In a randomized phase 3 trial (STARDOM1), the co-crystal of Tramadol-Celecoxib (CTC) illustrated better pain alleviation following oral surgery when compared to Tramadol or placebo, with a more favorable benefit-to-risk ratio when compared to Tramadol. This phase 3 multicenter, double-blind trial was conducted to contemplate the effectiveness and safety of CTC compared to Tramadol for moderate-to-severe pain experienced up to 72 hours following elective third molar extraction involving bone removal.

A total of 726 adults were randomly assigned to one of five groups in a ratio of 2:2:2:2:1. These groups received either orally administered CTC twice daily at doses of 100 mg (containing 44 mg of rac-Tramadol hydrochloride and 56 mg of Celecoxib; n = 164), 150 mg (66/84 mg; n = 160), or 200 mg (88/112 mg; n = 160), 100 mg Tramadol four times daily (n = 159), or placebo four times daily (n = 83). Subjects in the CTC groups were also given twice-daily placebo. The full analysis set encompassed all volunteers who underwent randomization.

The sum of pain intensity differences over the first 4 hours (SPID0-4) examined utilizing a visual analog scale (VAS) was the primary outcome ascertained. Key secondary outcomes encompassed the rate of responders attaining at least a 50% drop in pain intensity at 4 hours and the usage of rescue medication. Safety evaluations incorporated monitoring adverse events, lab parameters, and scores on the Opioid-Related Symptom Distress Scale (OR-SDS).

For both primary and key secondary endpoints, all the doses of CTC illustrated superiority over placebo (P < 0.001). Furthermore, CTC outperformed Tramadol in SPID0-4 (with analysis of covariance [ANCOVA] least squares mean differences [95% confidence interval (CI)] of -37.1 [-56.5, -17.6], -40.2 [-59.7, -20.6], and -41.7 [-61.2, -22.2] for 100, 150, and 200 mg CTC, respectively; P < 0.001) and the 4-hour 50% responder rate.

The rates of responders attaining at least a 50% reduction in pain at 4 hours were 32.9% (CTC 100 mg), 33.8% (CTC 150 mg), 40.6% (CTC 200 mg), 20.1% (Tramadol), and 7.2% (placebo). Moreover, the usage of rescue medication was remarkably lower in the 100-mg (P = 0.013) and 200-mg (P = 0.003) CTC groups as opposed to the Tramadol group. In the Tramadol alone arm, the occurrence of adverse events and OR-SDS scores were greatest.