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ANALGESIA

Nimesulide 90 mg Orally Twice Daily Does Not Influence Postoperative Morphine Requirements After Major Chest Surgery

Donal F. Harney^*, Michelle Dooley^*, Brendan Harhen^*, Niall McGuiness, Gerard Cagney^*, Connail McCrory, Desmond J. Fitzgerald^*, and Noreen P. Dowd

From the *Department of Clinical Pharmacology, Royal College of Surgeons, Department of Anaesthesia, St. James’s Hospital, Dublin, Ireland; and Independent Data Management, Cork, Ireland.

Address correspondence to Dr. Donal Harney, Department of Pain Medicine. Mercy University Hospital, Cork, Ireland. Address e-mail to donalharney{at}hotmail.com.

Abstract

BACKGROUND: Cyclooxygenase 2 inhibition has proven analgesic efficacy in a variety of surgical procedures. We postulated that perioperative cyclooxygenase 2 inhibition significantly reduces postoperative morphine requirements after major thoracic surgery and investigated the site of this potential analgesic effect.

METHODS: Ninety-two patients participated in this single-center, double-blind, randomized, placebo-controlled, parallel-group trial. Patients between the ages of 18 and 80 yr undergoing a thoracotomy or median sternotomy were randomized to receive either nimesulide or placebo in combination with a standard analgesic regimen perioperatively. Nimesulide was administered orally the evening before surgery and at 12-h intervals for 5 days postoperatively. The primary efficacy variables were morphine consumption and pain scores for the first 48 h postoperatively. The secondary efficacy variable was the effect of nimesulide on cyclooxygenase activity in cerebrospinal fluid (CSF).

RESULTS: Pain scores at rest or with movement, and total morphine consumption for the first 48 h postoperatively, were not statistically different between the groups. The mean difference in total morphine consumption up to 48 h postoperatively between the nimesulide and placebo group was a 9.0 mg reduction (95% CI: –28.9 to 10.9 mg) (P = 0.37). Adjusted mean (se) CSF 6-keto-PGF1 (6-keto-PGF1) concentrations increased by 54.7 (25.7) pg/mL from preoperatively to Day + 2 postoperatively in the placebo group, whereas adjusted mean (se) CSF 6-keto-PGF1 concentration decreased by 0.6 pg/mL (18.2 pg/mL) in the nimesulide group. These changes were not statistically different between the groups (P = 0.095).

CONCLUSION: Nimesulide, at a dose of 90 mg twice daily in combination with a standard analgesic regimen, does not influence pain scores, morphine requirements, or CSF prostaglandin levels after major thoracic surgery.

Prostaglandins, mostly PGE2 and prostacyclin, are important mediators of inflammation and pain.1,2 They are synthesized in the tissue by the enzyme cyclooxygenase (COX), of which there are multiple isoforms, most importantly COX-1 and COX-2.3 COX-1 is constitutively present in most cells. COX-2 is expressed constitutively in some cells, including the brain and spinal cord in humans and animals4–7 but is largely induced by cytokines, growth factors, or other inflammatory mediators.8 The relative role of the two enzymes in pain processing is unclear. Nonsteroidal antiinflammatory drugs (NSAIDs) produce analgesia by inhibiting the COX enzymes. Inhibitors of the enzyme COX-2 were developed to provide the analgesia efficacy of the nonspecific NSAIDS while limiting their toxicity. They have demonstrated analgesic efficacy in a variety of surgical procedures, although when and where they exert their analgesic effect is not completely understood. There is strong experimental evidence that prostaglandins acting within the spinal cord or at higher levels facilitate pain perception and enhance nociceptive neurotransmission9–11 Both COX enzymes required for prostaglandin synthesis and receptors for PGE2 and prostacyclin are found in dorsal root ganglia.12,13

In a previous unblinded study at this institution, a selective COX-2 inhibitor, nimesulide, was associated with a significant decrease in postoperative pain and morphine requirement in patients undergoing thoracotomy.14 This effect was thought to be due to suppression of COX-2-generated prostaglandins in the cerebrospinal fluid (CSF) as nimesulide prevented increases in CSF prostaglandin after thoracotomy. The aim of this study was to explore further the hypothesis that centrally induced COX-2 may generate prostaglandins that are important in the generation of postoperative pain and to examine CSF and systemic levels of the COX-2 inhibitor nimesulide. The primary objective was to assess in a large, double-blind, prospective, randomized, controlled trial the analgesic efficacy of nimesulide 90 mg orally twice daily, when added to standard analgesic therapy, in the management of postoperative pain in patients undergoing major thoracic surgery. In addition, we investigated CSF production of prostaglandins perioperatively and any correlation between CSF concentrations of the COX-2 inhibitor on generated prostaglandins.

METHODS

This was a prospective, single-center, double-blind, randomized (ratio 2:1, nimesulide: placebo), controlled, parallel-group study. Patients were enrolled after institutional ethical approval and written informed consent. Preoperative inclusion criteria included patients aged between 18 and 80 yr undergoing a thoracotomy for lung resection or median sternotomy for elective first-time coronary artery bypass grafting. Exclusion criteria included use of NSAIDs (except aspirin 75 mg once daily), corticosteroids, or any other drug known to interfere with prostaglandin production within 14 days of surgery. Patients with chronic pain were also excluded, as were patients taking opioids chronically. Intraoperative exclusion criteria included extension of thoracotomy incision to facilitate entire lung resection and/or chest wall resection. Patients were blindly assigned active therapy or placebo according to a computer-generated schedule, on a 2:1 ratio to provide 60 evaluable patients receiving active drug and 30 evaluable patients receiving placebo. These numbers were calculated to detect a 50% reduction in the amount of morphine required and a 40-mm reduction on 100 mm visual analog pain score at a 5% significance level with a statistical power of 90%.

Nimesulide or placebo was started on the evening before surgery at 22:00 h. The morning dose of study drug was administered at 06:00 h. Patients underwent surgeries at 08:00 h or 09:00 h.

Patients were administered a postoperative dose at 22:00 h on the evening of surgery, when all patients were tracheally extubated and awake in the intensive therapy unit. After this first postoperative dose, all other doses of study medication were administered at 12-h intervals until the fifth postoperative day.

In the anesthesia induction room, all patients undergoing thoracotomy had an intrathecal catheter (A/G D/34209, 22-guage spinal catheter on a 27-guage hollow stylet needle 04517725; Braun Medical, Melsungen, Germany) placed in the L3–4 interspace via an 18-guage epidural needle before induction of general anesthesia. After observing CSF from the hollow jet needle, the catheter was advanced off the stylet 5 cm into the intrathecal space. Free-flowing CSF was noted from the stylet before removing it and the catheter was then fixed. A sample of CSF (2 mL) was taken and a 1 mg bolus of preservative-free morphine was administered through the catheter. The morphine was administered as a single dose before incision and was the only intrathecal morphine dose administered to patients.

For thoracotomy patients, a standardized general anesthetic technique was used. Propofol was used for induction of anesthesia and tracheal intubation was facilitated with a nondepolarizing muscle relaxant. IV fentanyl 1 µg/kg was given intraoperatively to all patients. Anesthesia was maintained with sevoflurane and/or propofol infusion. A standard surgical technique was used. The thoracotomy incision was made above or below the sixth rib and minimal retraction was used. For the median sternotomy patients, a fast-track cardiac anesthetic technique was used with small-dose fentanyl (5 µg/kg) and propofol for induction and sevoflurane and/or propofol infusion for maintenance intraoperatively. A standard surgical approach was used with aorta right atrial cannulation for cardiopulmonary bypass. Core temperature drifted to 32°C during bypass. A left internal mammary to left anterior descending coronary artery anastomosis was performed in all patients and either one or two vein grafts, depending on the extent of coronary artery disease. IV propofol infusion was used to maintain anesthesia including during cardiopulmonary bypass. Tracheal extubation was done in the operating room in the case of thoracotomy patients and in the intensive therapy unit in the case of median sternotomy patients. NSAIDs or other opioids were not administered intraoperatively.

Postoperatively morphine sulfate was administered by the nursing staff (who was also blinded to study drug) to all patients. VAS scores were targeted to a score of 40 mm or less. Supplemental morphine was administered as 1 mg IV bolus. Once patients were alert, they were commenced on a patient-controlled analgesia (PCA) regimen consisting of morphine sulfate 1 mg bolus with a 6-min lockout. Patients were permitted to receive tramadol and paracetamol as rescue analgesics. Tramadol was selected for postoperative analgesic rescue because it has several mechanisms of activity including agonist activity at the µ opioid receptor as well as inhibition of noradrenaline and serotonin reuptake.15 One milligram of IV morphine is approximately equal to 15 mg of oral tramadol.15

Whole blood COX-1 and COX-2 activities were analyzed on two separate occasions as previously described.16,17 A baseline analysis of COX-1 and COX-2 activities was performed before administration of the initial dose of nimesulide and a second analysis performed at Day +3 before the morning dose of medication. Briefly, non-anticoagulated blood was allowed to clot in a nonsiliconized glass tube at 37°C for 1 h. Serum was separated by centrifugation at 1000g for 10 min, and stored at –200°C until assayed for thromboxane B2 by enzyme immunoassay. This assay measures thromboxane formation by platelets, where the only isoform of COX is COX-1. COX-2 activity was measured by incubating a 1-mL aliquot of blood containing 10 IU of heparin, with lipopolysaccharide derived from Escherichia coli (Sigma, St Louis, MO), for 24 h at 37°C. Lipopolysaccharide induces COX-2 expression by monocytes during the incubation whereas COX-1 activity is suppressed in the sample by the addition of 200 µmol/L aspirin. COX-2 expression is then measured indirectly by measuring levels of PGE2 by enzyme immunoassay.

CSF samples for prostaglandin production and nimesulide concentration were taken immediately before induction of anesthesia and again before administration of the morning doses of nimesulide. The initial 300 µL of CSF was discarded to account for dead-space in the catheter, and then 2 mL of CSF was then withdrawn slowly. CSF samples were stored at –20°C before analysis. Nimesulide concentrations were analyzed using mass spectrometry (Sciex API 3000 QqQ Triple Quadrupole). Nimesulide concentration was determined by negative ion, chemical ionization-GC/MS using deuterated internal standards, using a modified version of the method developed by Barrientos-Astigarraga et al.18

Measurements below the limit of quantification were assumed to be zero when calculating CSF nimesulide concentrations. The limit of quantification for the CSF nimesulide assay was 0.39 ng/mL. CSF 6-keto-PGF1 were analyzed by enzyme immunoassay (Assay Designs, Ann Arbor, MI).

Static (at rest) and dynamic (immediately after coughing) pain measurements were recorded using a VAS graded from 0 mm (no pain) to 100 mm (worst pain imaginable). Pain scores were performed preoperatively and daily, postoperatively, 10 min after administration of the morning dose of nimesulide.

Statistical Methods
Continuous variables were summarized using count, mean, standard deviation, median, first and third quartiles, minimum and maximum (SAS version 8.2.). Summary variables are expressed as mean ± sd, unless otherwise stated. Categorical variables were presented using counts and percents. Summary statistics were provided for all baseline characteristics.

Efficacy
An ANCOVA model was used to compare treatment groups with respect to total morphine and total nonmorphine opiate requirements up to Day + 2. The ANCOVA model included treatment with type of surgery as the covariate. Surgery type (median sternotomy or thoracotomy) was added to the ANCOVA model as a covariate. The interaction between treatment type and type of surgery was tested at a significance level of 0.1. If the interaction was significant, summary tables of the primary end-point by type of surgery were provided.

The between-group difference was estimated by least squares means with 95% confidence intervals. Summary statistics were provided for each study assessment time-point.

Pharmacokinetic data were summarized by study visit. Pharmacodynamic parameters were summarized by descriptive statistics, and an ANCOVA model was used to compare treatment groups (treatment differences were calculated as nimesulide versus placebo) with respect to relevant changes in each parameter. The ANCOVA model included treatment with type of surgery as covariate. Adjusted mean was used as the mean value when different surgeries (thoracotomy versus median sternotomy) are accounted for in the statistical analysis. The between-group difference was estimated by least squares means together with 95% confidence interval. There was no imputation for missing data.

Criteria for Evaluation
The primary end-point was morphine consumption up to the end of the second postoperative day (Day +2, approximately 48-h after surgery). The secondary end-points were nonmorphine opiate analgesic administration up to Day +2, and on each subsequent postoperative day over the total inpatient period, numeric pain scores at rest and upon coughing on Days + 1, +2, and +3, and CSF 6-keto PGF1 (which represents the degree of study drug activity in the CSF as measured by the levels of 6-keto-PGF1 , the principal metabolite of prostacyclin in CSF) measurements on Day 0, +1, and +2. In addition, we measured concentrations of nimesulide in the CSF and plasma preoperatively and on Day 1 and 2 postoperatively.

Pulmonary lung function tests were performed pre- and postoperatively on the first, second, and third day. Routine clinical chemistry, hematology, and urinalysis were performed pre and postoperatively on the first, third, and seventh days. Calprotectin (a nondegraded, neutrophils-specific marker that provides an indication of NSAID-induced gastric damage) concentrations in stools were measured preoperatively and postoperatively on Day 7. Adverse events and concomitant medication use were recorded throughout the study period.

RESULTS

We recruited 92 patients into this study, of which 82 (nimesulide n = 57, placebo n = 25) patients were included in the intention-to-treat population. Five patients had their operation cancelled on the morning of surgery, three from the nimesulide group and two from the placebo group. A further five were excluded after recruitment (two from the nimesulide group and three from the placebo group). Of the two patients in the nimesulide group, one had an unplanned chest wall resection and one was given steroids intraoperatively. Of the three excluded patients in the placebo group, two had unplanned valve plus coronary artery surgery and one received diclofenac sodium intraoperatively. The protocol defined the intention-to-treat population as all subjects who received randomization and contributed to any efficacy data. Thus, the 10 patients described above were not included in the intention-to-treat population. Patients’ demographic characteristics were similar in both groups (Table 1). In the nimesulide group, 44% of patients had a thoracotomy, and in the placebo group, 64% had a thoracotomy. Mean cardiopulmonary bypass time was 55 min for patients participating in this study.

Primary Efficacy Variable—-Morphine Consumption
In the nimesulide group, patients’ adjusted total morphine consumption up to Day + 2, was 59.1 ± 5.46 (se) mg. This compared to an adjusted mean morphine consumption of 68.1 ± 8.30 (se) mg for the placebo group (Table 2). This resulted in a mean treatment reduction of 9.0 mg morphine (95% CI: –28.9 to 10.9 mg), which was not statistically significant. Mean total morphine consumption was largest on Day + 1 both overall and within each group. By Day + 2 postoperatively mean morphine consumption was considerably reduced relative to previous days, both overall and within each group.

There were no differences in daily pain scores across the study period or between treatment groups, as measured on the VAS, either at rest or coughing. The adjusted difference in patients’ pain scores, at rest, up to Day + 2, was –0.3 (95% CI: –1.04 to 0.41) in the nimesulide group, which was not statistically significant. Similarly, the mean treatment difference in pain scores up to Day + 2 when coughing was –0.4 (95% CI: –1.18 to 0.35) and not statistically significant (P = 0.29) (Table 3 and 4).

Secondary Efficacy Results
In the nimesulide group, patients’ adjusted total nonmorphine opiate consumption was 27.8 ± 5.69 (se) mg of morphine equivalents up to Day + 2, compared with a 24.8 ± 8.65 (se) mg of morphine equivalents for the placebo group. The mean treatment reduction was 3.0 mg of morphine equivalents (95% CI: –17.8 to 23.8 mg), which was not statistically significant (P = 0.77) (Table 2). In both groups, mean nonmorphine opiate consumption was largest on Day + 2, which coincided with most patients’ discontinuance of PCA.

In the placebo group, CSF concentrations of 6-keto-PGF1 increased from 6.1 ± 7.3 pg/mL before surgery to 58.8 ± 120 pg/mL on Day + 2 after surgery. In the nimesulide group, CSF concentrations of 6-keto-PGF1 were 7.2 ± 9.3 pg/mL before surgery and 5.2 ± 4.5 pg/mL on Day + 2 after surgery. This represents an adjusted change in CSF concentrations of 6-keto-PGF1 from baseline to Day 3 of + 54.7 ± 25.7 (se) for the placebo group and –0.6 ± 18.2 (se) for the nimesulide group. Although this may seem like a trend towards a suppression of CSF prostaglandin production by nimesulide, there was substantial variability within the groups and the difference was not statistically significant (P = 0.10) (Table 5). Patients’ plasma nimesulide concentration was 25.3 ± 117.3 ng/mL at the time of surgery for those patients who were treated with nimesulide. The plasma concentration increased to 2229 ± 1207 ng/mL on postoperative Day + 3. There was no nimesulide detected in the plasma of patients in the placebo group. CSF nimesulide levels measured on the morning of surgery were 19.8 ± 19 ng/mL. The CSF nimesulide levels measured on the subsequent two postoperative days were 4.5 ± 3.7 ng/mL and 7.4 ± 5.7 ng/mL, for the nimesulide group.

View this table: [in this window] [in a new window]   Table 5. Analysis of 6-Keto-prostaglandin F1 Concentrations (pg/mL) from Pretreatment to Day +2 – ITT Population

Lipopolysaccharide-induced whole blood PGE2 concentration, an index of COX-2 activation, was suppressed by nimesulide (11.2 ± 14.4 ng/mL before treatment and 0. 3 ± 1.1 ng/mL (P < 0.05) on Day 3. Lipopolysaccharide-induced plasma PGE2 was unaltered in the placebo group. Nimesulide only marginally suppressed thromboxane B2 concentrations, a marker of COX-1 activity (70.9 ± 85.8 ng/mL before treatment and 37.4 ± 60.3 ng/mL (P = 0.13) on Day 3. Levels of thromboxane B2 were unchanged in the placebo group (Table 6). Interpretation of stool concentrations of treatment difference in calprotectin, from pretreatment to posttreatment, was 56.8 mg/mL (95% CI: –440 to 326) and not statistically significant (P = 0.75). There were no significant differences in forced expiratory volume in 1 minute, forced vital capacity, or peak expiratory flow between groups.

Postoperatively, one patient in the nimesulide group experienced massive hematemesis, which resolved with conservative management. One patient from the placebo group developed a prepyloric ulcer of moderate severity, which resolved with conservative management. Otherwise, patients in both groups had a relatively uncomplicated postoperative recovery. There were no renal complications in either group.

DISCUSSION

Inhibitors of COX-2 are important advances in perioperative pain management, though when and where these inhibitors exert their analgesic effect is not completely understood. There is a compelling body of evidence that COX-2 inhibitors decrease mild postoperative pain19 and decrease perioperative opioid requirements in moderate postoperative pain.20 This prospective, randomized, double-blind study demonstrates no significant reduction in pain or morphine consumption when nimesulide, a selective COX-2 inhibitor, is used in conjunction with a standard perioperative analgesic regimen in patients undergoing major thoracic surgery.

Classically, the COX-1 isoform is considered to be constitutively expressed in the brain and spinal cord, whereas COX-2 is induced after tissue injury.21,22 However, COX-2 is also constitutively expressed in human brain in amounts equivalent to COX-1,5 and COX-2 is the predominant isoform in the spinal cord of rats.23 Although COX-2 has been shown to be marginally upregulated in the lumbar spinal cord of rats after surgical incision, the magnitude and duration of upregulation is less than that reported in models of peripheral inflammation.24 Interestingly, decreased COX-1 levels in COX-1-deficient heterozygote mice decrease nociception in these animals compared with wild-type controls.4 Also, COX-1 messenger RNA is upregulated in the spinal cords of COX-2 null or COX-2 heterozygote-deficient mice, and this appears to compensate for the absence of COX-2 to maintain normal nociceptive responses. It is likely therefore that prostaglandins made by both COX enzymes are involved in pain processing, but the relative roles of these two isoforms in postoperative pain processing are unclear. This may explain the observed lack of benefit of the selective COX-2 inhibitor in our study. In one study, nimesulide and naproxen (COX-1 inhibitor) demonstrated equal efficacy in their ability to treat pain after cardiac surgery.25

In this study, there was no significant reduction in either PCA morphine or in morphine equivalents in the nimesulide group when compared with placebo. There was a wide variability in morphine consumption in the first 3 days postoperatively, and this was not influenced by the administration of nimesulide. Although the average reduction of 9.0 mg of morphine was not statistically significant, the 95% confidence bounds show that the reduction could be negative, or could be as large as 29 mg of morphine. We also note there were no differences in static and dynamic VAS pain score between placebo and nimesulide groups. Thoracic surgery can produce some of the most intense perioperative pain that patients can experience,26 which has lead to a multimodal preemptive analgesic approach to acute pain management for these patients. Moreover, there is wide interindividual variability in opioid requirements postoperatively27 and, in general, predictive factors of morphine requirements in the early postoperative period are inconsistent.

It has been proposed that COX-2 inhibitors exert their analgesia effect in part by preventing central sensitization. However, there is little information on whether COX-2 inhibitors actually reach therapeutic concentrations in human CSF. One study evaluating blood and CSF levels of celecoxib, rofecoxib, and valdecoxib (selective COX-2 inhibitors) demonstrated that the coxibs rapidly penetrated the CSF in concentrations apparently sufficient to inhibit COX-2 activity.28 We demonstrated that nimesulide does reach human CSF, but the levels of nimesulide detected appear to be insufficient to inhibit COX-2. Plasma nimesulide concentrations reached a mean concentration of 2229 ng/mL on Day + 3, and the resulting pharmacodynamic effect was an almost complete inhibition of the surrogate marker of COX-2 activity,17 lipopolysaccharide-induced PGE2 in whole blood.

A large difference was observed between nimesulide concentrations measured in plasma and those measured in CSF. On the day of surgery, patients’ mean CSF nimesulide concentration was 19.8 ng/mL. This reflects CSF concentrations 3 h after oral dosing, and demonstrates that nimesulide rapidly penetrates the CSF. This concurs with the findings of Dembo et al.28 who demonstrated that the times to first quantifiable CSF concentrations of three different COX-2 inhibitors were similar ranging from 1.3 to 4.3 h. Samples on Day + 1 and Day + 2 were taken 12 h postdosing. Samples taken on Day + 2 were consistently higher than samples taken on Day + 1 [nimesulide CSF concentration on Day + 1 was 4.5 ± 3.7 versus CSF concentration on Day + 2 was 7.4 ± 5.7]. Our result is consistent with results in the study by Buvanendran et al.29 showing that repeat daily dosing resulted in increased CSF rofecoxib levels.

The trend towards nimesulide suppression of central COX-2 activity, as measured by 6-keto-PGF1 concentrations, did not reach statistical significance. It appears that CSF nimesulide concentrations were insufficient to produce the expected pharmacodynamic effect of central COX-2 inhibition and the expected spinally mediated analgesic effect. Since the observed trend is consistent with the known mechanism of action, the study may have been under-powered to separate the differences in central COX-2 activity between the groups. It is also possible that secondary sensitization could be a consequence of COX-1 expression in the central nervous system rather than just COX-2 expression alone.30 Since nimesulide is 5- to 50-fold more selective for COX-2 then COX-1,31 it may also be the case that COX-2 inhibition alone may not target all potential pain generators within the central nervous system.30

We conclude that nimesulide, at a dose of 90 mg twice daily, did not significantly influence the morphine requirements in the management of postoperative pain after major thoracic surgery. Furthermore, the role of COX-2 inhibition for pain management after major surgery requires further analysis to determine the appropriate role in the analgesia matrix of postoperative pain relief.

ACKNOWLEDGMENTS

Ms. E. Mc Govern, Mr. V. Young, and Mr. M. Tolan kindly allowed their patients to be recruited. We thank Dr. F. Lyons who was involved in care of patients participating in this study, Ms. Judith Strawbridge, School of Pharmacy, RCSI for precise morphine equivalent calculations, Ms. J, Mc Cawley and Ms. P. Gordon who were involved in data collection, Ms M. O’Connell who was involved in electronic patient data access, and the nursing staff of Keith Shaw and Robert Adams wards who kindly helped to facilitate this study.

Footnotes

Accepted for publication August 30, 2007.

Supported by a grant from Clonmel Medical Ltd. (generic manufacturer of nimesulide in Ireland).

Study monitor: Java clinical research organization. Dublin, Ireland.

Statistical analysis: Independent Data Management, Cork, Ireland.

Study audited by Irish Medicines Board.

REFERENCES

1. Schaible HG, Grubb BD. Afferent and spinal mechanisms of joint pain. Pain 1993;55:5–54[Web of Science][Medline]
2. Murata T, Ushikubi F, Matsuoka T, Hirata M, Yamasaki A, Sugimoto Y, Ichikawa A, Aze Y, Tanaka T, Yoshida N, Ueno A, Oh-ishi S, Narumiya S. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 1997;388:678–82[Medline]
3. Herschman HR. Prostaglandin synthase 2. Biochim-Biophys-Acta 1996;1299:125–40[Medline]
4. Ballou LR, Botting RM, Goorha S, Zhang J, Vane JR. Nociception in cyclooxygenase isozyme-deficient mice. Proc Natl Acad Sci USA 2000;97:10272–6[Abstract/Free Full Text]
5. O’Neill GP, Ford-Hutchinson AW. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 1993;330:156–60[Web of Science][Medline]
6. Beiche F, Scheuerer S, Brune K, Geisslinger G, Goppelt-Struebe M. Up-regulation of cyclooxygenase-2 mRNA in the rat spinal cord following peripheral inflammation. FEBS Lett 1996;390:165–9[Web of Science][Medline]
7. Willingale HL, Gardiner NJ, McLymont N, Giblett S, Grubb BD. Prostanoids synthesized by cyclo-oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability. Br J Pharmacol 1997;122:1593–604[Web of Science][Medline]
8. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998;38:97–120[Web of Science][Medline]
9. Ebersberger A, Grubb BD, Willingale HL, Gardiner NJ, Nebe J, Schaible HG. The intraspinal release of prostaglandin E2 in a model of acute arthritis is accompanied by an up-regulation of cyclo-oxygenase-2 in the spinal cord. Neuroscience 1999;93:775–81[Web of Science][Medline]
10. Evans AR, Junger H, Southall MD, Nicol GD, Sorkin LS, Broome JT, Bailey TW, Vasko MR. Isoprostanes, novel eicosanoids that produce nociception and sensitize rat sensory neurons. J Pharmacol Exp Ther 2000;293:912–20[Abstract/Free Full Text]
11. Minami T, Uda R, Horiguchi S, Ito S, Hyodo M, Hayaishi O. Allodynia evoked by intrathecal administration of prostaglandin E2 to conscious mice. Pain 1994;57:217–23[Web of Science][Medline]
12. Bley KR, Hunter JC, Eglen RM, Smith JA. The role of IP prostanoid receptors in inflammatory pain. Trends Pharmacol Sci 1998;19:141–7[Medline]
13. Matsumura K, Watanabe Y, Onoe H, Watanabe Y. Prostacyclin receptor in the brain and central terminals of the primary sensory neurons: an autoradiographic study using a stable prostacyclin analogue [3H] iloprost. Neuroscience 1995;65:493–503[Web of Science][Medline]
14. McCrory C, Fitzgerald D. Spinal prostaglandin formation and pain perception following thoracotomy: a role for cyclooxygenase 2. Chest 2004;125:1321–1327[Web of Science][Medline]
15. Wilsey BL, Fishman SM. Minor and short acting opioids. In: Benzon HT, Raja SN, Molloy RE, Liu SS, Fishman SM, eds. Essential of pain medicine and regional anesthesia. 2nd ed. New York: Churchill Livingston, 2005:106–12
16. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287–94[Free Full Text]
17. Patrignani P, Panara MR, Greco A, Fusco O, Natoli C, Iacobelli S, Cipollone F, Ganci A, Creminon C, Maclouf J, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 1994;271:1705–12[Abstract/Free Full Text]
18. Barrientos-Astigarraga RE, Vannuchi YB, Sucupira M, Moreno RA, Muscara MN, De Nucci G. Quantification of nimesulide in human plasma by high-performance liquid chromatography/tandem mass spectrometry. Application to bioequivalence studies. J Mass Spectrom 2001;36:1281–6[Web of Science][Medline]
19. Wu CL, Tella P, Staats PS, Vaslav R, Kazim DA, Wesselmann U, Raja SN. Analgesic effects of intravenous lidocaine and morphine on post amputation pain: a randomized double-blind, active placebo-controlled, crossover trial. Anesthesiology 2002;96:841–8[Web of Science][Medline]
20. Sinatra RS, Shen QJ, Halaszynski T, Luther MA, Shaheen Y. Preoperative rofecoxib oral suspension as an analgesic adjunct after lower abdominal surgery: the effects on effort-dependent pain and pulmonary function. Anesth Analg 2004;98:135–40[Abstract/Free Full Text]
21. Hay CH, Trevethick MA, Wheeldon A, Bowers JS, de Belleroche JS. The potential role of spinal cord cyclooxygenase-2 in the development of Freund’s complete adjuvant-induced changes in hyperalgesia and allodynia. Neuroscience 1997;78:843–50[Web of Science][Medline]
22. Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001;410:471–5[Medline]
23. Ghilardi JR, Svensson CI, Rogers SD, Yaksh TL, Mantyh PW. Constitutive spinal cyclooxygenase-2 participates in the initiation of tissue injury-induced hyperalgesia. J Neurosci 2004;24:2727–32[Abstract/Free Full Text]
24. Kroin JS, Ling ZD, Buvanendran A, Tuman KJ. Upregulation of spinal cyclooxygenase-2 in rats after surgical incision. Anesthesiology 2004;100:364–9[Web of Science][Medline]
25. Alotti N, Bodo E, Gombocz K, Gabor V, Rashed A. Management of postoperative inflammatory response and pain with nimesulide after cardiac surgery. Orv Hetil 2003;144:2353–7[Medline]
26. Ochroch EA, Gottschalk A. Impact of acute pain and its management for thoracic surgical patients. Thorac Surg Clin 2005;15:105–21[Medline]
27. Dahmani S, Dupont H, Mantz J, Desmonts JM, Keita H. Predictive factors of early morphine requirements in the post-anesthesia care unit (PACU). Br J Anaesth 2001;87:385–9[Abstract/Free Full Text]
28. Dembo G, Park SB, Kharasch ED. Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans. Anesthesiology 2005;102:409–15[Web of Science][Medline]
29. Buvanendran A, Kroin JS, Tuman KJ, Lubenow TR, Elmofty D, Luk P. Cerebrospinal fluid and plasma pharmacokinetics of the cyclooxygenase 2 inhibitor rofecoxib in humans: single and multiple oral drug administration. Anesth Analg 2005;100:1320–4[Abstract/Free Full Text]
30. Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik Jelton TS, Simmons DL. Cox 3 a cycloxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyreticdrugs: cloning, structure, and expression. Proc Natl Acad Sci USA 2002;99:13926–31[Abstract/Free Full Text]
31. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA 1999;96: 7563–8. Erratum in: Proc Natl Acad Sci USA 1999;96:9666

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