Safety of Co-Crystal of Tramadol-Celecoxib (CTC) in Patients with Acute Moderate-to-Severe Pain: Pooled Analysis of Three Phase 3 Randomized Trials

Introduction: Multi-modal analgesia is desirable for the management of acute pain since it can provide effective pain relief at lower doses, thereby aiding tolerability. Co-crystal of tramadol-celecoxib (CTC) provides effective analgesia in models of acute pain. Co-crystallization can alter the pharmacokinetics of individual components, potentially improving tolerability. We sought to better understand the safety and tolerability of CTC in patients with acute postoperative pain.

Methods: We conducted a pooled analysis of safety data from three phase 3 randomized controlled trials in adults with acute moderate-to-severe pain following oral surgery, bunionectomy, and elective abdominal hysterectomy. We present data for CTC 200 mg twice daily (BID) and its comparators: tramadol 50 mg four times daily (QID) (one trial), tramadol 100 mg QID (two trials), celecoxib 100 mg BID (two trials), and placebo (three trials).

Results: In total, n = 551 patients received CTC 200 mg BID, n = 183 received tramadol 50 mg QID, n = 368 received tramadol 100 mg QID, n = 388 received celecoxib 100 mg BID, and n = 274 received placebo. The prevalence of adverse events (AEs) related to study drug up to 48 h was numerically lower with CTC 200 mg BID (35.9%) than with tramadol 50 mg QID (47.5%) and 100 mg QID (44.8%) but greater than with celecoxib 100 mg BID (12.4%) and placebo (20.4%). The most frequent AEs related to study drug up to 48 h were somnolence, nausea, dizziness, and vomiting, which occurred more frequently in patients receiving tramadol 100 mg QID than in those receiving CTC 200 mg BID.

Conclusion: CTC 200 mg BID appears to be better tolerated than tramadol 100 mg QID, possibly because of reduced total exposure to tramadol. This may contribute to a more favorable benefit-risk profile for CTC versus individual components, making it a promising treatment for acute pain.

Trial registration: ClinicalTrials.gov identifiers: NCT03108482, NCT02982161 (EudraCT: 2016-000592-24), NCT03062644 (EudraCT: 2016-000593-38).