Efficacy of tramadol analgesia in murine models of inflammation and sepsis.
Studies of inflammation and sepsis rely heavily on animal models to recreate complex immune responses. Many of these models require surgery to create the syndrome or to facilitate instrumentation to collect study parameters. Although standards for welfare would require the use of analgesics, the majority of these models do not include an analgesic regimen with the rationale that opioids would confound studies of inflammation. However, little scientific data define the effects of specific opioids in murine models of inflammation and surgery. In preliminary work, we have established that buprenorphine may not be the ideal analgesic agent in these cases. Therefore, we have renewed interest in the application of other agents such as tramadol. Tramadol is minimally immunosuppressive, lower in cost, and not a controlled substance, suggesting several advantages compared to many opioids. In preliminary studies, mice were given a recommended dosage of tramadol in the 24 hours surrounding cecal ligation and puncture surgery. After surgery, the septic, tramadol-treated animals had inflammatory profiles and survival outcomes that were very similar to those of animals not treated with analgesics. Although the results were definitely intriguing, several issues remain to be investigated and are the focus of this proposal. We hypothesize that tramadol will provide analgesia with minimal effects on select innate immune responses elicited in surgical models of inflammation and sepsis in mice. First and foremost, we must establish the dose range over which tramadol provides effective analgesia in a murine model involving a major surgery. From there, we can establish whether these doses will interfere with the inflammatory responses in aseptic and septic models of inflammation. The results of these studies could profoundly impact the use and selection of analgesics in sepsis and other surgical models.