Fixed-Dose Tramadol/Celecoxib Combination Efficacy in Post-Bunionectomy Pain
The fixed-dose combination of tramadol/celecoxib (CTC) was more effective than either tramadol or celecoxib alone in reducing pain intensity in patients with moderate to severe post-surgical pain following bunionectomy with osteotomy. 1
Primary Clinical Trial Evidence
The pivotal phase 3 trial (ESTEVE-SUSA-301) directly compared CTC 200 mg (containing 112 mg celecoxib/88 mg tramadol hydrochloride) every 12 hours against:
- Tramadol 50 mg every 6 hours - CTC demonstrated significantly greater pain relief (p < 0.001) 1
- Celecoxib 100 mg every 12 hours - CTC demonstrated significantly greater pain relief (p < 0.001) 1
- Placebo - CTC demonstrated significantly greater pain relief (p < 0.001) 1
The study enrolled 637 patients across 6 US clinical research centers, with mean baseline pain intensity of 6.7 on a 0-10 numerical rating scale. 1
Quantitative Pain Relief Results
The primary endpoint (SPID0-48) showed CTC's superiority:
- CTC least-squares mean: -139.1 (95% CI: -151.8, -126.5) 1
- Tramadol alone: -109.1 (95% CI: -121.7, -96.4) 1
- Celecoxib alone: -103.7 (95% CI: -116.4, -91.0) 1
- Placebo: -74.6 (95% CI: -92.5, -56.6) 1
A pooled analysis of two phase 3 trials reinforced these findings, demonstrating a least-squares mean difference in SPID0-48 of -21.8 (p = 0.002) for CTC versus tramadol and -72.8 (p < 0.001) for CTC versus placebo. 2
Synergistic Mechanism
The co-crystal formulation produces synergistic antinociceptive effects beyond simple additive benefits. Preclinical isobolographic analyses demonstrated synergistic mechanical antiallodynic effects (experimental ED50 = 2.0 ± 0.5 mg/kg versus theoretical ED50 = 3.8 ± 0.4 mg/kg) and thermal antihyperalgesic effects (experimental ED50 = 2.3 ± 0.5 mg/kg versus theoretical ED50 = 9.8 ± 0.8 mg/kg). 3
Safety Profile Comparison
CTC demonstrated improved tolerability compared to tramadol alone:
- Drug-related treatment-emergent adverse events occurred in 37.7% of CTC patients versus 48.6% in tramadol patients 1
- Total treatment-emergent adverse events: 358 for CTC versus 394 for tramadol 1
- No serious adverse events or deaths were reported 1
The co-crystal structure did not enhance adverse effects despite synergistic analgesic benefits, with no synergies observed for locomotor activity, motor coordination, ulceration potential, or gastrointestinal transit. 3
Clinical Context and Multimodal Analgesia
This combination aligns with contemporary multimodal analgesia principles. The World Journal of Emergency Surgery recommends combining acetaminophen, NSAIDs (including COX-2 selective inhibitors like celecoxib), and tramadol with stronger opioids reserved for breakthrough pain. 4 The American Society of Anesthesiologists supports multimodal approaches using combinations of different analgesic classes to improve pain control while reducing opioid requirements. 5
Important Clinical Considerations
Contraindications and precautions for celecoxib component:
- Contraindicated in coronary artery bypass graft (CABG) surgery 5, 6
- Caution in patients with cardiovascular disease risk factors 5, 6
- Monitor renal function, particularly in patients with pre-existing renal insufficiency 5, 6
Tramadol-specific concerns:
- Risk of serotonin syndrome when combined with other serotonergic medications 5
- Reduced efficacy in patients taking CYP2D6 inhibitors, as tramadol requires metabolism to its active metabolite 5
Answer to Question
The correct answer is B: either tramadol or celecoxib alone. The clinical trial demonstrated that the fixed-dose combination was significantly more effective than comparable daily doses of tramadol (50 mg every 6 hours) or celecoxib (100 mg every 12 hours) administered as monotherapy. 1 The trial did not compare CTC to acetaminophen alone (option A), oxycodone plus acetaminophen (option C), or oxycodone alone (option D).