Abstract
The goals of perioperative management are to relieve pain, achieve early mobilization after surgery, reduce length of hospital stay, and obtain adequate patient satisfaction. Several treatment options combining systemic analgesics and/or regional analgesia with or without opioids are available for postoperative pain; however, a gold standard has not been established although there is a progressive shift towards multimodal approaches to improve analgesia while minimizing opioid-related side effects.
EX-TRA-05 (DAVID-ART) was a randomised, double-blind, parallel, pivotal study, evaluating the analgesic efficacy and safety of the innovative oral combination of dexketoprofen/tramadol 25mg/75mg in comparison with the individual components (tramadol given at the higher dose of 100mg) on moderate to severe acute pain after total hip replacement. Repeated doses of study drug were administered every 8 hours and pain intensity (PI) was to be scored according to a 100mm visual analogue scale (VAS) on a programmed e-diary every 2 hours over a 56-hour period (i.e. along 7 repeated doses). A placebo arm was included at the first administration to validate the pain model. Rescue medication, metamizole 500mg, was available during the treatment period. The study primary endpoint was the mean sum of the pain intensity difference values throughout the first 8 hours (SPID8), which considered the 3 active treatment arms and placebo (ITT population; N=641). In this phase, a clear superiority of the combination over the single agents was demonstrated (p<0.05). An additional analysis was performed during the entire 0–56h repeated-dose period excluding those patients who had received placebo at the first dose (N=161). The estimated mean (SE) differences on PI-VAS over 24, 32 and 56 hours post first dose (0–24h, 0–32h, and 0–56h) between the combination and each single agent were evaluated.
Patients who received active analgesic from the first dose (mITT population; N=480) were aged 29–80 years (42% were ≥65 years). At randomisation, pain was moderate (≥40–60mm) in 51% patients and severe (>60mm) in 49%. For dexketoprofen/tramadol, mean (SD) PI-VAS values were 22 (4.0) over 24 hours; 21 (4.1) over 32 hours; and 19 (3.8) over 56 hours. The estimated differences versus dexketoprofen 25mg and tramadol 100mg were respectively 10 (0.7) and 7.6 (0.7) over 24 hours; 9.8 (0.6) and 7.2 (0.6) over 32 hours; and 8.1 (0.5) and 6.3 (0.5) over 56 hours (p<0.0001 for all comparisons), which confirmed the superiority of the combination versus both single agents throughout the periods analysed.
This significant higher decrease of PI favouring dexketoprofen/tramadol 25mg/75mg over dexketoprofen 25mg and tramadol 100mg, all given every 8 hours, during the first 56 hours post dose confirmed the superior analgesia shown after the first 0–8h post-dose period. The combination of dexketoprofen/tramadol 25mg/75mg is able to provide a level of analgesia above that achievable by each component alone, with a sustained effect when used as a multiple-dose regimen. The addition of this new combo to the analgesic armamentarium may contribute to facilitate early mobilization after surgery, thus positively impacting perioperative co-morbidities and length of in-hospital stay.
