Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Comparison of the Analgesic Efficacy and Safety of Intravenous Ketoprofen, Tramadol, and Morphine After Bony Impacted Mandibular Third Molar Surgery

Introduction Although opioids remain the standard of care for managing postsurgical pain, concerns persist regarding their safety, tolerability, and potential for addiction. Intravenous (IV) formulations of ketoprofen and tramadol have been widely available in numerous countries outside the United States and Canada. Methods This single-dose, single-center, double-blind, randomized study (n=185) evaluated the analgesic efficacy, dose-response relationship, duration of action, and safety of IV ketoprofen 50 mg (n=33) and 100 mg (n=31), IV tramadol 100 mg (n=33) and 150 mg (n=22), IV morphine 4 mg (n=33), and placebo (n=33) administered over two minutes upon the first occurrence of moderate-to-severe pain following surgical extraction of bony impacted mandibular third molars. Pain intensity and pain relief were assessed over eight hours. The primary efficacy endpoint was total pain relief over the first four hours (TOTPAR 0-4). Secondary efficacy endpoints included TOTPAR at additional time intervals, summed pain intensity difference (SPID), peak pain relief, peak pain intensity difference, time to rescue analgesia, patient global evaluation, and time to confirmed perceptible and meaningful pain relief. Safety assessments included volunteered and observed adverse events (AEs). Results For TOTPAR 0-4 and all other efficacy endpoints, IV ketoprofen 50 mg and 100 mg, and IV tramadol 100 mg and 150 mg were significantly superior to IV morphine 4 mg and placebo. IV ketoprofen at both doses also outperformed IV tramadol at both doses across the majority of outcome measures. No significant differences in efficacy were observed between IV morphine 4 mg and placebo. The proportion of subjects experiencing one or more AEs was comparable among the placebo, IV ketoprofen 50 mg, and IV ketoprofen 100 mg groups. In contrast, higher AE rates were reported in the IV tramadol and IV morphine groups relative to placebo. Dosing in the IV tramadol 150 mg group was discontinued early due to the occurrence of seizures in two patients (9%) immediately following administration. Conclusions Both IV ketoprofen and IV tramadol demonstrated superior analgesic efficacy compared to IV morphine and placebo in the management of postsurgical pain. Notably, IV ketoprofen consistently outperformed tramadol across efficacy endpoints. The lack of efficacy observed with IV morphine 4 mg raises concerns about potential analgesic assay insensitivity in postsurgical dental pain. The occurrence of seizures in subjects without known seizure risk factors highlights a potentially insufficient safety margin for tramadol in unselected patient populations.