopy: A novel noninvasive test to examine early diabetic peripheral neuropathy","volume":"33","author":"Tavakoli","year":"2010","journal-title":"Diabetes Care"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/12\/1894\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:12:51Z","timestamp":1781669571000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/12\/1894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,11]]},"references-count":19,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["nu18121894"],"URL":"https:\/\/doi.org\/10.3390\/nu18121894","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,11]]}}}