Inhibition of platelet aggregation resulting from inhibition of COX-1 in platelets by conventional NSAIDs is an important consideration as this may lead to prolonged bleeding. This is of particular concern in some surgical procedures as it may enhance the risk of bleeding complications and, therefore, may prohibit the pre- and intraoperative administration of conventional NSAIDs. Parecoxib sodium had no significant effect on bleeding time in healthy adult subjects compared with placebo. In contrast, administration of ketorolac 30 mg i.v. for 8 days caused a significant increase in bleeding time compared with both placebo and parecoxib sodium 40 mg i.v. in non-elderly subjects (Fig. 8).
The second parecoxib sodium safety study compared i.v. parecoxib sodium 10 mg b.i.d. and oral naproxen 500 mg b.i.d. (both for 7 days), i.v. ketorolac 15 mg q.i.d. (5 days) and placebo (7 days) . All patients receiving ketorolac had ulcers at the end of the study compared with 50% of those in the naproxen group, none of those in the parecoxib sodium group and 40% of those who received placebo .
There is now a wealth of data demonstrating the efficacy of COX-2-selective inhibitors for the treatment of chronic pain and the inflammation associated with OA and RA. Thus, COX-2-selective inhibitors such as celecoxib have been demonstrated to be as effective as the conventional NSAIDs diclofenac and naproxen. Furthermore, COX-2-selective inhibitors are far less likely to be associated with upper gastrointestinal ulceration, perforation and bleeding.
Parecoxib sodium is a novel parenteral prodrug formulation of the COX-2-selective inhibitor valdecoxib. The oral COX-2-selective inhibitors rofecoxib and celecoxib are associated with opioid-sparing effects and effective pain relief in postoperative surgical patients . However, the use of a water-soluble preparation such as parecoxib in this situation has clear and definite advantages.
Ketorolac is the only parenteral conventional NSAID currently available in the USA, and although it is an effective analgesic, it is associated with an array of adverse effects including decreased platelet aggregation, increased bleeding time, gastrointestinal ulceration and bleeding, and acute renal failure [15,58-60]. In fact, it is recommended in the USA that prescription of ketorolac should be limited to 5 days due to the severity of gastrointestinal bleeding and adverse effects that can arise with its use . Other conventional NSAIDs, e.g., diclofenac and the analgesic acetaminophen (paracetamol), are available in parenteral formulations in Europe [4,5,62]. However, all conventional NSAIDs are associated with inhibition of platelet function and gastrointestinal ulceration and, therefore, should be used with caution when they are administered to surgical patients .
There is a general reluctance to use conventional NSAIDs perioperatively, even for relatively minor procedures such as oral surgery, because of the increased bleeding risks they pose [59,64]. Therefore, there is a need for parenteral analgesic agents that can be administered to surgical patients without the risk of increased bleeding. An injectable COX-2-selective inhibitor that provides strong analgesic efficacy with an improved side-effect profile compared with conventional NSAIDs would fulfil such a role.
Parecoxib sodium has demonstrated excellent clinical efficacy in a variety of different surgical models. Thus, a 40 mg dose of parecoxib sodium provides efficacy at least equivalent in terms of onset and magnitude to the parenteral conventional NSAID ketorolac in managing pain following surgery in oral, orthopaedic and general surgical models [50-52]. Furthermore, in some models, parecoxib sodium 40 mg provides a longer duration of action than ketorolac. Single doses of parecoxib sodium are more effective in treating postoperative pain than a single, small (4 mg i.v.) dose of morphine following orthopaedic and general surgery, as demonstrated by a greater magnitude of pain relief and a longer duration of action [51,52].
Consistent with the COX-1-sparing nature of COX-2-selective inhibitors, parecoxib sodium has no statistically significant effect on platelet aggregation or bleeding time compared with placebo. This lack of effect on platelet function is of distinct benefit in surgical populations at risk from bleeding complications. Unlike conventional NSAIDs, the lack of platelet inhibition associated with parecoxib sodium suggests that it could be administered perioperatively without the risk of increased bleeding complications. COX-2 is induced both at the sites of surgical incision and in the CNS during surgery. Therefore, it is hypothesized that pre- and intraoperative administration of a COX-2-selective inhibitor would allow sufficient time for the onset of analgesia, through inhibition of COX-2, before the effects of the anaesthesia wear off. Parecoxib sodium, an effective, injectable COX-2-selective inhibitor that does not cause bleeding complications normally associated with conventional NSAIDs, might be suitable for such applications.
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