Omega-3 attenuates codeine-induced hepatic injury in female wistar rats via its antioxidative, anti-inflammatory, and anti-apoptotic effects

Abstract

Codeine is widely used for managing chronic and intermittent pain, particularly in females experiencing menstrual cramps; however, prolonged use has been associated with hepatic injury mediated by oxidative stress and apoptosis. Despite this growing concern, limited data exist on effective strategies to protect the liver against opioid-induced damage. This study investigated the protective role of omega-3 fatty acid supplementation against codeine-induced liver injury in female Wistar rats. Twenty female rats were divided into four groups (n = 5 each): vehicle control, omega-3-treated (400 mg/kg BW, p.o.), codeine-treated (10 mg/kg BW, p.o.), and codeine + omega-3 co-treated (10 mg/kg BW of codeine + 400 mg/kg BW of omega-3, p.o.) for eight weeks. Chronic codeine exposure significantly (p < 0.05) elevated hepatic injury biomarkers (AST, GGT, and LDH), oxidative stress indices (MDA and 8-OHdG), and inflammatory mediators (MPO and NO), accompanied by (p < 0.05) increased caspase-3 activity. In contrast, omega-3 supplementation markedly (p < 0.05)reduced these alterations, enhanced antioxidant defense, and preserved hepatic architecture. Moreover, omega-3 improved hepatic metabolic function, as indicated by decreased lactate levels and lactate/pyruvate ratios. These findings demonstrate that omega-3 fatty acid effectively attenuates chronic codeine-induced hepatic injury by mitigating oxidative stress, inflammation, and apoptosis, thereby preserving liver function and cellular integrity in female rats. The study is relevant as it highlights omega-3 fatty acid as a potential dietary intervention for reducing opioid-related hepatotoxicity and promoting safer long-term pain management.