Synergistic modulation of nociceptive and inflammatory pain by palmitoylethanolamide and Cucumis sativus extract in a monosodium-iodoacetate induced osteoarthritic rat model

Inflammopharmacology. 2026 Apr 7. doi: 10.1007/s10787-026-02197-3. Online ahead of print.

ABSTRACT

BACKGROUND: Osteoarthritis (OA) is a progressive degenerative joint disease characterized by chronic inflammation, cartilage degradation, and persistent pain, leading to functional disability and reduced quality of life. Current pharmacological treatments, particularly non-steroidal anti-inflammatory drugs (NSAIDs), provide symptomatic relief but are associated with significant adverse effects during long-term use. The present study evaluated the therapeutic efficacy and pharmacological synergy of a novel combination formulation, Ostizeel™, comprising palmitoylethanolamide (PEA) and Cucumis sativus extract (CSE), in a monosodium iodoacetate (MIA)-induced rat model of osteoarthritis.

METHODS: Forty-two female Wistar rats were randomized into seven experimental groups and treated orally with PEA, CSE, an NSAID standard, or their combinations for 28 days. Nociceptive behavior and functional recovery were assessed using movement-evoked pain scoring, Randall-Selitto mechanical hyperalgesia, von Frey allodynia testing, and dynamic weight-bearing analysis. Systemic inflammation and cartilage catabolism were evaluated by measuring serum interleukin-1β (IL-1β) and matrix metalloproteinase-13 (MMP-13) levels. Drug-drug interaction was assessed using the Bliss Independence model and a combination index derived from the Loewe additivity principle.

RESULTS: The combination treatment significantly improved pain thresholds and limb function compared with either monotherapy (p < 0.0001). Serum IL-1β and MMP-13 levels were reduced by approximately 50%, indicating potent anti-inflammatory and chondroprotective effects. Bliss Independence analysis yielded positive synergy scores across behavioural and biochemical endpoints, suggesting that the observed combination effects exceeded predicted additive responses.

CONCLUSION: Synergistic modulation of nociceptive and inflammatory pathways were demonstrated by PEA and CSE, which highlight Ostizeel™ as a promising pharmacological strategy for osteoarthritis management.

PMID:41945007 | DOI:10.1007/s10787-026-02197-3