Preoperative administration of etoricoxib in patients undergoing hip replacement causes inhibition of inflammatory mediators and pain relief

Abstract

Objective: Administering cyclooxygenase-2 inhibitors preoperatively appears attractive since these drugs reduce post-operative pain, but do not increase the risk of post-operative bleeds, asthmatic attacks and stress-related gastrointestinal ulcers. In a former investigation, we could show that post-operative administration of etoricoxib reduces prostaglandin production in wound fluid, but the onset of action is variable due to delayed post-operative absorption.

Methods: In this study, we investigated the preoperative administration of etoricoxib in patients undergoing hip replacement. They received 120 mg etoricoxib or placebo 2 h before surgery and 1 day after in a double-blinded, randomized, parallel group design.

Results: A total of 11 patients were randomized (placebo n = 5; verum n = 6). We found high and constant levels of the drug in blood, central nervous system and wound fluid already at the end of surgery (t(max) < 2 h). This was accompanied by inhibition of prostaglandin production in the wound tissue (treatment p < 0.05), suppression of interleukin 6 increase in plasma (treatment p < 0.01), and - despite existing standard pain relief procedures - higher satisfaction with analgesics (time vs. treatment p < 0.05) and less demand for opioids (treatment p < 0.01) and intrathecal bupivacaine (treatment p = 0.05) administration.

Conclusion: Administration of etoricoxib 2 h before surgery allows for an effective drug concentration in critical tissues, a reduction of the production of pro-inflammatory mediators and for better pain relief.

Trial registration: ClinicalTrials.gov NCT00746720.

© 2011 European Federation of International Association for the Study of Pain Chapters.

Figures

Figure 1

Study time schedule with four data recording days. Medication time on surgery day was set as time 0 h. IL6, interleukin 6; PGE2, prostaglandin E2.

Figure 2

(A) Etoricoxib concentration time courses in plasma, cerebrospinal fluid (CSF) and tissue exudates (hip drain) after administration of 120 mg at time 0 and 24 h [means ± standard deviation (SD); n = 6; see Table 2]. (B) Interleukin 6 (IL6) plasma concentrations in the placebo and etoricoxib group (significant group differences, see Table 3; means ± SD; n = 10–11). (C) Prostaglandin E2 (PGE2) concentrations in tissue exudates comparing placebo and verum group (means ± SD; n = 10; data with n = 1 are shown as single dots and are not included in the line graph; post hoc comparisons, see Table 3). (D) Patient estimates for satisfaction with post-surgery analgesia recorded on a numeric rating scale (NRS) with 0 = no efficacy to 5 = excellent efficacy (means ± SD; n = 10). (E) Number of patients’ requests for intrathecal (IT) local anaesthetic (bupivacaine) boli per patient (means ± SD; n = 9–10). (F) Opioid analgesic (piritramide) administration per patient in the etoricoxib and placebo group (means ± SD; n = 10). (D–F) Since the IT catheter for applying bupivacaine was absent in one patient in the placebo group, this patient was excluded from pain-related statistical analysis and from graph data (significant group differences are presented in graphs with Bonferroni adjusted p-values). AUCs, areas under the curve.

Figure 3

Pharmacokinetic and pharmacodynamic (PK/PD) relationship and pre- versus post-operative dosing effects: Local drug concentrations versus corresponding inhibitory effects on inflammatory mediators during the first 24 h after administration of 120 mg etoricoxib are presented. The effect size was derived from mean group differences with positive values indicating inhibitory effects on inflammatory mediators. Arrows specify the time course of the relationship. (A) Tissue exudate data for prostaglandin E2 (PGE2) were derived from our previous study (Renner et al., 2010) and showed a direct PK/PD relationship during drug accumulation. At later time points, the effect decreased in a clockwise hysteresis. Note: The drug was administered 20 h post-operatively allowing PGE2 to increase after surgery in both groups. (B–C) Tissue exudate data for PGE2 (B) and plasma interleukin 6 (IL6) (C) from the present study with a counterclockwise relationship indicating for a delayed drug response. Dosing time before surgery resulted in a delay of inhibitory effects (counterclockwise hysteresis).