Analgesic Efficacy of Subcutaneous–Oral Dosage of Tramadol after Surgery in C57BL/6J Mice

This study investigated the analgesic activity of tramadol in female C57BL/6J mice by using a single subcutaneous injection (25 mg/kg) of tramadol combined with the same dose given in drinking water for 24 h. We then evaluated the pharmacokinetics of tramadol and its active metabolite O-demethyltramadol (M1). To evaluate pain and analgesic efficacy, we performed clinical and behavioral assessment, burrowing tests, and activity analysis and measured body weight, food and water intake in mice that were untreated (control) or underwent analgesia only (T); anesthesia and surgery (AS); or anesthesia, surgery, and analgesia (AS+T). The plasma concentration of tramadol decreased rapidly whereas, for more than 18 h, the M1 level remained stable and above its minimal analgesic concentration for humans. Total food and water intake over 24 h was comparable among all groups. Although T mice consumed tramadol-treated water in sufficient amount and frequency, AS and AS+T animals showed decreased drinking frequency during the first 4 h after surgery. Compared with control and T groups, composite pain scores and burrowing latencies increased significantly in both AS and AS+T mice after surgery, suggesting postsurgical pain. However, AS and AS+T mice did not differ significantly after surgery. In conclusion, although naïve animals ingested a sufficient amount of the drug and plasma levels appeared sufficiently high, mice markedly reduced water intake immediately after surgery. Consequently, even in combination with an initial drug injection, the subsequent voluntary tramadol intake was insufficient to reduce signs of postsurgical pain significantly after laparotomy