Abstract

Background: Avoidance of major bleeding is important with spinal or peridural anaesthesia. Therefore, NSAIDs have to be used with caution in this setting since it has been assumed that with their inhibition of both cyclooxygenase- 1 (COX-1) and cyclooxygenase-2 (COX-2), they increase the risk of reduced platelet aggregagibility and thus bleeding. In contrast, selective COX-2 inhibitiors have no effect on platelet aggregation and can thus be applied up to the point of surgery. The recent withdrawal of Rofecoxib has relaunched the debate on safety of selective COX-2 inhibitors. Etodolac (Lodine®) was identified as a preferential COX-2 inhibitor in 1999; no increased risk of bleeding or cardiovascular side effects have been reported so far. A possible explanation for this is that Etodolac inhibits COX-2 synthesized during the inflammatory process while leaving the preformed COX-2 enzymes unaffected, thus maintaining a potential "protective" effect on platelet aggregation. However, the influence of Etodolac on platelet aggregation has never been formally evaluated. The objective of this study was therefore to determine the effect of Etodolac on platelet aggregation as compared to placebo in healthy volunteers.

Methods: The study was approved by the ethics committee. Nineteen healthy volunteers gave their written informed consent and were included. They were randomly assigned to receive 300 mg of Etodolac q 12 h for 7 days, followed by a 7 day washout phase and 7 days of placebo medication q 12 h or to receive the study medication in reverse sequence. Platelet aggregation was measured in platelet rich plasma according to the Born method on an APACT aggregometer using epinephrine, collagen and ADP as inducers of aggregation, which was quantified as % aggregation compared to the maximal amplitude.

Statistical Methods: Statistical analysis of the influence of Etodolac on platelet aggregation as compared to placebo was performed by ANOVA analysis using SPSS software, version 13.0, using an intention to treat approach. Comparison of platelet aggregation with Etodolac and placebo at different concentration levels of the inducers used was done with the signed rank test. All statistical tests were interpreted on the 5% significance level.

Results: The influence of Etodolac on platelet aggregation was not significantly different from that of placebo in any of the three concentration classes evaluated (see table). The sequence of randomization (Placebo → Etodolac vs. Etodolac → Placebo) was also without influence.

Conclusions: The results of this study indicated that Etodolac 300 mg q 12 h for 7 days does not exert a platelet inhibiting effect in healthy volunteers. Thus, given that the perioperative use of Etodolac renders a comparable analgesic effect when compared to other platelet activity influencing NSAIDs such as Diclofenac, Etodolac seems an attractive analgetic substance for perioperative use.

comparison of platletet aggregtaion during Etodolac vs placebo

μM (Epinehphrin, ADP), μg/ml (Collagen)1051.25P=
Placebo vs Etodolac, max. aggregation amplitude, median 
epinephrine 81% vs 80% 81% vs 78% 79% vs 80% ns 
ADP 80% vs 80% 81% vs 77% 75% vs 71% ns 
collagen 84% vs 82% 83% vs 83% 74% vs 75% ns 
μM (Epinehphrin, ADP), μg/ml (Collagen)1051.25P=
Placebo vs Etodolac, max. aggregation amplitude, median 
epinephrine 81% vs 80% 81% vs 78% 79% vs 80% ns 
ADP 80% vs 80% 81% vs 77% 75% vs 71% ns 
collagen 84% vs 82% 83% vs 83% 74% vs 75% ns 

Author notes

Disclosure: Employment: Dr. Plebani is an employee of Sigma-Tau. Honoraria Information: Dr. Korte received honoraria to be used as research support from Sigma-Tau.