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Randomized Controlled Trial
. 2019 Feb 19;9(2):e023715.
doi: 10.1136/bmjopen-2018-023715.

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
Affiliations
Randomized Controlled Trial

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 et al. BMJ Open. .

Erratum in

Abstract

Objectives: To compare efficacy/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: Efficacy 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 predefined 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 predefined 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 profile.

Trial registration number: EudraCT 2015-004152-22 and NCT02777970.

Keywords: clinical trials; oral medicine; pain management; primary care; public health.

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Conflict of interest statement

Competing interests: MH reports personal fees as a consultant for educational symposia by Menarini Group. CG-E reports personal fees from Menarini Group, outside the submitted work. TD reports grants from Menarini Group, during the conduct of the study; grants and personal fees from Institut Biochimique SA, outside the submitted work. AM, SM, EG, TBZ and GV declare no conflict of interest. We attest that we have obtained appropriate permissions and paid any required fees for use of copyright protected materials.

Figures

Figure 1
Figure 1
Participant flow chart of study. ITT population consisted of all patients randomised; safety population of all patients who received study drug; PP population of all patients of the ITT who did not experience relevant protocol deviation related to efficacy endpoints of primary interest. *One patient excluded from analysis being aged less than 18 years. ITT, intention to treat; PP, per protocol; TRAM/DKP, tramadol/dexketoprofen.
Figure 2
Figure 2
Mean TOTPAR at 6 hours (primary endpoint) and at 2, 4 and 8 hours for TRAM/DKP, TRAM/paracetamol and placebo with PAR was measured on a 5-point Verbal Rating Scale (0=‘no relief’ to 4=‘complete relief’). *Statistically significant comparison of TRAM/DKP versus TRAM/paracetamol (p<0.0001). PAR, pain relief; TRAM/DKP, tramadol/dexketoprofen; TOTPAR, total pain relief.
Figure 3
Figure 3
Time course of mean PAR over 8 hours for TRAM/DKP, TRAM/paracetamol and placebo with PAR measured on a 5-point Verbal Rating Scale (0=‘no relief’ to 4=‘complete relief’). The area under the curve for pain relief at a given time point corresponds to TOTPAR at the same time point. *Statistically significant TRAM/DKP versus TRAM/paracetamol (p<0.0001); †Statistically significant TRAM/DKP versus TRAM/paracetamol (p<0.0006); ††Statistically significant TRAM/DKP versus TRAM/paracetamol (p<0.00086). PAR, pain relief; TRAM/DKP, tramadol/dexketoprofen; TOTPAR, total pain relief.
Figure 4
Figure 4
Time course of mean PI over 8 hours for TRAM/DKP, TRAM/paracetamol and placebo with PI measured on 11-point Numerical Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst pain). *Statistically significant TRAM/DKP versus TRAM/paracetamol (p<0.0001); †Statistically significant (p=0.0021); ††TRAM/DKP versus TRAM/paracetamol (p=0.0052). PI, pain intensity; TRAM/DKP, tramadol/dexketoprofen.
Figure 5
Figure 5
Percentage of max TOTPAR at 2, 4, 6 and 8 hours for TRAM/DKP, TRAM/paracetamol and placebo with PAR measured on a 5-point Verbal Rating Scale (0=‘no relief’ to 4=‘complete relief’). *Statistically significant TRAM/DKP versus TRAM/paracetamol (p<0.0001). PAR, pain relief; TRAM/DKP, tramadol/dexketoprofen; TOTPAR, total pain relief.
Figure 6
Figure 6
Percentage of responder patient by treatment and time points. Response defined as at least 50% max TOTPAR or 30% PI reduction. *Statistically significant TRAM/DKP versus TRAM/paracetamol (p<0.01). PI, pain intensity; TRAM/DKP, tramadol/dexketoprofen; TOTPAR, total pain relief.
Figure 7
Figure 7
Percentage of patients achieving confirmed FPPAR within 30 min, 1 hour and 2 hours. TRAM/DKP versus TRAM/paracetamol. *P<0.0001. FPPAR, first perceptible pain relief; TRAM/DKP, tramadol/dexketoprofen.
Figure 8
Figure 8
Kaplan-Meier estimation of time to patient report of confirmed first perceptible pain relief (FPPAR) represents the cumulative percentage of patients reporting confirmed FPPAR over the time (in minutes) in the TRAM/DKP arm and TRAM/paracetamol arm. TRAM/DKP, tramadol/dexketoprofen.
Figure 9
Figure 9
Kaplan-Meier estimation of time to patient report of meaningful pain relief (MPAR) represents the cumulative percentage of patients reporting MPAR over the time (in minutes) in the TRAM/DKP arm and TRAM/paracetamol arm. TRAM/DKP, tramadol/dexketoprofen.
Figure 10
Figure 10
Mean scores of patients’ global evaluation by treatment arm assessed on 5-point Verbal Rating Scale (1=poor to 5=excellent). *Statistically significant TRAM/DKP versus TRAM/paracetamol (p<0.0001). TRAM/DKP, tramadol/dexketoprofen.
Figure 11
Figure 11
Percentage of subjects who rated the treatment as poor, fair, good, very good or excellent on patients’ global evaluation by treatment arm. TRAM/DKP, tramadol/dexketoprofen.
Figure 12
Figure 12
Percentage of patient taking first rescue medication within 2, 4, 6 and 8 hours after drug intake. * Statistically significant TRAM/DKP versus TRAM/paracetamol (p<0.01). TRAM/DKP, tramadol/dexketoprofen.
Figure 13
Figure 13
Kaplan-Meier estimation of time to RM intake represents the cumulative percentage of patients using RM over the time (in minutes) in the TRAM/DKP arm and TRAM/paracetamol arm. RM, rescue medication; TRAM/DKP, tramadol/dexketoprofen.
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