01712-A: Determining the Effect of Pain Medication on Immune Function: Part 2
Grant Status: Closed
Project SummaryIntroduction: Opioids are often used to treat pain in many situations, including during the post-operative period and often in dogs with a high risk for infection. In addition to providing excellent pain control, opioids directly modulate the immune system. In other species, certain opioids suppress the beneficial aspects (e.g., phagocytosis and microbial killing) while promoting detrimental aspects (e.g., excessive cytokine production) of the immune response to infection while other opioids have little effect. Thus, the selection of intra-and post-operative opioids could affect the incidence of post-operative infection in dogs. Despite extensive work in other species supporting the profound immunologic effects of opioids, to date there is no published information pertaining to the effects of opioids on immune function in dogs. In this investigation, we will evaluate the effects of tramadol, and O-desmethyltramadol (biologically active metabolite of tramadol) on phagocytic function and cytokine production. Since hundreds of thousands of dogs undergo surgery or suffer trauma necessitating administration of opioids every year, and postoperative infection rate in dogs have been reported as high as 27%, the results of this study could have a dramatic and widespread impact on canine health. Materials and Methods: With informed owner consent, blood samples were collected from healthy pet dogs. Blood was incubated with low, intermediate, and high concentrations of tramadol and its metabolite, o-desmethyltramadol. Following incubation, two different assays were performed to measure the ability of canine neutrophils and monocytes in blood to engulf bacteria (phagocytosis) and kill engulfed bacteria (respiratory burst). In addition, blood was cultured with parts of bacteria called pathogen associated molecular patterns to determine the ability of white blood cells to respond to this threat via production of pro-inflammatory TNF and anti-inflammatory IL-10. Results: Blood samples were collected from 6 healthy dogs. Phagotest and Phagoburst assays were performed on all samples. There was no statistically significant difference between drug groups and blood incubated without drug, and no difference in leukocyte stimulated production of TNF. However, we found a statistically significant decrease in the ability of neutrophils to produce IL-10 following incubation with the tramadol metabolite o-desmethyltramadol. Furthermore, this decreased production appears concentration dependent. Conclusions: In conclusion, PMNs of dog blood incubated with various concentrations of tramadol and o-desmethyltramadol, have no change in phagocytic function or respiratory burst when compared to incubation with control solution. However, o-desmethyltramadol blunts production of IL-10 in response to lipoteichoic acid and lipopolysaccharide. IL-10 is a cytokine central to controlling inflammatory responses; its main role is to act as an anti-inflammatory and immunosuppressive cytokine and regulate the balance of pro-and anti-inflammatory responses. This underlines the importance of understanding how tramadol and its metabolites may change immune system function prior to treatment in dogs with underlying immune system dysfunction. Dogs with a blunted ability to effectively quell an overzealous inflammatory response may be at higher risk of complications related to infection, which can then lead to increased morbidity and mortality in dogs treated with these drugs for pain control. Further sample collection and application for further funding is ongoing.
Publication(s)Manuscript in preparation.
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