Research into cyclooxygenase inhibition lead to the identification of a constitutional cyclooxygenase activity (cyclooxygenase 1, COX-1), which can be distinguished from a cytokine-induced cyclooxygenase activity (cyclooxygenase 2, COX-2) 1. With the use of cyclooxygenase inhibitors as anti-inflammatory agents and analgesics, unwanted side effects such as mucosal toxicity can occur. It was postulated that such side effects are mainly associated to the effects of COX-1 inhibition 2; and that preferential inhibition of COX-2 would therefore decrease this type of toxicity 3. This lead to the development of preferential COX-2 inhibitors with effective anti-inflammatory and analgesic effects documented 45. As postulated, it became apparent that COX-2 inhibition was indeed associated with a lower degree of mucosal toxicity 6. It was also shown that COX-2 activity is not involved in platelet thromboxane biosynthesis 7 and that selective COX-2 inhibition thus does not effect platelet thromboxane A2 (TxA2) dependent platelet aggregation 8. No such studies were published on the use of Etodolac (Lodine^®, Sigma-Tau Pharma AG, Zofingen, Switzerland) in humans so far.

Analgesic drugs that modify enzymatic pathways can influence platelet aggregability and use of non-steroidal anti-inflammatory drugs (NSAIDs) may lead to increased perioperative bleeding risk 910, a side effect seen with COX inhibitors 11. Perioperative bleeding is becoming a more important issue for various reasons, including the increased frequency of regional anesthesia.

Etodolac, a COX inhibitor that was introduced in the 1980s has been marketed world-wide. In 1999, it was identified as a preferential COX-2 inhibitor 12. Which was, however, shown not to be significantly selective towards COX-2 131415. However, up to date in medical practice neither an increased risk of bleeding nor an increased risk of cardiovascular side effects had been observed 161718.

Only minimal renal side effects have been described 192021, with one patient with rheumatoid arthritis developing a membranous nephropathy 22.

A previous study 23 showed that the analgesic effect of a short-term treatment with etodolac after coronary artery bypass operation is superior to tramadol. In that study, a trend toward a faster pain reduction with etodolac as compared with diclofenac was observed, suggesting that the analgesic effect of etodolac in that setting is at least as effective as that of diclofenac. Therefore, it is of interest to know in addition whether Etodolac has any effect on platelet aggregation. The objective of this study was thus to investigate the influence of Etodolac in therapeutic doses on platelet aggregation as compared to placebo in healthy volunteers as no studies on platelet aggregation with the use of Etodolac has been published so far.

The ITT population comprised 19 subjects (11 females).

The PP population included 15 subjects (8 females). Mean age ± standard deviation (SD) in this population was 37.1 ± 9.5 years.

No abnormal laboratory value was observed in any volunteer during the study.

Of the ITT population comprising 19 subjects; one volunteer was taken off study after visit 1 due to possible adjudication bias (this person was referred by the sponsor); three volunteers had protocol violations, leaving a PP population of 15 subjects. All 3 volunteers with protocol violations finished the study but were not included in the PP population. Two of the protocol violations were related to mistakes with the intake of the study medication, one was related to a substantial delay in the time of blood sampling.

There were no significant differences in the results of the ITT population as compared to the PP population. In both populations, no difference between the effect of Etodolac or placebo on platelet aggregation studies was observed, neither with high nor low or medium concentrations of ADP, epinephrine or collagen (p= 0.1998). There was also no evidence that the sequence (Placebo followed by Etodolac versus Etodolac followed by Placebo) had any effect on platelet aggregation (p= 0.8314).

Results comparing the influence of placebo or Etodolac on platelet aggregation as induced by epinephrine, collagen or ADP are displayed in Figure 1 and Figure 2, Figure 3 (for clarity, only the results of the highest concentrations used for each substance are displayed). It can be seen that there is no significant difference in inducible platelet aggregation when volunteers are treated with Etodolac or placebo.

Only one adverse event (abdominal discomfort) according to the study protocol was observed; it was judged to be possibly related to the study medication, but not to be clinically relevant. Of the four volunteers that were not included in the PP population, two each were in the placebo (cross over to etodolac) and the etodolac (cross over to placebo) group. The ITT population comprised 9 volunteers in the etodolac group and 10 volunteers in the placebo group (see figure 4).

The main finding of our study is that etodolac at regular analgesic doses (300 mg every 12 h for 7 days) has no inhibitory effect on platelet aggregation performed according to the Born method when compared to placebo.Until now, it has been assumed that NSAIDs with non-selective inhibition of both the COX-1 and COX-2 enzymes increase the risk of bleeding due to their COX-1 inhibitory effect, resulting in reduced platelet aggregation 25. Given that there is no relevant influence on platelet aggregation, selective inhibition of COX-2 supposedly reduces the risk of associated bleeding problems. In fact, a number of studies have demonstrated that selective COX-2 inhibition do not affect platelet aggregation (or affect it to a significantly lesser extent) 2627282930, but this has not been undisputed 31. COX-2 inhibiting drugs might be appropriate tools to provide a perioperative analgesic approach without the risk of increased bleeding. These observations with a seemingly well tolerated drug 1617 might be particularly interesting since Rofecoxib, a selective COX-2 inhibitor, was withdrawn from the market due to its cardio-vascular and renal side effects 32, reigniting the debate on the safety of selective COX-2 inhibitors 333435.

Others have shown that neither short- nor long-term exposure to etodolac was associated with cardionegative or -protective effects as compared to ibuprofen, rofecoxib and celecoxib 18.

As NSAIDs are frequently used postoperatively for analgesic treatment 3637, side effects from these drugs are important when assessing postoperative morbidity. Most NSAIDs have been shown to influence platelet aggregation not only in vitro, but also to a clinically potentially relevant extent 910. As shown in this study and in contrast to most other NSAIDs, etodolac has no influence on platelet aggregation ex vivo. This parallels the post marketing experience available today 193839.Limitations of our study are the small sample size and the fact that it was performed in volunteers; however, the population size was based on stringent sample size calculation and there was no difference in results between the ITT population and the PP population.

Evaluation of the platelet COX-1 and -2 pathways can be achieved using various inductors of platelet aggregation.

When investigating the influence of COX inhibitors, the use of arachidonic acid can result in a too sensitive assay, as described by Becker et al. 40. In that study, the use of arachidonic acid led to the observation that 97% of all patients showed no aggregation after COX inhibition, prohibiting the statistical evaluation of these results. Such an approach was also suggested by Akagi et al. 41, who found no additional effect of etodolac on top of aspirin in an animal model. Therefore, we used ADP, collagen and epinephrine for aggregation induction in three different (low, medium and high) concentrations.

The fact that we used only the Born method as the “gold standard” for platelet aggregation studies might be perceived as a potential study weakness, since other methods are also available. However, clinical studies evaluating different platelet aggregation study methodologies in parallel in patients undergoing coronary stent implantation 42 did not reveal any predictive differences between the different assays. And the ADP – induced platelet aggregation according to Born showed a better ability to detect differences in platelet aggregation when compared with the VASP assay 43.

As data from this study (and in accordance with animal studies) show that etodolac has no influence on platelet aggregation in healthy volunteers at regular doses, it seems that this substance might be an important addition to the analgesic armentarium in the perioperative setting. Others have shown that etodolac is efficacious in postoperative pain control in cardiac surgery 23, where platelet aggregation inhibition is an important issue with regard to catheters used for analgesic therapy. In the aforementioned animal study 41, no additional effect of etodolac on top of aspirin in inhibiting platelet aggregation was found. It would be interesting to further investigated this combination in a clinical study.

We believe that our study adds to the body of knowledge suggesting that etodolac is indeed advantageous in situations where nonsteroidal analgesics are desirable but where adequate hemostasis is a concern at the same time.

Our study shows that etodolac - applied in regular analgesic doses to volunteers - does not show an inhibitory effect on platelet aggregation and therefore seems to be an attractive analgesic substance for the perioperative setting.