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Postsurgical Safety of Opioid-sparing Cyclooxygenase-2 Inhibitors

Babul, Najib Pharm.D.‡; Sloan, Paul M.D.; Lipman, Arthur G. Pharm.D.

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To the Editor:—

We read with great interest the excellent meta-analysis by Marret et al.1 and the accompanying editorial by Professor Kehlet2 on the effects of combined opioid and nonsteroidal antiinflammatory drugs (NSAIDs) use to relieve postsurgical pain. Marret et al. conclude that NSAIDs (cyclooxygenase 2 [COX-2] selective and nonselective), in the aggregate, provide approximately 30% reduction in morphine consumption, with associated reductions in postoperative nausea and vomiting and sedation, but not pruritus, urinary retention, and respiratory depression. Although the efficacy data support the use of multimodal analgesia involving opioids and COX-2 selective NSAIDs, we believe the safety data on the short-term perioperative use of COX-2 selective inhibitors are less than clear for the following reasons.
First, the US New Drug Application for rofecoxib was based almost exclusively on studies in patients with chronic pain. Studies to directly support the postsurgical pain indication consisted of 741 patients, of whom 85% received one dose for dental pain and 15% received five doses for orthopedic pain.* Marret et al. note that the cardiovascular risk of rofecoxib was associated with “long-term use.” However, in the absence of robust studies in high-risk surgical patients and based on data on parecoxib, one cannot preclude similar safety risks with short-term postsurgical use of rofecoxib.
Second, although parecoxib (the injectable prodrug of the now withdrawn valdecoxib) is an effective analgesic, there remain serious unanswered questions about the safety of short-term use in the postsurgical setting. An important early adverse postsurgical safety signal came from a coronary artery bypass graft study included in the original US New Drug Application. In the parecoxib and 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% vs. 0.7%) and cerebrovascular events (2.6% vs. 0.7%) and deaths (4 vs. 0), parecoxib received a nonapprovable letter from the Food and Drug Administration in 2001. The Food and Drug Administration concluded that “the adverse event profile of parecoxib was generally worse than that of placebo in this trial. Although not statistically significantly different, the number of deaths, myocardial infarctions, cerebrovascular accidents, pulmonary embolisms, along with renal and pulmonary complications were also numerically more frequent for parecoxib during this IV dosing period than placebo. In fact, during the entire study period, the incidence of these clinically relevant adverse events associated with parecoxib/valdecoxib was statistically significantly different than placebo. Similarly, during the entire study period, more patients in the parecoxib/valdecoxib versus the placebo group withdrew from the study due to an adverse event.”
Third, follow-up studies conducted with parecoxib have raised additional safety issues. In one trial,3 cardiovascular events (including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) occurred significantly more frequently in the parecoxib and valdecoxib group than with placebo (2.0% vs. 0.5%; P = 0.03). In another trial,4 there were significantly more sternal wound infections with parecoxib than with placebo (3.2% vs. 0%; P = 0.03).
Fourth, 3 yr ago, the European Medicines Evaluation Agency issued a public statement on parecoxib regarding the risk of serious hypersensitivity and skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and exfoliative dermatitis, as well as anaphylaxis and angioedema.5 The European Medicines Evaluation Agency has since contraindicated the use of parecoxib in patients with ischemic heart disease and stroke. Excluding individuals with silent ischemia, this translates to approximately 20 million at-risk patients in the United States. Immediately before its withdrawal in the United States, the Food and Drug Administration required a similarly worded box warning for valdecoxib. Notably, the warning indicated (1) a higher risk of serious skin reactions within the first 2 weeks, (2) a greater propensity for such reactions with valdecoxib than other COX-2 inhibitors, and (3) a recommendation to discontinue valdecoxib at the first appearance of skin rash. Since self-limiting pruritus and hypersensitivity are common in the postsurgical setting, causality assessment in patients with early signs of serious and unrelated skin reactions may prove difficult.
Fifth, there are indications that the increased COX-2 levels observed under pathologic conditions in endothelial cells and atherosclerotic lesions provides atheroprotection and modulates vascular remodeling through its principal metabolite, prostacyclin.6 In addition, in patients with acute pain, there is considerable spinal up-regulation of COX-1, which may provide a further rationale for the use of drugs that inhibit both isoforms of COX in acute pain.
Finally, survey data continue to support the view that postsurgical pain is undertreated. Although the efficacy of COX-2 selective NSAIDs such as parecoxib is comparable to nonselective NSAIDs, further safety data are required to support their short-term use in the perioperative setting.
Najib Babul, Pharm.D.‡
Paul Sloan, M.D.
Arthur G. Lipman, Pharm.D.
‡TheraQuest Biosciences, Blue Bell, Pennsylvania. nbabul@theraquestinc.com
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References

1. Marret E, Kurdi O, Zufferey P, Bonnet F: Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects: Meta-analysis of randomized controlled trials. Anesthesiology 2005; 102:1249–60

2. Kehlet H: Postoperative opioid sparing to hasten recovery: What are the issues? Anesthesiology 2005; 102:1083–5

3. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM: Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352:1081–91

4. Ott E, Nussmeier NA, Duke PC, Feneck RO, Alston RP, Snabes MC, Hubbard RC, Hsu PH, Saidman LJ, Mangano DT: Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg 2003; 125:1481–92

5. EMEA public statement on parecoxib sodium (Dynastat, Rayzon, Xapit): Risk of serious hypersensitivity and skin reactions EMEA/25175/02 October 22, 2002

6. Egan KM, Lawson JA, Fries S, Koller B, Rader DJ, Smyth EM, Fitzgerald GA: Cyclooxygenase-2-derived prostacyclin confers atheroprotection on female mice. Obstet Gynecol Surv 2005; 60:309–10

* Food and Drug Administration Summary Basis for Approval for Vioxx, NDA 21-042. Available at: http://www.fda.gov/cder/drug/. Accessed September 21, 2005. Cited Here...
† Food and Drug Administration Medical Officer Review: Parecoxib NDA 21-294. http://www.fda/gov/cder/drug/. Accessed September 21, 2005. Cited Here...

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Health Technology Assessment
Paracetamol and selective and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) for the reduction of morphine-related side effects after major surgery:a systematic review
McDaid, C; Maund, E; Rice, S; Wright, K; Jenkins, B; Woolacott, N
Health Technology Assessment, 14(): 1-+.

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