INTRODUCTION: Phase 3 clinical trials in moderate-to-severe acute pain have shown that co-crystal of tramadol-celecoxib (CTC) has improved efficacy and comparable tolerability versus immediate-release tramadol 50 mg alone, with a similar tramadol daily dose, over a 48-h treatment period. However, it is not known how first-dose tolerability compares, given that the administered dose of tramadol is higher in CTC 200 mg (88 mg) versus immediate-release tramadol 50 mg. This was explored in a post hoc analysis of a pivotal phase 3 trial. METHODS: A randomized, double-blind, factorial, active- and placebo-controlled phase 3 trial was conducted in patients with moderate-to-severe acute postoperative pain (NCT03108482) and has been previously reported. This post hoc analysis evaluated the prevalence of the four most common study drug-related, opioid-associated, treatment-emergent adverse reactions reported in phase 3 CTC clinical trials: somnolence, nausea, dizziness, and vomiting. Prevalence was evaluated in 2-h intervals, up to 6 h post first dose (just before second-dose administration) of CTC 200 mg or immediate-release tramadol 50 mg p.o. Descriptive analysis was performed. RESULTS: Each group comprised 183 participants for analysis. The proportions of patients reporting drug-related, treatment-emergent adverse reactions of somnolence, nausea, dizziness, and vomiting were similar between treatment groups at 2, 4, and 6 h following the first dose. CONCLUSIONS: This post hoc analysis indicates that the higher dose of tramadol (88 mg) given in CTC 200 mg did not result in an increase in drug-related adverse reactions after first-dose administration, and had a similar tolerability profile, compared with immediate-release tramadol 50 mg alone (the lowest dose recommended for the management of moderate-to-severe acute pain). This is in line with earlier findings for the 48-h treatment period of this phase 3 trial and may be explained by CTC's differentiated physiochemical properties related to its co-crystal structure. These findings may have utility for practicing clinicians. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03108482.