Efficacy of N-acetylcysteine in enhancing paracetamol's analgesic effect and inhibiting hepatotoxicity: a preclinical mouse model.

Introduction: Paracetamol (PCM) is extensively administered in clinical settings to alleviate mild to moderate pain and/or decrease fever. However, noncompliance with prescribed dosages can lead to severe and irreversible liver damage from PCM overdose. Although N-acetylcysteine (NAC) serves as the standard antidote for PCM toxicity, no commercially available combination of PCM and NAC has been marketed to mitigate its toxic effects. Methods: Male and female C57Bl6/J mice were assigned to 4 groups. Group A received oral PCM exclusively, administered every 6 hours (4 doses within 24 hours), whereas groups B-D were administered PCM alone, a combination of PCM/L-NAC (N-acetyl-l-cysteine), or PCM/D-NAC (N-acetyl-d-cysteine) every 4 hours (6 doses within 24 hours). Results: Both PCM/L-NAC and PCM/D-NAC combinations yielded superior analgesia compared with the standard regimen. Furthermore, L-NAC administration mitigated the increase of glutamate pyruvate transaminase, a key hepatic marker associated with PCM hepatotoxicity. In addition, a protective effect from D-NAC in conjunction with PCM on glutathione levels was suggested. Our findings suggest that NAC enhances the analgesic properties of PCM while concurrently reducing its hepatotoxic potential in mice. Moreover, data indicate that L-NAC may represent a more effective candidate than D-NAC for this purpose, particularly regarding hepatoprotection. Conclusion: This study presents novel insights into the synergistic effects of the PCM/NAC combination on pain relief and hepatic safeguarding, warranting consideration for the development of novel therapeutic strategies targeting pain and fever management in patients.