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Strategies aimed at reducing NSAID dosage while preserving analgesic efficacy are therefore warranted. We investigated whether ultramicronized palmitoylethanolamide (PEAum), an endogenous prohomeostatic lipid amide with improved bioavailability, could enhance the antinociceptive effects of meloxicam in preclinical models of acute and chronic inflammatory pain. Acute pain was induced by intraplantar lipopolysaccharide (LPS) injection, while chronic pain was induced by intra-articular injection of Complete Freund\u2019s Adjuvant (CFA). Mechanical hyperalgesia and allodynia were measured by the Paw pressure and von Frey tests, respectively. In the LPS model, PEAum confirmed its superior anti-hyperalgesic profile compared with micronized and native PEA. PEAum (10\u00a0mg\/kg) markedly enhanced the analgesic activity of low-dose meloxicam (3\u00a0mg\/kg), with the combination fully reversing inflammatory hypersensitivity and outperforming high-dose meloxicam (30\u00a0mg\/kg). In the CFA model, the same association completely counteracted mechanical hyperalgesia, reproducing the antalgic effect of high-dose meloxicam. A pharmacodynamic study demonstrated that pharmacological blockade of PPAR-\u03b1 with the selective receptor antagonist GW6471 (2\u00a0mg\/kg) significantly reduced, but did not abolish, the analgesic effect of the combination, suggesting both PPAR-\u03b1-dependent and independent mechanisms. Overall, the combined treatment produced a greater-than-additive antinociceptive effect, demonstrating a synergistic interaction between PEAum and meloxicam in both acute and chronic inflammatory pain. This synergy enables substantial meloxicam dose-reduction while maintaining full analgesic activity, supporting a promising dose-sparing strategy for inflammatory pain management.<\/jats:p>","DOI":"10.1007\/s10787-026-02380-6","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:24:18Z","timestamp":1791264258000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing meloxicam efficacy in acute and chronic inflammatory pain: a novel dose-sparing approach using ultramicronized palmitoylethanolamide"],"prefix":"10.1007","author":[{"given":"Samuele","family":"Trisolini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Toti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Lucarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Di Cesare Mannelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Ghelardini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Micheli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"2380_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2024.117899","volume":"112","author":"M Arfeen","year":"2024","unstructured":"Arfeen M, Srivastava A, Srivastava N et al (2024) Design, classification, and adverse effects of NSAIDs: a review on recent advancements. 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Carla Ghelardini and Lorenzo Di Cesare Mannelli received a grant from Epitech (Padua, Italy).","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal manipulations were carried out according to Directive 2010\/63\/EU of the European Parliament and of the European Union Council (22 September 2010) on the protection of animals used for scientific purposes. The ethical policy of the University of Florence complies with the Guide for the Care and Use of Laboratory Animals of the US National Institutes of Health (NIH Publication No. 85\u201323, revised 1996; University of Florence assurance number: A5278-01). Formal approval to conduct the experiments described was obtained from the Italian Ministry of Health (No. 300\u20132021-PR) and from the Animal Subjects Review Board of the University of Florence. Experiments involving animals have been reported according to ARRIVE guidelines (McGrath and Lilley\n                      \n                      ). All efforts were made to minimize animal suffering and to reduce the number of animals used.","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}}]}}