Safety of Cox-2 Selective Nonsteroidal Antiinflammatory Drugs for Postsurgical Pain (2006)

To the Editor: We read with interest Dr. White’s editorial (1) on the perioperative use of cyclooxygenase (COX)-2 selective nonsteroidal antiinflammatory drugs (NSAIDs). It laments the withdrawal of rofecoxib (Vioxx®; Merck, Whitehouse Station, NJ), noting its good efficacy and safety after surgical procedures and an absence of serious cardiovascular complications with short-term use. The editorial further notes that parecoxib, the injectable prodrug of the now-withdrawn valdecoxib (Bextra®; Pfizer, New York, NY), has been “widely anticipated by anesthesiologists.” Although the editorial acknowledges “unexplained complications” with the use of parecoxib, it suggests that these may have resulted from the use of parecoxib in combination with valdecoxib over a period of 14 days. Several issues raised by this editorial deserve further elaboration: 1. The United States New Drug Application for rofecoxib was based largely on studies in chronic pain. Studies to directly support the postsurgical pain indication consisted of 741 patients, of whom 85% received a single dose for dental pain and 15% received five doses of postorthopedic pain (2). Perhaps there have been “no case reports of serious cardiovascular complications” in this population because of the absence of robust studies in high-risk surgical patients. 2. The suggestion that serious and life-threatening safety problems seen with short-term IV parecoxib followed by oral valdecoxib may be attributable to valdecoxib and not parecoxib is not supported by data. Parecoxib is a water-soluble ester prodrug of the very poorly soluble valdecoxib; it is rapidly hydrolyzed to valdecoxib on systemic administration. 3. The first important adverse postsurgical safety signal for parecoxib came from a coronary artery bypass grafting study in the original New Drug Application (4). In the parecoxib/valdecoxib group, 19.0% had serious adverse events versus 9.9% in the placebo group. Citing deficiencies in the data, including a numerically higher incidence of myocardial infarctions (1.9% versus 0.7%), cerebrovascular events (2.6% versus 0.7%), and deaths (4 versus 0), parecoxib was denied approval in 2001. The FDA concluded that the “adverse event profile of parecoxib was generally worse than that of placebo” and that “during the IV dosing period, there were numerically more parecoxib/valdecoxib patients with clinically relevant adverse events.” 4. Subsequent confirmatory studies have raised serious additional safety questions. In one follow-up study (5), cardiovascular events (including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) were more frequent among the patients given parecoxib and valdecoxib than among those given placebo (2.0% versus 0.5%; P = 0.03). In another study (6), parecoxib was associated with significantly more sternal wound infections (3.2%) than occurred in control patients (0%). A meta-analysis of two randomized clinical trials of short-term parecoxib/valdecoxib for postsurgical pain after CABG (3) found a nonsignificant, three-fold higher risk of cardiovascular events with valdecoxib relative to placebo (95% confidence interval, 1.2-7.9). The authors note that “in the absence of evidence of safety, it is prudent to avoid the use of valdecoxib altogether or use it only as a drug of last resort.” 5. In 2002, the European Medicines Evaluation Agency (EMEA) warned about the risk of serious hypersensitivity reactions with parecoxib, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and exfoliative dermatitis, as well as anaphylaxis and angioedema (7). The EMEA has since contraindicated the use of parecoxib in patients with ischemic heart disease and stroke (8). A few months before valdecoxib’s withdrawal, a black box warning was issued in the United States. In particular, it noted that: i) serious skin reactions have sometimes resulted in death; ii) patients appear to be at higher risk within the first 2 wk of treatment; iii) the serious skin reactions appear to be greater for valdecoxib compared with other COX-2 agents; iv) valdecoxib should be discontinued at the first appearance of skin rash. Because self-limiting pruritus and hypersensitivity are common in the postsurgical setting, this latter recommendation may prove difficult to implement. 6. There are indications that the increased COX-2 observed under pathological conditions in endothelial cells and atherosclerotic lesions may be part of an “anti-arteriosceloritic” defense mechanism through its principal metabolite, prostacyclin, and that COX-2 derived prostacyclin modulates vascular remodeling (9-11). 7. Survey data continue to support the view that postsurgical pain is undertreated. We share Dr. White’s view regarding the need for new pain treatment options in the anesthesiologist’s armamentarium. However, available data would appear to suggest a need for caution with the preioperative use of parecoxib. Najib Babul, PharmD TheraQuest Biosciences, Blue Bell, PA, [email protected] Paul Sloan, MD Department of Anesthesiology, University of Kentucky Hospital, Lexington, KY Arthur G. Lipman, PharmD College of Pharmacy, Pain Management Center, University of Utah Health Sciences Center, Salt Lake City, UT