Enhancing meloxicam efficacy in acute and chronic inflammatory pain: a novel dose-sparing approach using ultramicronized palmitoylethanolamide

Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs), such as meloxicam, are widely used for the management of inflammatory pain in human and veterinary medicine, although their clinical utility is limited by dose-dependent adverse effects. 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’s 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 mg/kg) markedly enhanced the analgesic activity of low-dose meloxicam (3 mg/kg), with the combination fully reversing inflammatory hypersensitivity and outperforming high-dose meloxicam (30 mg/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-α with the selective receptor antagonist GW6471 (2 mg/kg) significantly reduced, but did not abolish, the analgesic effect of the combination, suggesting both PPAR-α-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.