Co-Crystal of Tramadol-Celecoxib Noninferior to Tramadol for Pain After Hysterectomy

The novel co-crystal formulation of tramadol-celecoxib (CTC) was found to be noninferior to tramadol for cumulative pain scores following abdominal hysterectomy, according to the results of a study published in the European Journal of Pain.

The STARDOM2 trial (ClinicalTrials.gov Identifier: NCT03062644) was a randomized, double-blind, parallel-group, placebo- and active comparator-controlled, phase 3 trial conducted between 2017 and 2018 at 65 sites in 7 countries in Eurasia. Patients (N=1136) undergoing abdominal hysterectomy were randomly assigned in a 2:2:2:2:2:1 ratio to receive rac-tramadol hydrochloride 44 mg with celecoxib 56 mg in a single, 100-mg capsule taken twice daily (CTC 100; n=207), tramadol 66 mg with celecoxib 84 mg in a single, 150-mg capsule taken twice daily (CTC 150; n=207), tramadol 88 mg with celecoxib 112 mg in 2 100-mg capsules taken twice daily (CTC 200; n=208), 2 immediate-release tramadol 50-mg capsules taken 4 times daily (n=208), celecoxib 100 mg taken twice daily (n=206), or 3 placebo capsules taken 4 times daily (n=102). The primary endpoint was the sum of pain intensity differences over 4 hours.

The mean ages of study participants ranged from 48.1 to 48.7 years, almost all study participants were White, mean BMI ranged from 27.8 to 28.3 kg/m², and the mean predose pain intensity-visual analogue scale (PI-VAS) score ranged from 64.3 to 65.4 mm.

Compared with placebo, CTC 200 mg (least squares mean difference [LSMD], -20.0; 95% CI, -34.4 to -5.6 mm·h; P =.003), CTC 150 mg (LSMD, -16.8; 95% CI, -31.2 to -2.4 mm·h; P =.001), tramadol (LSMD, -21.8; 95% CI, -36.2 to -7.3 mm·h; P =.003), and celecoxib (LSMD, -18.5; 95% CI, -32.9 to -4.1 mm·h; P =.012) more greatly reduced PI-VAS scores.

Among the active comparators, all CTC doses met the criteria for noninferiority compared with tramadol (all P <.001).

Compared with placebo, more recipients of CTC 200 mg responded to treatment, defined as a 50% reduction from baseline in pain intensity (odds ratio [OR], 2.18; 95% CI, 1.15-4.14; P =.017). Recipients of CTC 200 mg (OR, 0.49; 95% CI, 0.27-0.89; P =.019) and 150 mg (OR, 0.42; 95% CI, 0.23-0.78; P =.006) were less likely than placebo recipients to require rescue medication in 4 hours.

Among the entire study population, 32% of patients reported a treatment-emergent adverse event. Recipients of CTC 150 mg had the lowest proportion of patients reporting adverse events (29.3%), and recipients of tramadol had the highest event rate (39.4%). The most frequent events reported were nausea (6.7%), somnolence (6.6%), and constipation (5.7%).

A limitation of this study is the inability of these findings to be generalizable due to the lack of diversity among the study population.

This study found that CTC was noninferior to tramadol at managing pain following abdominal hysterectomy. In addition, CTC was associated with fewer adverse events compared with tramadol. Investigators concluded, “This safety profile, combined with noninferior efficacy despite considerably lower total opioid exposure, shows that CTC 200 mg has a clinically relevant, improved benefit/risk profile compared with tramadol alone.”

Disclosure: This study was funded by Mundipharma Research GmBH & Co. Multiple authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please refer to the original article for a full list of disclosures.