Dexketoprofen/tramadol 25 mg/75 mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy

Abstract

Background: Dexketoprofen trometamol plus tramadol hydrochloride is a new oral combination of two analgesics, which have different mechanisms of action for the treatment of moderate to severe acute pain.

Methods: Randomised, double-blind, parallel, placebo and active-controlled, single and multiple-dose study to evaluate the analgesic efficacy and safety of dexketoprofen/tramadol 25 mg/75 mg in comparison with the single agents (dexketoprofen 25 mg and tramadol 100 mg) in moderate to severe acute pain after abdominal hysterectomy. Patients received seven consecutive doses of study drug within a 3-day period, each dose separated by an 8-hour interval. A placebo arm was included during the single-dose phase to validate the pain model. Efficacy assessments included pain intensity, pain relief, patient global evaluation and use of rescue medication. The primary endpoint was the mean sum of pain intensity differences over the first 8 h (SPID8).

Results: The efficacy analysis included 606 patients, with a mean age of 48 years (range 25-73). The study results confirmed the superiority of the combination over the single agents in terms of the primary endpoint (p <0.001). Secondary endpoints were generally supportive of the superiority of the combination for both single and multiple doses. Most common adverse drug reactions (ADRs) were nausea (4.6%) and vomiting (2.3%). All other ADRs were experienced by less than 2% of patients.

Conclusions: The study results provided robust evidence of the superiority of dexketoprofen/tramadol 25 mg/75 mg over the single components in the management of moderate to severe acute pain, as confirmed by the single-dose efficacy, repeated-dose sustained effect and good safety profile observed.

Trial registration: EU Clinical Trials Register (EudraCT number 2012-004545-32, registered 04 October 2012); Clinicaltrials.gov ( NCT01904149, registered 17 July 2013).

Fig. 1

Study CONSORT flow diagram. Participant flow with the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome. Five patients in the ITT population received incorrect kit study treatment: *one patient was randomized to receive DKP (first dose placebo) but received DKP/TRAM (first dose placebo) instead; † one patient was randomized to receive DKP/TRAM (first dose active) but received TRAM (first dose active) instead; ‡ one patient was randomized to receive DKP (first dose active) but received TRAM (first dose placebo) instead; § one patient was randomized to receive TRAM (first dose placebo) but received DKP (first dose active) instead; ¶ one patient was randomized to receive TRAM (first dose active) but received DKP (first dose active) instead. ** Received at least one dose; alloc. allocated, ITT intention-to-treat, PP per protocol. The ITT population included all patients randomised; the safety population included all patients randomised who received at least one dose of study treatment; the PP population included all ITT patients with no major protocol violations; DKP/TRAM dexketoprofen trometamol/tramadol hydrochloride 25 mg/75 mg, DKP dexketoprofen trometamol 25 mg, TRAM tramadol hydrochloride 100 mg; n: number of patients

Fig. 2

Mean SPID over 8 h (single-dose phase) (Primary Endpoint). SPID summed pain intensity differences, DKP/TRAM dexketoprofen trometamol/tramadol hydrochloride 25 mg/75 mg, DKP dexketoprofen trometamol 25 mg, TRAM tramadol hydrochloride 100 mg. Pain intensity (PI) was measured on a 0–100 visual analogue scale (VAS) with left end labelled “no pain” and right end labelled “worst possible pain”; * statistically significant versus both DKP and TRAM (p <0.001); † statistically significant versus placebo (p <0.05)

Fig. 3

Time course of mean PI (VAS) scores at rest (single-dose phase). PI pain intensity, VAS visual analogue scale, DKP/TRAM dexketoprofen trometamol/tramadol hydrochloride 25 mg/75 mg, DKP dexketoprofen trometamol 25 mg, TRAM tramadol hydrochloride 100 mg. PI was measured on a 0–100 VAS with left end labelled “no pain” and right end labelled “worst possible pain”; * statistically significant versus both DKP and TRAM (p <0.05); † statistically significant versus TRAM only (p <0.05); ‡ statistically significant versus placebo (p <0.05)

Fig. 4

Time course of mean PI (VAS) scores at rest (multiple-dose phase). PI pain intensity, VAS visual analogue scale, DKP/TRAM dexketoprofen trometamol/tramadol hydrochloride 25 mg/75 mg, DKP dexketoprofen trometamol 25 mg, TRAM tramadol hydrochloride 100 mg. PI was measured on a 0–100 VAS with left end labelled “no pain” and right end labelled “worst possible pain”; statistical significance was achieved versus DKP (p = 0.003) over the 48-hour multiple-dose period (mixed model for repeated measures approach)

Fig. 5

Time course of mean PI (VAS) scores on movement (multiple-dose phase). PI pain intensity, VAS visual analogue scale, DKP/TRAM dexketoprofen trometamol/tramadol hydrochloride 25 mg/75 mg, DKP dexketoprofen trometamol 25 mg, TRAM tramadol hydrochloride 100 mg. PI was measured on a 0–100 VAS with left end labelled “no pain” and right end labelled “worst possible pain”; pain on movement: elicited pain upon sitting; Statistical significance was achieved versus DKP (p <0.001) over the 48-hour multiple-dose period (mixed model for repeated measures approach)

Fig. 6

Time course of mean SPID at rest (single-dose phase). SPID summed pain intensity differences, DKP/TRAM dexketoprofen trometamol/tramadol hydrochloride 25 mg/75 mg, DKP dexketoprofen trometamol 25 mg, TRAM tramadol hydrochloride 100 mg. Pain intensity (PI) was measured on a 0–100 visual analogue scale (VAS) with left end labelled “no pain” and right end labelled “worst possible pain”; * statistically significant versus both DKP and TRAM (p <0.05); † statistically significant versus placebo (p <0.05)

Fig. 7

Time course of mean PAR (VRS) scores (single-dose phase). PAR pain relief, VRS verbal rating scale, DKP/TRAM dexketoprofen trometamol/tramadol hydrochloride 25 mg/75 mg, DKP dexketoprofen trometamol 25 mg, TRAM tramadol hydrochloride 100 mg. PAR was measured on a five-point VRS (0 = none, 1 = slight, 2 = moderate, 3 = good, 4 = complete) during the single-dose phase of the study; * statistically significant versus both DKP and TRAM (p <0.05); † statistically significant versus TRAM only (p <0.05); ‡ statistically significant versus placebo (p <0.05)