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


METHODS
Prospective randomized blinded study.


METHODS
University teaching hospital.


METHODS
Thirty patients undergoing thoracotomy for lobectomy were recruited.


METHODS
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.


METHODS
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.
McCrory
Connail
C
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland.
Fitzgerald
Desmond
D
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage; D007527:Isoenzymes / Q000032:analysis / Q000502:physiology*; D010149:Postoperative Pain / Q000503:physiopathology* / Q000517:prevention & control; D010465:Perception / Q000502:physiology; D011013:Pneumonectomy; D011446:Prospective Studies; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000502:physiology*; D011453:Prostaglandins / Q000096:biosynthesis* / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D013908:Thoracotomy
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011453:Prostaglandins; D013449:Sulfonamides; D015121:6-Ketoprostaglandin F1 alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C012655:nimesulide; D007052:Ibuprofen