1 Pharmacia, 5200 Old Orchard Road, Skokie, IL 60077, USA. 2 Hessingsche Orthopedic Clinic, Hessingstr, Augsburg, Germany
Corresponding author. E-mail: richard.c.hubbard@pharmacia.com Declaration of interest. The study was sponsored by Pharmacia Corporation and parecoxib sodium was provided by Pharmacia Corporation.
Accepted for publication: October 2, 2002
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Abstract |
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Methods. Elective total primary knee arthroplasty was performed under spinal anaesthesia, with a single dose of spinal bupivacaine 1020 mg, and intraoperative sedation with midazolam 0.51.0 mg i.v., or propofol <6 mg kg1 h1. 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 (12 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: 16672
Keywords: analgesics, opioid; enzymes, cyclo-oxygenase-2, inhibition; pain, postoperative
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Introduction |
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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.
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Methods |
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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 1020 mg, and intraoperative sedation with midazolam 0.51.0 mg i.v., or propofol <6 mg kg1 h1. 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 (12 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 02, 24, 46, 69, 912, 1218, 1824, 2436 and 3648 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 KaplanMeier product limit estimator with Millers 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 CochranMantelHaenszel test, adjusted by centre. Effect of sex on morphine consumption was analysed using Fishers 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.
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Results |
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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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Discussion |
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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.
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Acknowledgements |
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References |
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2 Guignard B, Bossard AE, Coste C. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000; 93: 40917[CrossRef][ISI][Medline]
3 Holmes B, Ward A. Meptazinol. A review of its pharmaco dynamic and pharmacokinetic properties and therapeutic efficacy. Drugs 1985; 30: 285312[ISI][Medline]
4 Lewis KS, Han NH. Tramadol: a new centrally acting analgesic. Am J Health Syst Pharm 1997; 54: 64352[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: 2358[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: 72731[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 drugsdifferences and similarities. N Engl J Med 1991; 324: 171625[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: 78796[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: 76972[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: 1095105[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: 316[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: 1581014
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: 19218
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: 7217
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: 33443
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: 30614[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: 46576[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: 14228[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: 6571[ISI][Medline]
21 Delbos A, Boccard E. The morphine-sparing effect of propacetamol in orthopedic postoperative pain. J Pain Symptom Manage 1995; 10: 27986[CrossRef]
22 Miller RG. Survival Analysis. Somerset: John Wiley and Sons, 1998; 745
23 Simon R, Lee YJ. Nonparametric confidence limits for survival probabilities and median survival time. Cancer Treat Rep 1982; 66: 3742
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: 20518[CrossRef][ISI][Medline]
27 Moote C. Efficacy of nonsteroidal anti-inflammatory drugs in the management of postoperative pain. Drugs 1992; 44: 1429
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: 43841[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: 94852[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: 612[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: 7327[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: 1038[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: 98102[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: 158
35 Reuben SS, Connelly NR. Postoperative analgesic effects of celecoxib or rofecoxib after spinal fusion surgery. Anesth Analg 2000; 91: 12215
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: 101831[CrossRef][ISI][Medline]