Dexketoprofen/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain

Abstract

Background: Combination analgesics are effective in acute pain, and a theoretical framework predicts efficacy for combinations. The combination of dexketoprofen and tramadol is untested, but predicted to be highly effective.

Methods: This was a randomised, double-blind, double-dummy, parallel-group, placebo-controlled, single-dose trial in patients with moderate or severe pain following third molar extraction. There were ten treatment arms, including dexketoprofen trometamol (12.5 mg and 25 mg) and tramadol hydrochloride (37.5 mg and 75 mg), given as four different fixed combinations and single components, with ibuprofen 400 mg as active control as well as a placebo control. The study objective was to evaluate the superior analgesic efficacy and safety of each combination and each single agent versus placebo. The primary outcome was the proportion of patients with at least 50 % max TOTPAR over six hours.

Results: 606 patients were randomised and provided at least one post-dose assessment. All combinations were significantly better than placebo. The highest percentage of responders (72%) was achieved in the dexketoprofen trometamol 25 mg plus tramadol hydrochloride 75 mg group (NNT 1.6, 95% confidence interval 1.3 to 2.1). Addition of tramadol to dexketoprofen resulted in greater peak pain relief and greater pain relief over the longer term, particularly at times longer than six hours (median duration of 8.1 h). Adverse events were unremarkable.

Conclusions: Dexketoprofen trometamol 25 mg combined with tramadol hydrochloride 75 mg provided good analgesia with rapid onset and long duration in a model of moderate to severe pain. The results of the dose finding study are consistent with pre-trial calculations based on empirical formulae.

Trial registration: EudraCT (2010-022798-32); Clinicaltrials.gov (NCT01307020).

Fig. 1

Percentage of patients showing response (≥50 % max TOTPAR) over 6 h post-dose (Primary Endpoint). Maximum TOTPAR corresponds to the theoretical maximum possible time-weighted sum of the PAR scores, measured on a 5-point VRS (0 = ‘none’ to 4 = ‘complete’)

Fig. 2

NNT for ≥ 50 % max TOTPAR compared with placebo over six hours post dose. Maximum TOTPAR corresponds to the theoretical maximum possible time-weighted sum of the PAR scores, measured on a 5-point VRS (0 = ‘none’ to 4 = ‘complete’). Bars show 95 % confidence interval of NNT, with colour change as point estimate (Note that TRAM37.5 was not significantly better than placebo)

Fig. 3

Time course of mean PAR scores (0–24 h). PAR measured on a 5-point VRS (0 = ‘none’ to 4 = ‘complete’)

Fig. 4

Cumulative frequency (Kaplan-Meier estimation) of RM intake (0–24 h)

Fig. 5

PGE at the end of the assessment period. PGE measured on a 5-point VRS (1 = ‘poor’ to 5 = ‘excellent’)