Metamizole outperforms meloxicam in sepsis: insights on analgesics, survival and immunomodulation in the peritoneal contamination and infection sepsis model

Front Immunol. 2024 Aug 30:15:1432307. doi: 10.3389/fimmu.2024.1432307. eCollection 2024.

Abstract

Background: Limited availability and side effects of opioids have led to an increased use of non-opioid analgesia in animal disease models. However, by affecting the immune-inflammatory reactions, analgesia may disrupt the resolution of the host inflammation and modulate the survival in septic animals. This study used a clinically relevant sepsis mouse model of peritoneal contamination and infection (PCI) to investigate the antinociceptive and anti-inflammatory properties of two non-opioid analgesics.

Methods: Adult C57BL/6J mice were intraperitoneally injected with a human feces suspension and received either no analgesics (Non-A), Meloxicam, or Metamizole orally. The mice were monitored for pain and illness. Mortality was assessed at 7 days post-PCI. A separate group of mice was sacrificed 24 hours after infection. Blood, peritoneal lavage fluid (PLF), liver, and spleen were harvested for pathogen load quantification via qPCR, macrophage phenotyping, neutrophil infiltration/activation, and systemic/tissue cytokine release by flow cytometry.

Results: Meloxicam but not Metamizole reduced the mortality of septic mice by 31% on day 7 compared to the Non-A group. Both analgesics effectively alleviated pain but did not affect illness severity, body weight, and temperature. Meloxicam quadrupled the bacterial burden in the blood and PLF. In high IL-6 responders, Meloxicam treatment was associated with reduced circulating IL-10 and IL-1β compared to the Non-A septic group. In low IL-6 responders, Meloxicam increased circulating MCP-1 levels and decreased PGE2 levels compared to Non-A septic mice. Notably, Meloxicam reduced spleen neutrophil infiltration by 20% compared to two other sepsis groups.

Conclusion: Metamizole and Meloxicam effectively relieved pain and increased the animals' basal activity in the PCI sepsis model. Meloxicam prolonged survival yet triggered maladaptive responses due to its immunosuppressive features that decreased tissue bacterial clearance during sepsis. In contrast, Metamizole constitutes a safe and effective non-opioid alternative for analgesic control in the non-surgical PCI sepsis model.

Keywords: CXCR2; NSAID analgesic; clinical severity; immunophenotype; sepsis.

MeSH terms

  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Cytokines / blood
  • Cytokines / metabolism
  • Dipyrone* / pharmacology
  • Dipyrone* / therapeutic use
  • Disease Models, Animal*
  • Humans
  • Immunomodulation / drug effects
  • Male
  • Meloxicam* / therapeutic use
  • Mice
  • Mice, Inbred C57BL*
  • Peritonitis / drug therapy
  • Peritonitis / immunology
  • Peritonitis / microbiology
  • Peritonitis / mortality
  • Sepsis* / drug therapy
  • Sepsis* / immunology
  • Sepsis* / mortality

Substances

  • Meloxicam
  • Dipyrone
  • Analgesics
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Open Access funding enabled and organized by Projekt DEAL. The authors acknowledged the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project Number 316213987– SFB 1278 “PolyTarget” (Project C06, D01, B08, and Z01) and Project Number 852813223. CS, MB, AP, and MF were supported by the Federal Ministry for Education and Research (Bundesministerium für Bildung und Forschung, BMBF), funding program Photonics Research Germany (Grant ID: 13N15709 and 13N15716) associated with the Leibniz Center for Photonics in Infection Research (LPI).