Cyclooxygenase-2 Inhibitors in Postoperative Pain Management: Current Evidence and Future Directions

Postoperative pain management has gone through revolutionary innovations over the past century with the widespread clinical introduction of systemic and neuraxial opioids, regional local anesthetic techniques, patient-controlled analgesia, and coanalgesic therapies such as NSAIDS. Current needs for improvement in postoperative pain management include (1) more effective relief of pain and suffering for all postoperative patients (2) preventing and/or treating other postoperative symptoms (which may or may not be related to analgesic therapies) such as nausea, pruritus, sedation, and cognitive dysfunction; and (3) promoting recovery from surgery by preventing and/or treating postoperative physiologic dysfunction such as atelectasis and ileus. Thus, therapeutic improvements in postoperative pain management should advance at least one of these goals without impeding the others. In the interest of relieving postoperative pain for all patients, further attention needs to be given to special populations such as patients undergoing tonsillectomy, ocular procedures, spinal fusion, and other surgeries for which nonselective NSAIDs have a relative contraindication. Current evidence published to date does not suggest that COX-2Is provide a major advantage over traditional NSAIDs. However, it is possible that their development will lead to specific drugs with a superior therapeutic profile. For example, after oral surgery, valdecoxib was recently shown to be significantly more effective than rofecoxib, which in turn was shown to be more effective than codeine-acetaminophen diclofenac. It remains to be determined whether these differences in analgesic efficacy can be replicated using multidose trials with equipotent dose comparisons and after other, more painful procedures. However, such observations lead to the anticipation that future advances in drug development may result in COX-2Is with clinically important advantages over traditional NSAIDs. Several COX-21 trials have demonstrated an opioid-sparing effect after surgery, and comparisons with opioids have reported fewer postoperative side effects. Thus, COX-2Is are at least as effective as non-selective NSAIDs in reducing opioid requirements and/or opioid-related adverse effects after surgery. Provided that recent evidence of fewer gastrointestinal complications with COX-2Is from arthritis studies holds true in the postoperative setting, it is hoped that patients with gastrointestinal risk factors (e.g., previous gastritis, ulcers), in whom NSAIDs are contraindicated, may safely benefit from the addition of a COX-2I to their postoperative analgesic regimen. Both experimental and clinical evidence suggest that NSAIDs impair bone healing. Thus, spinal fusion surgery patients present another group who may be denied the benefits of NSAIDs because of fear of postoperative deleterious effects on bone graft healing. Early evidence from a rabbit model and a small spinal fusion clinical trial suggesting that COX-2Is do not interfere with bone healing has led to the optimistic proposal that COX-2Is may be a useful alternative for these patients. More recent data does in fact support a role for COX-2 in bone healing, and further clinical investigation is needed to address this problem. Issoui et al. were unable to demonstrate any difference in postoperative recovery times across postoperative patients receiving acetaminophen, celecoxib, their combination, or placebo. No study has been reported to date that compares COX-2Is to nonselective NSAIDs with respect to postoperative recovery or postoperative physiologic impairment. Such investigations as have been previously conducted with nonselective NSAIDs are needed to identify whether COX-2Is have any advantage. Cardiovascular risks of COX-2Is discussed above remain controversial, and more recent evidence suggests that COX-2Is may not confer greater cardiovascular danger than nonselective NSAIDs. However, comparative postoperative studies that carefully track cardiovascular outcomes are needed to resolve this controversy. Discovery of the COX-2 enzyme and subsequent development of selective COX-2Is has contributed to a resurgence of therapeutic research in postoperative pain. However, whether these developments have resulted in any tangible improvements in patient care requires further study. Comparative COX-2I trials published to date generally suggest similar analgesic efficacy to nonselective NSAIDs in postoperative pain. Also, these mostly single-dose studies suggest similar safety and tolerability as compared to currently used NSAIDs. Additional data from larger, multicenter, multidose comparative trials could determine whether individual COX-2Is are more efficacious, cost-effective, and/or safe versus nonselective NSAIDs with respect to gastric, renal, and coagulation problems and whether COX-2Is confer greater cardiovascular risk in the postoperative setting. Multiple unresolved questions (table 6) remain to be answered. Until then, cost-benefit considerations will likely guide therapeutic choices in the absence of strong evidence supporting any major advantage of COX-2Is.