1 Gay-Escoda C, et al. BMJ Open 2019;9:e023715. doi:10.1136/bmjopen-2018-023715 Open access Tramadol/dexketoprofen (TRAM/DKP) compared with tramadol/paracetamol in moderate to severe acute pain: results of a randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third molar extraction pain model (DAVID study) Cosme Gay-Escoda, 1 Magdi Hanna, 2 Antonio Montero, 3 Thomas Dietrich, 4 Stefano Milleri, 5,6 Ewa Giergiel, 7 Tóth Bagi Zoltán, 8 Giustino Varrassi 9 To cite: Gay-Escoda C, Hanna M, Montero A, et al. Tramadol/dexketoprofen (TRAM/DKP) compared with tramadol/paracetamol in moderate to severe acute pain: results of a randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third molar extraction pain model (DAVID study). BMJ Open 2019;9:e023715. doi:10.1136/ bmjopen-2018-023715 ► Prepublication history for this paper is available online. To view these fles please visit the journal online (http://dx.doi. org/10.1136/bmjopen-2018- 023715). Received 7 May 2018 Revised 31 October 2018 Accepted 5 November 2018 For numbered affliations see end of article. Correspondence to Dr Magdi Hanna; magdihanna6262@aol.com Research © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. ABSTRACT Objectives To compare effcacy/safety of oral tramadol 75 mg/dexketoprofen 25 mg (TRAM/DKP) and TRAM 75 mg/ paracetamol 650 mg (TRAM/paracetamol) in moderate to severe pain following surgical removal of impacted lower third molar. Design Multicentre, randomised, double-blind, placebo- controlled, phase IIIb study. Participants Healthy adult patients scheduled for surgical extraction of at least one fully/partially impacted lower third molar requiring bone manipulation. 654 patients were randomised and 653 were eligible for analysis. Interventions Surgery was performed under local anaesthetic. No sedation was permitted. Patients rated pain intensity (PI) using an 11-Numerical Rating Scale (NRS) (0 no pain; 10 worst pain). Participants experiencing moderate/severe pain (≥4) within 4 hours of surgery were randomised (2:2:1 ratio) to a single oral dose of TRAM/DKP 75/25 mg, TRAM/paracetamol 75/650 mg or placebo. Main outcome measures Effcacy was based patients’ electronic diaries. Analgesia and pain were recorded as follows: pain relief (PAR) on a 5-point Verbal Rating Scale (0=‘no relief’, 1=‘a little (perceptible) relief’, 2=‘some (meaningful) relief’, 3=‘lot of relief’, 4=‘complete relief’) at the predefned postdose time points t15 min, t30 min, t1 hour, t1.5 hour, t2 hour, t4 hour, t6 hour and t8 hour and PI on the 11-point NRS at t0 and at the same predefned postdose time points. Onset of analgesia documented using double stopwatch method over a 2-hour period. Primary endpoint was total pain relief over 6 hours (TOTPAR6). Rescue medication was available during the treatment period. Results TRAM/DKP was superior to TRAM/paracetamol and placebo at the primary endpoint TOTPAR6 (p<0.0001). Mean (SD) TOTPAR6 in the TRAM/DKP group was 13 (6.97), while those in the active control and placebo groups were 9.2 (7.65) and 1.9 (3.89), respectively. Superiority of TRAM/DKP over active comparator and placebo was observed at all secondary endpoints. Incidence of adverse events was comparable between active groups. Conclusions TRAM/DKP (75/25 mg) is effective and superior to TRAM/paracetamol (75/650 mg) in relieving moderate to severe acute pain following surgical removal of impacted lower third molar, with a faster onset of action, greater and durable analgesia, together with a favourable safety profle. Trial registration number EudraCT 2015-004152-22 and NCT02777970. Strengths and limitations of this study ► The main strength of this study is that with nearly 800 patients screened, it is one of the largest to be carried out in patients with moderate to severe acute pain in the impacted third molar extraction model. ► The rigorous study design—multicentre, ran- domised, double-blind, placebo-controlled, phase IIIb—coupled with the large patient cohort means that the quality of the evidence is high. ► This is a unique head-to-head study of tramadol/ dexketoprofen against tramadol/paracetamol an established combination rather than just a place- bo-controlled study. ► The results show that tramadol hydrochloride/dex- ketoprofen 75/25 mg oral fxed combination is ef- fective and superior over tramadol hydrochloride/ paracetamol 75/650 mg in relieving moderate to severe acute pain following surgical removal of im- pacted lower third molar. ► One of the limitations of this study is as this was a single-dose study that assessed the short-term an- algesic effcacy of tramadol/dexketoprofen in com- parison with tramadol/paracetamol and this could be addressed in a future multidose study of longer duration. on May 23, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-023715 on 6 February 2019. Downloaded from on May 23, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-023715 on 6 February 2019. Downloaded from on May 23, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-023715 on 6 February 2019. Downloaded from on May 23, 2020 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-023715 on 6 February 2019. Downloaded from