Spinal prostaglandin formation and pain perception following thoracotomy: a role for cyclooxygenase-2.

Abstract

STUDY OBJECTIVE: Prostaglandins (PGs) generated in the spinal cord may play a major role in pain perception. Consequently, the suppression of spinal cyclooxygenase (COX) and PG formation may contribute to the analgesic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in pain following surgery. Which isoform of COX is responsible for postsurgical pain and, consequently, should be targeted, is unclear. DESIGN: Prospective randomized blinded study. SETTING: University teaching hospital. PATIENTS: Thirty patients undergoing thoracotomy for lobectomy were recruited. INTERVENTIONS: Patients were randomized to receive the COX-2 selective inhibitor nimesulide, 100 mg orally twice daily, or ibuprofen (nonselective), 400 mg orally three times daily, in an open-label study. In addition, there was a randomized control group that received no NSAIDs. Cerebrospinal fluid (CSF) was analyzed for 6-keto-PGF(1)alpha, the principle metabolite of prostacyclin. COX-1 and COX-2 activity was determined by measuring serum thromboxane (TX) B(2) and endotoxin-induced PGE(2) generation in whole blood. MEASUREMENTS: Pain perception was measured by visual analog scores, and blinded assessment of opioid analgesic requirements and expiratory peak flow measurements were performed. RESULTS: At the doses used, nimesulide was selective for COX-2, while ibuprofen was nonselective based on serum TXB(2) levels. The mean (+/- SEM) levels of 6-keto-PGF(1)alpha in CSF increased following surgery from 32 +/- 4.9 to 127 +/- 29 pg/mL (p < 0.001), and this was suppressed by nimesulide (49 +/- 9.3 pg/mL; p = 0.0025) but not by ibuprofen (122 +/- 35 pg/mL). Pain scores (p < 0.001), morphine requirement (p = 0.0175), and the fall in peak expiratory flow rate (p < 0.001) were significantly lower in the nimesulide group. CONCLUSIONS: Increases in spinal PG synthesis after thoracotomy are repressed by a selective COX-2 inhibitor. This suggests that the inducible COX-2 mediates central PG synthesis, which may be important in the generation of pain, as the use of nimesulide also resulted in significant decreases in postoperative pain perception.