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Two subjects receiving a single intravenous (IV) dose of tramadol 150 mg for severe postsurgical pain developed seizures within four minutes of drug administration despite rigorous screening and exclusion of patients at risk for seizures. Both subjects were participating in a randomized, double-blind study comparing the analgesic efficacy, dose-response relationship, duration of action, and safety of IV ketoprofen 50 mg and 100 mg, IV tramadol 100 mg and 150 mg, IV morphine 4 mg, and matching placebo administered over two minutes for moderate or severe postsurgical pain after removal of two or more third molars, including at least one mandibular, bony impacted third molar. The seizures were deemed to be life-threatening by the investigator and led to termination of the IV tramadol 150 mg treatment arm. Importantly, for all analgesic efficacy outcomes, IV tramadol 150 mg was neither statistically nor numerically superior to IV tramadol 100 mg; however, it was associated with more frequent and severe adverse events. IV ketoprofen 50 mg and 100 mg consistently outperformed IV tramadol 100 mg and 150 mg; the efficacy of IV tramadol at both doses was approximately half that provided by IV ketoprofen; adverse events after single doses of ketoprofen were mild or moderate and comparable to placebo. The occurrence of seizures in two subjects (9% of participants receiving IV tramadol at 150 mg) shortly after drug administration, despite rigorous screening for seizure risk, suggests that for postsurgical pain, even a single bolus dose of IV tramadol 100 mg may provide an insufficient safety margin in the real-world clinical setting. Accordingly, we recommend that IV tramadol for postsurgical pain be administered to adults either as a low-dose, repeated bolus (e.g., 25 to 50 mg every five to 15 minutes) or via a controlled infusion when doses exceed 50 mg, preferably in combination with a mechanistically differentiated analgesic.