Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of therapy for the management of acute pain. Cyclooxygenase (COX) enzyme is of particular interest because it is the major target of NSAIDs. Although NSAIDs are remarkably effective in the management of pain and inflammation, their use is limited by several adverse effects including gastrointestinal bleeding and ulceration, impaired renal function, and inhibition of platelet aggregation. Discovery of a second cyclooxygenase, COX-2, led to the hypothesis that NSAID side effects could be decreased, as the inhibition of COX-2 is more directly implicated in ameliorating inflammation while the inhibition of COX-1 is related to adverse effects in the GI tract. This stimulated the development of selective COX-2 inhibitors (coxibs) that are better tolerated than nonselective NSAIDs but comparable in analgesic efficacy. This article provides an overview on the therapeutic use of selective COX-2 inhibitors for relief of acute pain, largely based on clinical trials in patients undergoing the surgical removal of impacted third molars, with focus on analgesic efficacy and the potential safety associated with their use compared to dual COX-1/COX-2 inhibitors.

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Nociceptive input from surgical insult and postoperative inflammation contribute to the development of central sensitization, yet their relative contributions have not been evaluated. COX‐1 and ‐2 catalyze prostaglandin synthesis, with COX‐1 being primarily responsible for PGE2 production over the first 1–2 hours with COX‐2 regulation at later time points. This study evaluated the effect of COX‐2 mediated prostanoid production to nociceptive input contributing to the development of central sensitization in the oral surgery model with either 50 mg rofecoxib or placebo administered preoperatively and lidocaine or long‐acting bupivicaine used for local anesthesia. Microdialysis was used to collect submucosal perfusate from the surgical site for four hours postoperatively and pain report recorded concurrently. Both rofecoxib and bupivicaine suppressed pain in the immediate postoperative period independently and additively. PGE2 levels were significantly suppressed by rofecoxib as compared to placebo across the last two hours of the postoperative period (p < 0.05). TXB2 levels did not differ significantly between groups during the postoperative period. The local anesthetic did not have any effect on PGE2 or TXB2 levels. The suppression of PGE2 during the later time points suggests that inhibition of cytokine mediated postoperative inflammation limits the development of sensitization following surgery. Clinical Pharmacology & Therapeutics (2004) 75, P4–P4; doi:

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Aims COX‐1 expression is significantly decreased and COX‐2 expression significantly increased 4 hours after surgery, but both return to pre‐surgical levels by 48 hours in acutely inflamed human tissue (Lee et al, Soc. for Neurosci. 2004). This study evaluated the effect of a dual COX‐1/‐2 inhibitor (ibuprofen) and a selective COX‐2 inhibitor (rofecoxib) on expression patterns of pro‐inflammatory genes related to prostaglandin (PG) formation in the oral surgery model. Methods Pre‐ and post‐surgical (48 hours) biopsy samples were taken from 64 patients undergoing surgical removal of impacted third molars. For evaluation of transcriptional activity, real‐time PCR assays were performed. Results We found little detectable change in COX‐1 expression but wide variation in COX‐2 expression associated with drug administration: no change in the placebo group but increased COX‐2 mRNA from ibuprofen (p<.01) and rofecoxib (p<.05) treatment. Three other enzymes related to PG production; sPLA2IIA, mPGES and cPGES, were significantly increased (ibuprofen > rofecoxib > placebo), and 15‐PGDH related to PG degradation, was significantly decreased (ibuprofen < rofecoxib < placebo). Conclusions These findings demonstrate that a dual COX‐1/‐2 inhibitor and a selective COX‐2 inhibitor change expression patterns of pro‐inflammatory genes following tissue injury that stimulate the arachidonic acid cascade and may attenuate the inhibitory actions of these drugs by increased production of PG. Clinical Pharmacology & Therapeutics (2005) 77, P9–P9; doi: