Assessment of Opioid-Induced Immunomodulation in Experimental and Clinical Sepsis.

Abstract

We hypothesized opioid exposure would be associated with immunosuppression in patients with sepsis and secondary infection in a murine sepsis model. This was a two-phase preclinical and clinical study. The clinical phase included a subgroup of patients with sepsis from an existing randomized controlled trial while the preclinical phase used a murine model of sepsis with C57BL/6 mice. In the clinical phase, a post hoc analysis was performed in subjects receiving fentanyl versus no opioid receipt. In the preclinical phase, a murine cecal slurry-induced sepsis model followed by secondary infection was used. Mice were randomized to fentanyl versus no fentanyl concomitantly. In clinical sepsis, a significant decrease in interleukin-23 (IL-23) level in patients with fentanyl exposure was observed and lower IL-23 was associated with mortality (p < 0.001). Other measured cytokines showed no significant differences. Concomitant fentanyl exposure during murine sepsis was associated with a significantly higher bacterial burden (p < 0.001) after secondary infection; however, immune cell counts and plasma cytokine levels were largely unaffected by fentanyl. Minimal alterations in cytokines were seen with opioid exposure during clinical sepsis. In a preclinical model, opioid exposure during sepsis was associated with ineffective bacterial clearance upon secondary infection. Further studies are warranted to evaluate the immunomodulatory role of opioids and their implications, especially in the post-sepsis period.