Parecoxib sodium has opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anaesthesia

R. C. Hubbard*,1, T. M. Naumann2, L. Traylor1 and S. Dhadda1

1 Pharmacia, 5200 Old Orchard Road, Skokie, IL 60077, USA. 2 Hessing’sche Orthopedic Clinic, Hessingstr, Augsburg, Germany

Corresponding author. E-mail: richard.c.hubbard@pharmacia.com
{dagger}Declaration of interest. The study was sponsored by Pharmacia Corporation and parecoxib sodium was provided by Pharmacia Corporation.

Accepted for publication: October 2, 2002


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. This multicentre, double-blind, placebo-controlled study compared the opioid-sparing effectiveness and clinical safety of parecoxib sodium over 48 h, in 195 postoperative patients after routine total knee replacement surgery.

Methods. Elective total primary knee arthroplasty was performed under spinal anaesthesia, with a single dose of spinal bupivacaine 10–20 mg, and intraoperative sedation with midazolam 0.5–1.0 mg i.v., or propofol <6 mg kg–1 h–1. Patients were randomized to receive either parecoxib sodium 20 mg twice daily (bd) i.v. (n=65), parecoxib sodium 40 mg bd i.v. (n=67), or placebo (n=63) at the completion of surgery, and after 12, 24, and 36 h. Morphine (1–2 mg) was taken by patient-controlled analgesia or by bolus doses after 30 min.

Results. Patients receiving parecoxib sodium 20 mg bd and 40 mg bd consumed 15.6% and 27.8% less morphine at 24 h than patients taking placebo (both P<0.05). Both doses of parecoxib sodium administered with morphine provided significantly greater pain relief than morphine alone from 6 h (P<0.05). A global evaluation of study medication demonstrated a greater level of satisfaction among patients taking parecoxib sodium than those taking placebo. Parecoxib sodium administered in combination with morphine was well tolerated. However, a reduction in opioid-type side-effects was not demonstrated in the parecoxib sodium groups.

Conclusion. Parecoxib sodium provides opioid-sparing analgesic effects in postoperative patients.

Br J Anaesth 2003; 90: 166–72

Keywords: analgesics, opioid; enzymes, cyclo-oxygenase-2, inhibition; pain, postoperative


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Postsurgical pain has commonly been managed with opioid analgesics alone. Although effective, opioids (e.g. morphine) are associated with adverse effects such as respiratory depression, sedation, nausea, vomiting, constipation, and intestinal ileus.14 The availability of an effective, but safer analgesic, that would be co-administered and reduce the amount of opioids used, would therefore be an advantage. Conventional non-steroidal anti-inflammatory drugs (NSAIDs) such as ketorolac have been shown to produce opioid-sparing effects when administered to postoperative surgical patients.5 6 However, these agents are associated with reduced platelet function, leading to prolonged bleeding time, and gastric ulceration.710 The clinical utility of conventional NSAIDs has, therefore, been considered to be limited in the postoperative setting.

Cyclo-oxygenase-2 (COX-2) selective inhibitors, which only inhibit COX-2 and not COX-1 at therapeutic doses, have been developed. Several studies have shown that they provide efficacy similar to conventional NSAIDs, but with improved safety and tolerability.1114 However, until now, COX-2 selective inhibitors have only been available as oral formulations, which many patients may be unable to take, especially in the perioperative period. Parecoxib sodium is the first parenteral form of a COX-2 selective inhibitor developed for acute pain. It is an amide pro-drug that is rapidly hydrolysed in vivo to the active form, valdecoxib, a COX-2 selective inhibitor with a COX-2:COX-1 selectivity ratio of approximately 28 000:1. Clinical studies have demonstrated that parecoxib sodium is effective in several models of postoperative pain.1517 In additional studies, parecoxib sodium has been shown to have no effect on platelet function or gastric mucosa at doses up to 40 mg twice daily (bd).1820

The present study was designed to compare the opioid-sparing effectiveness and clinical safety of parecoxib sodium 20 mg bd i.v. and 40 mg bd i.v. over a 48-h period in postoperative patients after total knee replacement, a surgical model known to cause severe pain.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This was a multicentre, randomized, double-blind, placebo-controlled, multiple-dose study conducted at 10 sites in Belgium, France, Germany, and Sweden. Enrolment ranged from 13 to 33 patients per participating investigator, and was conducted between December 1999 and August 2000. The protocol and amendments were reviewed by the appropriate independent ethics committees, and the study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki.

Patients
Patients aged >=18 yr, who had undergone routine total primary replacement of one knee, performed under a standardized regimen of spinal anaesthesia, were included in the study. All patients received a single dose of spinal bupivacaine 10–20 mg, and intraoperative sedation with midazolam 0.5–1.0 mg i.v., or propofol <6 mg kg–1 h–1. Eligible patients were in satisfactory health, as determined by medical history and physical examination. Women were eligible for the study only if they were not lactating and verified as not being pregnant.

Patients were excluded from the study if they had undergone a revision to a previous knee replacement, emergency knee replacement, or knee replacement as a result of a trauma. Patients with asthma or bronchospasm, requiring treatment with glucocorticoids, were excluded, as were those with inflammatory bowel disease, a chronic or acute renal or hepatic disorder, or a significant coagulation defect. Patients were not considered eligible if they had upper gastrointestinal ulceration or bleeding up to 60 days before receiving study medication. In addition, patients were excluded if they had used long-acting NSAIDs in the 4 days before the first dose of study medication, or if they had taken antidepressants, narcotic analgesics, antihistamines, anxiolytics, hypnotics, sedatives, NSAIDs, or corticosteroids up to 24 h before receipt of the study medication (except routine preoperative medication).

Study design
During the pretreatment period, defined as 14 days before the administration of study medication, written informed consent and medical history were obtained, and patients underwent physical examination, and testing of vital signs and clinical laboratory values. Elective total primary knee arthroplasty was performed under spinal anaesthesia. Duration of analgesia was defined as the time from initiation of spinal analgesia until the first toe movements after operation. Patients were eligible for enrolment at the end of surgery.

Patients were randomized, according to a computer-generated randomization schedule, to receive either parecoxib sodium 20 mg bd i.v., parecoxib sodium 40 mg bd i.v., or placebo i.v. at the completion of surgery, and at 12, 24, and 36 h after the administration of the first dose of study medication. Morphine doses (1–2 mg) could be taken by patient-controlled analgesia (PCA) or by bolus, and were permitted at any time from 30 min after the end of surgery. Patients remained at the study site until after the final assessment at 48 h. Those requiring further analgesia at any time point in addition to morphine and the study medication were withdrawn from the study after completing pain assessments and a global evaluation of the study medication.

Patients’ assessments
Patients assessed their pain intensity as ‘none’, ‘mild’, ‘moderate’ or ‘severe’ at 2, 4, 6, 9, 12, 18, 24, 36 and 48 h after administration of the first dose of study medication. If patients were asleep during the scheduled time for pain assessment, they were not awakened, except at the 12-, 24-, and 36-h assessments, which were performed immediately before the receipt of study medication. Ambulation was restricted for 15 min before each pain assessment.

Patients also provided a global evaluation of study medication at 24 h (before the administration of the third dose of study medication), and at 48 h after the administration of the first dose of study medication, using a four-point scale (1=poor, 2=fair, 3=good, 4=excellent).

Efficacy and safety endpoints
Efficacy measures included the cumulative amount of morphine consumed at 2, 4, 6, 9, 12, 18, 24, 36, and 48 h, and the amount of morphine consumed in the periods 0–2, 2–4, 4–6, 6–9, 9–12, 12–18, 18–24, 24–36 and 36–48 h after the first dose of study medication. Other efficacy measures were the proportion of patients requiring morphine between the time points; time to the first dose of morphine; time to the last dose of morphine; and patients’ global evaluation of the study medication.

Safety was assessed for the 48 h after the first dose of study medication by the incidence of treatment-emergent adverse events, results from physical examinations, and changes from baseline in vital signs and clinical laboratory values (biochemistry, haematology and urinalysis).

Statistical analyses
The sample size calculation was based on the amount of morphine expected to be consumed within 24 h, and determined that 60 patients per group would be sufficient to detect a difference of >=20% decrease in the total amount of morphine used over the 24-h postoperative dose period between parecoxib sodium 20 mg bd, parecoxib sodium 40 mg bd, and placebo groups.21

All efficacy analyses were performed on the modified intent-to-treat (ITT) cohort. This included all patients who were randomized, received at least one dose of study medication, underwent a surgical procedure of no more than 4 h duration, did not require additional analgesic medication within the first 30 min, and were connected to PCA within 140 min of surgery.

The cumulative amount of morphine administered at each time point, and the amount of morphine consumed during each fixed time interval, was analysed using analysis of variance (ANOVA), with treatment and centre as factors. The median time to the first and last dose of morphine was calculated using the Kaplan–Meier product limit estimator with Miller’s adjustment. For patients who withdrew from the study before 48 h, the time to the last dose of morphine was considered censored at the time of withdrawal.22 Ninety-five per cent confidence intervals for the median time to the last dose of morphine were calculated using the Simon and Lee method.23 Overall and pair-wise log-rank tests were used to determine the statistical significance of the treatment group differences in the distribution of time to the first dose of morphine and to the last dose of morphine. The proportion of patients requiring morphine during each time period, and patients’ global evaluation were analysed using the Cochran–Mantel–Haenszel test, adjusted by centre. Effect of sex on morphine consumption was analysed using Fisher’s exact test.

Time-specific pain intensity (categorical) was analysed using ANOVA. Linear interpolation was used to estimate one to two missing values, and the last-observation-carried-forward method was used if there were three or more consecutive missing values, or if there were no evaluations after a certain time point.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
A total of 195 patients were randomized to placebo (n=63), parecoxib sodium 20 mg bd (n=65), or parecoxib sodium 40 mg bd (n=67). The physical characteristics of the treatment groups were comparable; most patients were female (68–78%) and Caucasian (97–100%). In addition, there were no differences between treatment groups in the type of surgical procedure (surgery on right or left knee), duration of surgery, or duration of anaesthesia (Table 1).


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Table 1 Patient characteristics. Data are actual values, or mean (range or %)
 
A total of 19 (10%) patients were withdrawn from the study (Table 2), thus 176 (90%) patients completed it. The analyses of efficacy measures were performed on the ITT cohort, which included all patients who were randomized, received at least the first dose of study medication, whose operative time was <4 h, did not require analgesia within 30 min of the end of surgery, and whose PCA was instituted within 140 min of wound closure. The ITT cohort included 189 patients: 63 patients in the placebo group; 61 patients in the parecoxib sodium 20 mg bd group; and 65 patients in the parecoxib sodium 40 mg bd group.


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Table 2 Patient numbers during the study
 
Morphine use
Analysis of the modified ITT cohort demonstrated that patients receiving parecoxib sodium 20 mg bd or 40 mg bd consumed significantly less morphine at 24 h than patients taking placebo (both P<0.05; Fig. 1). Mean cumulative amounts of morphine consumed over 24 h were 43.5 mg in the placebo group, and 36.7 mg and 31.4 mg in the parecoxib sodium 20 mg bd and 40 mg bd groups, respectively.



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Fig 1 Amount of PCA morphine (mg) consumed within 24 h of surgery in the parecoxib sodium and placebo groups. *P<0.05, significant difference between parecoxib sodium groups and placebo.

 
Patients in the parecoxib sodium groups consumed less morphine than patients in the placebo group throughout the study. The reductions in morphine consumption with parecoxib sodium compared with placebo were significant during the 6–9 and 18–24 h time intervals for the 20 mg bd dose, and during the 4–6, 6–9 and 18–24 h time intervals for the 40 mg bd dose (Fig. 2). At each time point after surgery, both doses of parecoxib sodium reduced the cumulative morphine consumption compared with placebo (Fig. 3). These reductions were significant for patients taking parecoxib sodium 40 mg bd at every time point from 6 h (P<0.004). In patients taking parecoxib sodium 20 mg bd, significant reductions in morphine consumption compared with placebo were obtained at 9 and 24 h.



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Fig 2 Mean PCA morphine consumed during fixed time intervals after surgery in patients taking parecoxib sodium 20 mg bd i.v., parecoxib sodium 40 mg bd i.v. and placebo. *P<0.05, significant difference in morphine consumption between parecoxib sodium groups and placebo.

 


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Fig 3 The cumulative amount of mean PCA morphine consumed over 48 h after surgery in patients taking parecoxib sodium 20 mg bd i.v., parecoxib sodium 40 mg bd i.v., and placebo. Patients in the parecoxib sodium groups consumed less morphine than patients in the placebo group throughout the study. The differences were significant (*P<0.004) at every time point from 6 h for parecoxib sodium 40 mg bd i.v., and at 9 and 24 h for parecoxib sodium 20 mg bd i.v.

 
In each time period, the proportion of patients requiring morphine was lower in the parecoxib sodium groups than in the placebo group (except the parecoxib sodium 40 mg bd group at 2–4 h). At 9–12 h, the parecoxib sodium 40 mg bd group had a significantly (P<0.011) lower percentage of patients requiring morphine than the placebo group. The three treatment groups were comparable with respect to both median time to the first dose of morphine (range 1.53–2.02 h) and median time to the last dose of morphine (range 44.02–46.30). The use of morphine was not affected by the patient’s sex (P=0.19).

Pain intensity
Parecoxib sodium administered with morphine provided greater pain relief than morphine alone at every time point after surgery compared with placebo. The reductions in pain intensity with both doses of parecoxib sodium were statistically significantly different compared with placebo at 6 h, 24 h, and 36 h (P<0.05; Fig. 4). There were no significant differences in pain intensity between the two parecoxib sodium treatment groups at any time point.



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Fig 4 Mean pain intensity scores over the 48 h after surgery in patients using PCA morphine with either parecoxib sodium 20 mg bd i.v., parecoxib sodium 40 mg bd i.v. or placebo. Pain intensity was scored as none (0), mild (1), moderate (2), or severe (3). *P<0.05, significantly different from placebo.

 
Patients’ global evaluation of study medication
The patients’ global evaluation of study medication showed that patients treated with parecoxib sodium had greater patient satisfaction scores than those taking placebo treatment. At 24 h after the first dose of study medication, both doses of parecoxib sodium were associated with significantly better scores than placebo (P<0.018). The percentage of patients who rated their study medication as ‘good’ or ‘excellent’ was 71% and 79% in the parecoxib sodium 20 mg bd and 40 mg bd groups, compared with 53% in the placebo group (Fig. 5). At 48 h, parecoxib sodium 40 mg bd was associated with statistically significantly better scores than placebo (P=0.004). A total of 92% of patients rated their study medication as ‘good’ or ‘excellent’, compared with 70% in the placebo group. After 48 h of treatment, parecoxib sodium 20 mg bd i.v. had numerically, but not statistically significantly, better scores than placebo (P=0.083). A total of 84% of parecoxib sodium 20 mg bd-treated patients rated their study medication as ‘good’ or ‘excellent’.



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Fig 5 Global evaluation of study medication at 24 h in patients taking PCA morphine and either parecoxib sodium 20 mg bd i.v., parecoxib sodium 40 mg bd i.v., or placebo. Both doses of parecoxib sodium were associated with better scores than placebo; these differences were significant for parecoxib sodium 40 mg bd i.v. (P=0.004).

 
Safety
All 195 patients were included in the analysis of safety. The overall incidence of adverse events among the three treatment groups was similar. Adverse events were reported for 68.3% (43/63) of patients in the placebo group, 66.2% (43/65) of patients in the parecoxib sodium 20 mg bd group, and 70.1% (47/67) of patients in the parecoxib sodium 40 mg bd group. Patients receiving parecoxib sodium 40 mg bd experienced significantly less fever than placebo patients (1.5% vs 19.0%; P<0.001; Table 3). The incidence of opioid-type side-effects (nausea, vomiting, constipation, intestinal ileus, central nervous system effects) was similar. The use of antiemetic medication was not different between groups. Most (>85%) of the adverse events in each group were mild to moderate in severity. Adverse events experienced by >5% of patients in any treatment group are summarized in Table 3.


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Table 3 Number (%) of adverse events experienced by >5% of patients in any treatment group. *P<0.001 vs placebo
 
Only one patient in each parecoxib sodium group discontinued treatment as a result of adverse events: pruritus and rash in one patient taking parecoxib sodium 20 mg bd; and vomiting in one patient taking parecoxib sodium 40 mg bd. In the placebo group, three patients discontinued treatment because of adverse events: they were nausea and vomiting; nausea and hypertension; and nausea. One placebo-treated patient died during the study from an acute pulmonary embolism.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This study shows that parecoxib sodium 20 mg and 40 mg bd i.v. produces significant opioid-sparing effects compared with placebo in postoperative patients after knee replacement surgery. Mean morphine consumption over 24 h was reduced by 15.6% and 27.8% in the parecoxib sodium 20 mg bd and 40 mg bd groups, respectively. At each time point over the 48-h postoperative period, both doses of parecoxib sodium reduced morphine consumption in a dose-dependent manner compared with placebo. The combination of better pain control and tolerability in the presence of parecoxib sodium affected the patients’ global evaluation of the study medication as, at 24 and 48 h, there was a greater level of satisfaction among patients taking parecoxib sodium than those taking placebo.

The use of analgesic combination therapy to achieve reductions in opioid use and improved pain control, as recommended by The Royal College of Anaesthetists and others, is supported in this study.2426 Patients in the parecoxib sodium treatment groups not only required less morphine, but experienced greater pain relief than patients receiving morphine alone at every time point after surgery compared with placebo. These results demonstrate one advantage of multi-model therapy, that patients experience less pain even though they require less narcotic.

Parecoxib sodium is a COX-2 selective inhibitor, which reduces the number of adverse events associated with non-selective COX-1 inhibition. These include upper gastrointestinal ulceration and bleeding, renal dysfunction, and bleeding related to platelet inhibition. In this study, parecoxib sodium 20 mg bd i.v. and 40 mg bd i.v. were safe and well tolerated, as most of the adverse events in each group were mild to moderate in intensity. There were no clinically important adverse gastrointestinal, platelet- related, or renal side-effects observed in this trial, although the numbers studied were relatively small.

A reduction in opioid-type side-effects was not demonstrated in this study, however. Some postoperative side-effects, such as nausea and vomiting, which had a higher incidence in patients taking parecoxib sodium 40 mg bd than in patients taking parecoxib sodium 20 mg bd or placebo, are affected by multiple factors in the surgical environment. For example, the type of surgery, the anaesthetic and associated medication, and the pain itself.27 It may not be a reasonable expectation that the occurrence of such multifactorial events in the immediate postoperative period would be modified by postoperative administration of parecoxib sodium. There are several other potential explanations for the absence of any reduction in opioid-type side-effects. First, opioid symptoms and physiological effects were not prospectively identified for specific measurement in this trial. The use of specific data collection instruments (such as the Opiate Symptom Distress Questionnaire; On file, Pharmacia), physical examination (such as listening for bowel sounds), or physiological monitoring (oxygen saturation) are methods that may be able to evaluate more clearly the effects of opioid reduction. Second, the degree of reduction in opioid use may not have been sufficient to result in clinically meaningful reductions in their side-effects, or the trial may have been too small to identify differences between treatment groups. A trial of this size may also be underpowered to identify reductions in uncommon symptoms, such as respiratory depression. A review of published opioid-sparing trials with ketorolac demonstrates that opioid-sparing effects are variable and not always significantly demonstrated.2834 The use of a patient population more susceptible to opioid side-effects than the carefully selected population in this clinical trial may be required. Consequently, additional clinical studies, using different clinical designs or different patient populations, will be helpful to define more fully any clinical benefit of the opioid-sparing effects of parecoxib sodium.

COX-2 selective inhibitors that provide opioid-sparing effects, without disrupting platelet function, are ideal in the management of postoperative patients. Although oral COX-2 selective inhibitors have demonstrated opioid-sparing effects when administered preoperatively to patients undergoing spinal fusion surgery,35 parecoxib sodium is the only injectable form of a COX-2 selective inhibitor in development. This is particularly important in the acutely painful postoperative setting because many surgical patients cannot tolerate oral medication or may have variable perioperative gastrointestinal absorptive function.

Parecoxib sodium has demonstrated analgesic efficacy in several postoperative pain models, and has shown a rapid onset of action and long duration.16 17 36 The results of the present study indicate that parecoxib sodium also provides a significant opioid-sparing effect when administered over a 48-h period in postoperative patients after total knee replacement, a surgical model known to cause severe pain.


    Acknowledgements
 
The authors would like to extend their thanks to the following investigators who participated in the trial: Dr Kai Bernsmann (St Josef Hospital, Bochum Germany), Dr Frederic Camu (Academisch Ziekenhuis, Brussels, Belgium), Dr Christian Conseiller (Hospital Cochin, Paris, France), Dr Erna Van Droogenbroeck (Aalsters Stededijke Ziekenhuis, Aalst, Belgium), Dr Kristine Fonck (Univ Ziekenhuis Gent, Gent, Belgium), Dr Rene Heylen (Sol Campus St Jan, Gent, Belgium), Dr Vincent L. Hoffman (Univ Ziekenhuis Antwerpen, Edegem, Belgium), Dr Klaus Ruhnau (Marien Hospital Buer gGmbH, Gelsenkirchen, Germany) and Dr Soren Toksvig-Larsen (Landskrona Hospital, Landskrona, Sweden).


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Bovill JG, Sebel PS, Stanley TH. Opioid analgesics in anesthesia: with special reference to their use in cardiovascular anesthesia. Anesthesiology 1984; 61: 731–55[ISI][Medline]

2 Guignard B, Bossard AE, Coste C. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000; 93: 409–17[CrossRef][ISI][Medline]

3 Holmes B, Ward A. Meptazinol. A review of its pharmaco dynamic and pharmacokinetic properties and therapeutic efficacy. Drugs 1985; 30: 285–312[ISI][Medline]

4 Lewis KS, Han NH. Tramadol: a new centrally acting analgesic. Am J Health Syst Pharm 1997; 54: 643–52[ISI][Medline]

5 Burns JW, Aitken HA, Bullingham RE, McArdle CS, Kenny GN. Double-blind comparison of the morphine sparing effect of continuous and intermittent i.m. administration of ketorolac. Br J Anaesth 1991; 67: 235–8[Abstract]

6 Gillies GW, Kenny GN, Bullingham RE, McArdle CS. The morphine sparing effect of ketorolac tromethamine. A study of a new, parenteral non-steroidal anti-inflammatory agent after abdominal surgery. Anaesthesia 1987; 42: 727–31[ISI][Medline]

7 Borda IT, Koff R, eds. NSAIDs: a Profile of Adverse Effects. Philadelphia: Hanley and Belfus Inc.; 1995

8 Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs—differences and similarities. N Engl J Med 1991; 324: 1716–25[ISI][Medline]

9 Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991; 115: 787–96[ISI][Medline]

10 Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994; 343: 769–72[ISI][Medline]

11 Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 1999; 74: 1095–105[ISI][Medline]

12 Geis GS. Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? J Rheumatol 1999; 26: 31–6[ISI][Medline]

13 Gierse JK, McDonald JJ, Hauser SD, Rangwala SH, Koboldt CM, Seibert K. A single amino acid difference between cyclo oxygenase-1 (COX-1) and -2 (COX-2) reverses the selectivity of COX-2 specific inhibitors. J Biol Chem 1996; 271: 15810–14[Abstract/Free Full Text]

14 Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999; 282: 1921–8[Abstract/Free Full Text]

15 Desjardins PJ, Grossman EH, Kuss ME, et al. The injectable cyclooxygenase-2-specific inhibitor parecoxib sodium has analgesic efficacy when administered preoperatively. Anesth Analg 2001; 93: 721–7[Abstract/Free Full Text]

16 Rasmussen L, Steckner K, Hogue C, Kuss ME, Torri S, Hubbard R. Intravenous parecoxib sodium for acute pain after postorthopedic knee surgery. Am J Orthop 2002; 31: 334–43

17 Barton SF, Langeland FF, Snabes MC, et al. Efficacy and safety of intravenous parecoxib sodium in relieving acute post-operative pain following gynecologic laparotomy surgery. Anesthesiology 2002; 97: 306–14[ISI][Medline]

18 Noveck RJ, Laurent A, Kuss ME, Talwalker S, Hubbard RC. The COX-2 specific inhibitor, parecoxib sodium, does not impair platelet function in healthy elderly and non-elderly individuals. Clin Drug Invest 2001; 21: 465–76[ISI]

19 Harris SI, Kuss M, Hubbard RC, Goldstein JL. Upper gastrointestinal safety evaluation of parecoxib sodium, a new parenteral cyclooxygenase-2-specific inhibitor compared with ketorolac, naproxen and placebo. Clin Ther 2001; 23: 1422–8[CrossRef][ISI][Medline]

20 Stoltz RR, Harris SI, Kuss ME, et al. Upper GI mucosal effects of parecoxib sodium in healthy elderly subjects. Am J Gastroenterol 2002; 97: 65–71[ISI][Medline]

21 Delbos A, Boccard E. The morphine-sparing effect of propacetamol in orthopedic postoperative pain. J Pain Symptom Manage 1995; 10: 279–86[CrossRef]

22 Miller RG. Survival Analysis. Somerset: John Wiley and Sons, 1998; 74–5

23 Simon R, Lee YJ. Nonparametric confidence limits for survival probabilities and median survival time. Cancer Treat Rep 1982; 66: 37–42

24 Acute Pain Management Guidelines Panel. Acute Pain Management: Operative or Medical Procedures and Trauma. Clinical Practice Guidelines. AHCPR 02-0032. Rockville: Agency for Health Care Policy Research, Public Health Service, US Department of Health and Human Services, 1992

25 Guidelines for the Use of Non-steroidal Anti-inflammatory Drugs in the Perioperative Period. The Royal College of Anaesthetists, March 1998

26 Carr DB, Goudas LC. Acute pain. Lancet 1999; 353: 2051–8[CrossRef][ISI][Medline]

27 Moote C. Efficacy of nonsteroidal anti-inflammatory drugs in the management of postoperative pain. Drugs 1992; 44: 14–29

28 Fredman B, Olsfanger D, Flor P, Jedeikin R. Ketorolac does not decrease postoperative pain in elderly men after transvesical prostatectomy. Can J Anaesth 1996; 43: 438–41[ISI][Medline]

29 Vanlersberghe C, Lauwers MH, Camu F. Preoperative ketorolac administration has no preemptive analgesic effect for minor orthopaedic surgery. Acta Anaesthesiol Scand 1996; 40: 948–52[ISI][Medline]

30 Parker RK, Holtmann B, Smith I, White PF. Use of ketorolac after lower abdominal surgery. Effect on analgesic requirement and surgical outcome. Anesthesiology 1994; 80: 6–12[ISI][Medline]

31 Green CR, Pandit SK, Levy L, Kothary SP, Tait AR, Schork MA. Intraoperative ketorolac has an opioid-sparing effect in women after diagnostic laparoscopy but not after laparoscopic tubal ligation. Anesth Analg 1996; 82: 732–7[Abstract]

32 Blackburn A, Stevens JD, Wheatley RG, Madej TH, Hunter D. Balanced analgesia with intravenous ketorolac and patient-controlled morphine following lower abdominal surgery. J Clin Anesth 1995; 7: 103–8[CrossRef][ISI][Medline]

33 Reuben SS, Connelly NR, Lurie S, Klatt M, Gibson CS. Dose-response of ketorolac as an adjunct to patient-controlled analgesia morphine in patients after spinal fusion surgery. Anesth Analg 1998; 87: 98–102[Abstract]

34 Rogers JE, Fleming BG, Macintosh KC, Johnston B, Morgan-Hughes JO. Effect of timing of ketorolac administration on patient-controlled opioid use. Br J Anaesth 1995; 75: 15–8[Abstract/Free Full Text]

35 Reuben SS, Connelly NR. Postoperative analgesic effects of celecoxib or rofecoxib after spinal fusion surgery. Anesth Analg 2000; 91: 1221–5[Abstract/Free Full Text]

36 Daniels SE, Grossman EH, Kuss ME, Talwalker S, Hubbard RC. A double-blind, randomized comparison of intramuscularly and intravenously administered parecoxib sodium versus ketorolac and placebo in a post-oral surgery pain model. Clin Ther 2001; 23: 1018–31[CrossRef][ISI][Medline]