The current controversy regarding the risk of serious cardiovascular complications with long-term use of the cyclooxygenase (COX) type 2 inhibitors has raised medicolegal concerns in the anesthesia community about the continued use of these compounds in the perioperative period (1). Both the traditional nonsteroidal antiinflammatory drugs (NSAIDs) and the more highly selective COX-2 compounds have gained widespread popularity as analgesia adjuvants before and after surgery because of their ability to reduce the requirement for opioid analgesics and potentially facilitate the recovery process by decreasing opioid-related side effects (e.g., postoperative nausea, vomiting, ileus/constipation, urinary retention) (2).
The voluntary withdrawal of rofecoxib (Vioxx™) from the market by Merck would seem more logical if the drug were only used for treating chronic pain syndromes. However, numerous clinical studies over the past 5 years support the safety and efficacy of administering this long-acting COX-2 inhibitor before and after a wide variety of surgical procedures in order to minimize postoperative pain and improve early recovery (3–11). In fact, it had been suggested that rofecoxib was the most cost-effective drug in this class (12). Despite extensive use of rofecoxib in the perioperative period throughout the world, there have been no case reports of serious cardiovascular complications associated with its short-term use.
The availability of a parenterally active COX-2 inhibitor like parecoxib (Dynastat™) has been widely anticipated by anesthesiologists because it would allow greater flexibility for both treating and preventing pain in the postoperative period. Early clinical studies demonstrated that both pre- and/or postoperative use of parecoxib, a prodrug of valdecoxib (Bextra™) produced significant opioid-sparing effects and improved patient satisfaction with their pain management (13–16). Most of the placebo-controlled studies have suggested that use of parecoxib improved pain control and reduced postoperative side effects. However, investigators reported unexpected complications when parecoxib was used in combination with the oral formulation (valdecoxib) over a period of 14 days in patients with preexisting cardiovascular disease (17,18).
In the current issue of Anesthesia & Analgesia, Beaussier et al. (19) compared parecoxib to the IV prodrug of acetaminophen, propacetamol, in patients undergoing inguinal hernia repair. Although the intensity of pain at rest was less severe and a larger percentage of patients in the parecoxib group (87% vs 70%) rated their pain management as “good or excellent,” the postoperative opioid analgesic requirements were similar in both treatment groups. These findings suggest that parecoxib may not provide substantial benefits over acetaminophen in the postoperative period. However, the lack of a placebo control group makes it difficult to determine the clinical significance of these findings. Analogous to the earlier placebo-controlled studies involving parecoxib, this study also failed to examine clinically meaningful outcome variables (e.g., hospital discharge time, resumption of activities of daily living, return to work). Another potential limitation in the study design related to the fact that the study medication was administered at the end of surgery rather than prior to the start of the operation. Finally, the failure to utilize local anesthesia as part of a multimodal analgesic regimen further limits the clinical relevance of these findings.
In the study by Beaussier et al. (19), the dose of the acetaminophen prodrug was approximately 30 mg/kg IV. Since Korpela et al. (20) demonstrated that the opioid-sparing effects of acetaminophen were dose-dependent, it is possible that a larger dose of the acetaminophen prodrug (e.g., 40–60 mg/kg) would have been more effective in this acute pain model. Since an investigational IV formulation of acetaminophen is currently available for clinical testing (21), it would be interesting to compare maximally effective doses of the IV COX-2 inhibitor to IV acetaminophen in preventing pain after surgery.
Of interest, Ng et al. (22) recently reported that parecoxib (40 mg) was actually less effective than the nonselective NSAID ketorolac (30 mg) in preventing pain after gynecologic laparoscopic procedures. Although concerns have been raised about the use of the traditional NSAIDs such as ketorolac and ibuprofen in the perioperative period (23) because of the increased risk of bleeding (24,25), this remains a controversial subject (26,27). Controversy also exists regarding the risk of serious adverse effects of parecoxib (and valdecoxib) in patients with preexisting cardiovascular disease (17,18). Concerns have also been raised regarding the possible deleterious effects of COX-2 inhibitors on bone healing (28,29).
What then should be the role of the COX-2 inhibitors in the perioperative period? In light of the widespread clinical experience using COX-2 inhibitors in this setting without any apparent problem, and the extensive clinical research database supporting both the safety and the efficacy of short-term (3–5 days) perioperative use of these compounds for improving pain control (7,8), the COX-2 inhibitors should still be considered as part of a standard multimodal analgesic regimen. However, given the comparable analgesic efficacy and lower cost of traditional (nonselective) NSAIDS such as ibuprofen and ketorolac (22,26,30), these compounds may prove to be more cost-effective adjuvants in the perioperative period. Alternatively, other non-opioid analgesics such as acetaminophen (21,25,31,32) or gabapentin (33,34) may prove to be more cost-beneficial than the COX-2 inhibitors as part of a multimodal analgesic regimen in the future.
Finally, given the recent controversy involving the COX-2 inhibitors and the long-standing concerns regarding the perioperative use of traditional NSAIDs, it is clear that there remains a need for safer and more effective non-opioid analgesics to minimize pain and facilitate the recovery process after surgery. We hope that the study by Beaussier et al. (19) will serve to encourage other investigators to pursue clinical research on the role of non-opioid analgesics in the management of postoperative pain. Future comparative studies involving new non-opioid analgesics should emphasize clinically relevant outcome variables rather than simply examining their opioid-sparing properties and effects on pain scores.
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