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Tramadol metabolism and systemic inflammation after major abdominal surgery: a prospective observational study

Introduction: A systemic inflammation may affect tramadol metabolism within first 24 postoperative hours. Objectives: The aim of this study was to examine concentrations of tramadol, O- demethyltramadol (ODT) and N-demethyltramadol (NDT) in patients admitted to the intensive care unit (ICU) after major abdominal surgery in the patients with and without criteria for systemic inflammation. Methods: For this study Ethics committee approval was obtained and all the patients wrote informed consent. In between of 50 postsurgical patients, a group of 47 patients who had both CYP2D6 gene polymorphism analyses and tramadol and it’s metabolites measured were analyzed. The development of a systemic inflammation was assessed based on preoperative levels of CRP, PCT, leukocyte count, plasma cholinesterase activity (ChE), arterial blood gas, and postoperative clinical indicators. Postoperatively, patients received 100 mg of tramadol IV. every 6 hours for the next 24 hours. Tramadol, ODT and NDT levels were determined 1, 2 and 4 hours after the first dose, and before the second, third and fifth doses of tramadol by high-performance liquid chromatography. Pain was assessed before and 30 minutes after tramadol administrations. Results: According to CYP2D6 polymorphism there were 2 poor (PM), 22 intermediate (IM), 22 extensive (EM) and 1 ultrafast metabolizer (UM). Tramadol effectively reduced pain in all patients except PM. The highest levels of ODT were measured in the EM and IM, 97.4 (52.5–139) and 51.7 (25.7–93.5) μg/L, respectively (P = 0.03). ODT levels in all measurements were higher in EM compared to IM and PM, P < 0.05. ChE activity of £4244 U/L was a cut-off value in prediction of systemic inflammation. There was a statistically significant increase in NDT levels in IM and EM patients with low ChE activity (LChE group, n = 18) compared to patients with normal ChE activity (NChE group, n = 25). The ranges were from 11.58 (4.2–21.9) to 59.31 (18.5–92.6) μg/L vs. 3.93 (3.5–5.6) to 26.31 (17.4–48.9) μg/L in LChE and NChE, respectively. Genetically determined difference in ODT levels between IM and EM no longer existed in states of systemic inflammation in all measurements. Despite these differences, tramadol was effective in patients who were EM and IM in reducing pain at all measurement points (P < 0.001), but not in 2 patients who were categorized as poor metabolizers (P>0.05). Conclusion: The results of this study confirm that CYP2D6 polymorphism is a major factor in O-demethylation of tramadol. In the systemic inflammation characterized by low ChE activity there is a significant shift in the tramadol metabolism towards N-demethylation. Further studies should evaluate whether tramadol dose may be reduced in the patients with systemic inflammation.

tramadol metabolism, inflammation, critical care, postoperative

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