Tramadol/Dexketoprofen Analgesic Efficacy Compared with Tramadol/Paracetamol in Moderate to Severe Postoperative Acute Pain: Subgroup Analysis of a Randomized, Double-Blind, Parallel Group Trial-DAVID Study

Plain Language Summary The combination tramadol/dexketoprofen (TRAM/DPK) was recently shown to exert a better analgesic effect than the combination tramadol/paracetamol (TRAM/paracetamol) after surgical removal of impacted lower third molar in a clinical trial enrolling more than 600 patients. A subanalysis of the results of this study was performed to assess if the severity of pain intensity (PI) at baseline might modify the analgesic effect and its duration. The results of the subanalysis showed that the analgesic efficacy of TRAM/DKP was independent of baseline PI and persistent up to 6 h, whereas the effect of TRAM/paracetamol progressively decreased with increasing baseline PI and persisted for a shorter period. The incidence of adverse drug reactions was not increased in patients with severe baseline PI. These results confirmed the better analgesic efficacy of TRAM/DKP vs TRAM/paracetamol, irrespective of the baseline PI. Introduction Recently the DAVID study demonstrated the better analgesic efficacy of tramadol hydrochloride/dexketoprofen 75/25 mg (TRAM/DKP) over tramadol hydrochloride/paracetamol 75/650 mg (TRAM/paracetamol) in a model of moderate to severe acute pain following surgical removal of an impacted third molar. The aim of this subpopulation analysis was to gain a deeper understanding of the relationship between baseline pain intensity (PI) level and the effectiveness in pain control of the TRAM/DKP combination in comparison with the TRAM/paracetamol combination. This will further improve and facilitate the accurate design of future acute pain studies for the use of the TRAM/DKP combination. Methods Patients experiencing at least moderate pain, defined as a PI score >= 4 in an 11-point numerical rating scale (NRS) were stratified according to NRS-PI at baseline (NRS >= 4, 5, 6, 7, or 8) or aggregated in two groups: (i) moderate pain, NRS-PI >= 4 to <= 6; (ii) severe pain, NRS-PI > 6. Analgesic efficacy was assessed at pre-specified time points by using pain relief (PAR) on a 5-point verbal rating scale (VRS) and PI on an 11-point NRS. The primary endpoint was total PAR over 6 h post-dose (TOTPAR6); secondary endpoints included, among others, the time course of mean PAR and PI scores over 8 h, TOTPAR over 2, 4, and 8 h post-dose, and the sum of PI difference (SPID) over 2, 4, 6, and 8 h. Safety evaluation was based on the incidence, seriousness, intensity, and causal relationship of treatment-emergent adverse events (TEAEs). Results The analgesic efficacy evaluated by TOTPAR6 (primary endpoint) remained steady across increasing baseline PI-NRS cutoff groups with TRAM/DKP, but not with TRAM/paracetamol. The study also demonstrated the superiority of TRAM/DKP combination over TRAM/paracetamol in terms of TOTPAR over 2, 4, and 8 h post-dose and SPID at 2, 4, 6, and 8 h post-dose in both baseline PI groups (moderate or severe); similarly, the time course of PAR and PI indicated better efficacy with TRAM/DKP as soon as 30 min and up to 4-6 h. The incidence of adverse drug reactions was not increased in the severe baseline PI group. Conclusion Overall, the results of this subgroup analysis of the DAVID study confirmed the superiority of the analgesic efficacy of TRAM/DKP vs TRAM/paracetamol, irrespective of the baseline PI.