1. Salcido, Richard "Sal MD"

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By now, everyone has heard the news about the potential problems with the cyclooxygenase-2 (COX-2) inhibitors rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra). In review:


* rofecoxib was pulled from the market in September 2004 when data from a prospective, randomized, placebo-controlled clinical trial demonstrated an increased relative risk for cardiovascular events such as heart attack and stroke.1


* the Food and Drug Administration (FDA) issued a public health advisory about celecoxib and valdecoxib in December 2004.2 The FDA advised health care providers to carefully consider emerging information about COX-2 inhibitors and to weigh the benefits of the drugs against the potential risks to patients before prescribing them.2 Data continue to be reviewed by the FDA, and an FDA panel was scheduled to meet last month to further discuss the issue.2 At press time, celecoxib and valdecoxib were still on the market.



In a related move, the FDA also said in December 2004 that the nonsteroidal anti-inflammatory drug (NSAID) naproxen (Aleve, Naprosyn) should be used with caution. According to the FDA, preliminary results of a study of long-term use of naproxen suggest an increase in cardiovascular events associated with the use of naproxen when compared with placebo.2 However, this may turn out to be a statistical error once the FDA further analyzes the data.3


Good News, Bad News

The COX-2 inhibitors are intended to reduce pain and inflammation associated with acute and chronic arthritic and musculoskeletal conditions. They were considered a major breakthrough when they were launched because unlike older anti-inflammatory drugs, they were easier on the stomach and potentially decreased the well-known gastrointestinal (GI) complications associated with NSAIDs, such as GI ulcers and GI bleeding.


Unfortunately, the emerging evidence offsets the positive effects of these new drugs. Research has shown that the COX-2 inhibitors may have negative effects on platelet function and contribute to platelet aggregation or enhanced clotting in the vessels of patients with coronary artery or cerebrovascular disease. This predisposes these patients to heart attack and stroke.1,2


Ironically, deposition of cholesterol plaque in vessel walls is, in part, an inflammatory process. On the surface, therefore, it seems logical that an anti-inflammatory medication would have some value in preventing this inflammatory process. However, apparently when the plaque ruptures, it has the potential to form a nexus for certain clotting factors. These clotting factors clog the arteries and have significant potential to cause ischemia and infarction of the tissues-which could include healing wound tissue.


The Wound Model and Anti-Inflammatories

What does this have to do with wound care? Think about the model of wound healing. Wounds often have a significant inflammatory component, from the initial stages of wound development through healing. We treat the inflammation associated with the wound after the precipitating event, during tissue breakdown, and again in the healing stage.


In our quest to mitigate the ravages of a prolonged inflammatory stage on the wound, we often use anti-inflammatory agents. Given the recent news that COX-2 inhibitors may be dangerous to patients at risk for heart attack and stroke-including many of our wound care patients-we may have to rethink this approach. In addition, there is little support in the literature for using anti-inflammatory drugs to treat chronic wounds.


Animal Models

Nor can we find evidence in favor of this treatment approach in reports of animal models. In fact, we find quite the opposite.


A decade ago, my colleagues and I hypothesized that the NSAID ibuprofen would prevent pressure ulcers.4 We believed that reducing the inflammation associated with the wound model would decrease the neutrophil ischemia and reperfusion injury associated with infarction of the tissue at risk. This, we thought, would enhance wound healing. Unfortunately, our hypothesis was not proved correct. Ibuprofen not only did not enhance healing, but it actually tended to make the lesions worse.4


In another study, a potent and commonly used anti-inflammatory agent-the steroid cortisone-was used in experimental colonic anastomosis in rats.5 The purpose of the study was to determine whether steroids would enhance wound healing. Again, the anti-inflammatory agent used in this study made the colonic anastomosis weaker than the control agent.5


In a more recent study, investigators examined the effect of the COX-2 inhibitor rofecoxib on wound healing in experimentally induced bowel anastomosis in a rat model.6 Again, their findings demonstrated impaired wound healing with use of the COX-2 inhibitor.6


The aforementioned animal studies are considered to have strength-of-evidence ratings of "C." There are no human studies with higher strength-of-evidence ratings, nor are there case reports in the literature.


The Jury Is Still Out

The inflammatory stage is a natural and useful part of the healing process but if necessary, we must strive to control and ameliorate the consequences of chronic destructive inflammation.


However, given the need to couple evidence-based medicine with informed clinical judgment, we should consider that the jury is still out when it comes to our understanding of the use of COX-2 inhibitors and other anti-inflammatory agents in wound healing.




1. Merck announces voluntary worldwide withdrawal of Vioxx. Available online at; accessed January 21, 2005. [Context Link]


2. FDA talk paper. FDA issues public health advisory recommending limited use of Cox-2 inhibitors. Available online at; accessed January 23, 2005. [Context Link]


3. Bazell R. Naproxen risks may have been overstated. Available online at; accessed January 22, 2005. [Context Link]


4. Salcido R, Donofrio JC, Fisher SB, et al. Evaluation of ibuprofen for pressure ulcer prevention: application of a rat pressure ulcer model. Adv Wound Care 1995;8(4):30-2, 34, 38-40 passim. Erratum in Adv Wound Care 1995;8(6):6. [Context Link]


5. Del Rio JV, Beck DE, Opelka FG. Chronic perioperative steroids and colonic anastomotic healing in rats. J Surg Res 1996;66:138-42. [Context Link]


6. Cahill RA, Sheehan KM, Scanlon RW, Murray FE, Kay EW, Redmond HP. Effects of a selective cyclo-oxygenase 2 inhibitor on colonic anastomotic and skin wound integrity. Br J Surg 2004;91:1613-8. [Context Link]