Rofecoxib does not adversely affect skin graft survival in a rat model

Abstract

Selective cylco-oxygenase (COX-2) inhibitors are increasingly used in the management of acute, perioperative pain. However, the effects of COX-2 inhibitors on skin graft healing have not been reported. Therefore, the objective of this study was to assess the effect of the selective COX-2 inhibitor, rofecoxib, on skin graft healing in a rat model. Full-thickness, dorsal, skin grafts, measuring 2 7 cm, were raised and reapplied to their original beds in two groups of adult, male Sprague-Dawley rats. In a randomized, blinded manner, control (n 8) and treatment (n 9) groups received either placebo or rofecoxib, 12 hours before harvest and then every 24 hours for two additional doses. The skin grafts were assessed 7 days after surgery using computerized planimetry performed by a blinded technician. The mean dorsal skin graft percent viability for the control and treatment groups was 49% (19% to 71%) and 46% (29% to 65%), respectively (p 0.714). The authors conclude that the selective cyclo-oxygenase (COX-2) inhibitor, rofecoxib, does not adversely affect full thickness skin grafting in a rat model; however, further human application studies are warranted. Necrosis and contracture of skin grafts used to correct tissue defects continues to be a significant and unpredictable complication. Iatrogenic complications from pharmacologic agents, although unintentional, should be avoided; therefore, investigations of commonly administered medications as they relate to wound healing are warranted. Rofecoxib (Vioxx; Merck & Co., Inc., Whitehouse Station, New Jersey) is a nonsteroidal antiinflammatory drug (NSAID) that preferentially inhibits the activity of the COX-2 enzyme. The isoenzyme COX-2 is primarily associated with inflammation. Antagonism of the COX-2 receptor reduces prostaglandins that mediate inflammation, pain, and fever, potentially avoiding the gastrointestinal bleeding risks associated with COX-1 receptor blockade. As such, COX-2 inhibitors are gaining popularity for use as anti-inflammatory and analgesic agents. The US Food and Drug Administration (FDA) has approved rofecoxib for the treatment of primary dysmenorrhea, symptoms of osteoarthritis, and acute pain in adults. The recommended dosage for acute pain is 50 mg once daily for 3 days. Surgeons frequently use rofecoxib in the perioperative period to promote analgesia and reduce narcotic requirements. The FDA is currently evaluating reported cases of thrombotic events, including myocardial infarction, cerebrovascular accidents, pulmonary embolism, and deep vein thrombosis, possibly associated with the use of COX-2 inhibitors. Additionally, COX-2 inhibitors have been implicated in bone graft loss. Hypothetically, COX-2 inhibitors may increase risk for thrombotic events by inhibiting vascular PGI2 production, which results in a change in the balance of prostaglandins toward the prothrombotic eicosanoid TXA2. Thromboxane A2 (TXA2) is normally held in check by its more abundant antagonist, prostacyclin (PGI2). 4 Although PGI2 inhibits platelet aggregation and vasoconstriction, TXA2 promotes platelet aggregation and vasoconstriction. Because of these circumstances, we hypothesized that rofecoxib would have a deleterious effect on skin graft survival because of possible thrombogenic insult and vasoconstrictive effects. Therefore, a study was undertaken to investigate the effects of rofecoxib on full thickness skin graft survival in the laboratory rat.