University Division of Anaesthesia, Critical Care and Pain Management and 1 Department of Obstetrics and Gynaecology, Leicester Royal Infirmary, Leicester LE1 5WW, UK
*Corresponding author. E-mail: anae{at}le.ac.uk Presented in part to the Anaesthetic Research Society, Middlesborough meeting, 10th July 2003. The abstract for this meeting has been published in the British Journal of Anaesthesia.
Accepted for publication: February 1, 2004
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Method. We studied 36 ASA I/II patients who received a standardized general anaesthetic for laparoscopic sterilization. Patients were allocated randomly to receive either parecoxib 40 mg i.v. or ketorolac 30 mg i.v., at induction. After surgery, patients were assessed on awakening and then at 1, 2, and 3 h. Abdominal pain at rest and on inspiration, in addition to nausea and sedation were assessed on a 100 mm visual analogue scale.
Results. Of 36 patients, one was excluded from analysis. In the remaining patients, pain scores at rest and on inspiration were significantly lower in patients given ketorolac compared with those given parecoxib. This difference was attributable to the higher pain scores on awakening and at 1 h postoperatively in the parecoxib group compared with the ketorolac group. Despite this initial difference, there was no significant difference between the two groups in the number of patients receiving rescue analgesia. The median (interquartile range) time to consumption of rescue cocodamol of 60 (4674) min in the parecoxib group was not significantly shorter than that of 100 (70130) min in the ketorolac group. The amount of cyclizine given, nausea and sedation did not differ significantly between the groups.
Conclusion. We found that parecoxib 40 mg i.v. given at induction of anaesthesia was less effective than or ketorolac 30 mg i.v., in the first hour after laparoscopic sterilization.
Br J Anaesth 2004; 92: 8469
Keywords: analgesics anti-inflammatory, cyclooxygenase-2 inhibitors; analgesics non-opioid, ketorolac; analgesics non-opioid, parecoxib
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Parecoxib is a specific inhibitor of cycloxygenase-2 enzymes (COX-2). It is a pro-drug metabolized by the liver to valdecoxib that is associated with analgesic effects. In comparison, ketorolac, an established non-selective NSAID is administered in the active form.
To provide effective postoperative pain relief for common short surgical procedures such as laparoscopic sterilization, the rapidity of onset of analgesia is a major consideration. There is a difference in pharmacokinetic profiles between parecoxib and ketorolac that may influence their effect on early postoperative pain, and it is possible that parecoxib may not be as effective as ketorolac after short surgical procedures. Thus, the aim of this study was to investigate if there was any difference in postoperative analgesia between parecoxib and ketorolac, after i.v. administration at induction of anaesthesia to patients having laparoscopic sterilization. We used patients pain scores on awakening as our primary outcome variable.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All patients were given a standardized general anaesthetic comprising propofol, 24 mg kg1 i.v., fentanyl 1.5 µg kg1 i.v., ondansetron 4 mg i.v. and a non-depolarizing neuromuscular blocking agent i.v.. Their lungs were ventilated with nitrous oxide and isoflurane in oxygen. Residual neuromuscular block was antagonized with a mixture of neostigmine and glycopyrrolate. After application of Filshie clips, 10 and 20 ml of levobupivacaine 2.5 mg ml1 were administered to incisional sites and into the peritoneal cavity, respectively.
Patients were allocated randomly to receive, either parecoxib 40 mg i.v. or ketorolac 30 mg i.v., at induction of anaesthesia. Both solutions were colourless in a volume of 2 ml, and were prepared by an anaesthetist who was not involved further in the study. The randomization procedure involved computer-generated random numbers and the use of opaque envelopes containing instructions on an A4 sheet of paper that was folded twice.
After surgery, patients were assessed on awakening, and after a further 1, 2 and 3 h by a member of staff blinded to the drug given. Abdominal pain at rest and on movement was assessed using a standard 100 mm visual analogue scale (VAS), in which 0 mm represented no pain and 100 mm the worst pain ever. Nausea and sedation were assessed similarly, from 0 mm for no nausea and fully awake, to 100 mm to worst ever nausea and very drowsy, respectively. Patients who were too drowsy to answer questions were marked at 100 mm for sedation and 0 for nausea.
Patients were advised that they could ask for rescue analgesia at any time after surgery. In addition, during the hourly postoperative assessments, patients were asked if they needed rescue analgesia, which comprised two tablets of cocodamol 30/500 (codeine phosphate 30 mg, acetaminophen 500 mg) for mild to moderate pain, and morphine 10 mg i.m. for severe pain.
From a study in which patients received ketorolac 30 mg for laparoscopic sterilization, we estimated that to have an 80% chance of detecting a 25 mm reduction in the first pain score, it was necessary to study 17 patients per group.4 A 25 mm reduction in pain score on a 100 mm VAS was considered to be an important clinical difference between the two drugs because the VAS appears to have a precision of ±20 mm after general anaesthesia.5 In the postoperative period, it was shown by BlandAltman repeatability plots that the repeatability coefficients over three assessment periods were 13.523.0 mm.5
Data were processed in Excel 2000, Prism 2.0 and SPSS 11.0. The KolmogorovSmirnov test was used to test for normality, and the Students t test, 2 test, MannWhitney U-test and multivariate analysis of variance for repeated measures were used to test for significance. In addition, the KaplanMeier survival analysis was used to obtain the time to first analgesia; the log rank test was used to test for its significance.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This difference in analgesic effect may be explained, in part, by the difference in doses of parenteral ketorolac and parecoxib. The initial recommended dose of i.v. parecoxib is 40 mg, followed by 2040 mg 612 hourly..6 The initial recommended i.v. dose of ketorolac is 10 mg, followed by 1030 mg, 46 hourly. Thus, the higher initial dose of ketorolac used in our study would be expected to be associated with more rapid onset of analgesia.
In addition, our results are consistent with our knowledge of the pharmacokinetics of both drugs. Parecoxib is a prodrug, which is converted in the liver to the active moiety, valdecoxib. After parecoxib 50 mg i.v., the Cmax of valdecoxib of 1.02 mg litre1 is achieved after 0.6 h.7 On the other hand, ketorolac is administered in its active form and would be available for immediate COX inhibition and hence regulation of prostaglandin synthesis. Thus, after a short procedure, patients receiving parecoxib would be expected to have a delayed onset of analgesia with concomitant higher pain intensity scores compared with patients given ketorolac.
However, our study differs from a randomized controlled trial of patients having gynaecological laparotomy in which similar doses of parecoxib and ketorolac were administered.8 Patients were given rescue analgesia when their pain intensity scores were at least 45 mm (on a VAS of 0100 mm) or when their categorical pain intensity was moderate or severe within 6 h after discontinuation of patient controlled analgesia. It was found that the median (95% CI) time to onset of rescue analgesia of 14(928) min after parecoxib 40 mg i.v. and of 10(914) min after ketorolac 30 mg i.v. did not differ significantly. In addition, pain relief, pain intensity difference, and time to rescue analgesia did not differ significantly between the two groups. These results are in agreement with another study in which various doses of parecoxib i.v. were compared with ketorolac 60 mg i.v. for pain after oral surgery.9 In that study, there was no difference in time to onset of analgesia between parecoxib and ketorolac groups.
The delayed onset of analgesia of parecoxib in our study may have occurred as a result of a reduction in liver blood flow that occurs during general anaesthesia. Our patients were anaesthetized and there may have been a concomitant reduction in rate of conversion of parecoxib to valdecoxib.10 In contrast, in the trials by Barton8 and Daniels,9 all patients were studied in the postoperative period when the rate of liver blood flow and conversion of parecoxib to valdecoxib were likely to be normal.
In summary, we found that initial abdominal pain scores were significantly higher in the parecoxib group compared with those in the ketorolac group, after laparoscopic sterilization. Ketorolac 30 mg appeared to be associated with a more rapid onset of analgesia compared with parecoxib 40 mg.
![]() |
Acknowledgement |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Ng A, Smith G, Davidson AC. Analgesic effects of parecoxib following total abdominal hysterectomy. Br J Anaesth 2003; 90: 7469
3 Pavy TJ, Paech MJ, Evans SF. The effect of intravenous ketorolac on opioid requirement and pain after cesarean delivery. Anesth Analg 2001; 92: 10104
4 Cade L, Kakulas P. Ketorolac or pethidine for analgesia after elective laparoscopic sterilisation. Anaesth Intens Care 1995; 23: 15861[ISI][Medline]
5 DeLoach LJ, Higgins MS, Caplan AB, Stiff JL. The visual analogue scale in the immediate postoperative period: intrasubject variability and correlation with a numeric scale. Anesth Analg 1998; 86: 1026[Abstract]
6 British Medical Association, Royal Pharmaceutical Society of Great Britain. Sedative and Analgesic Peri-operative Drugs. In British National Formulary 44. Suffolk: William Clowes, 2002; 615
7 Cheer SM, Goa KL. Parecoxib (Parecoxib Sodium). Drugs 2001; 61: 113341[ISI][Medline]
8 Barton SF, Langeland FF, Snabes M, LeComte DBS, Kuss ME, Dhadda SS, Hubbard RC. Efficacy and safety of intravenous parecoxib sodium in relieving acute postoperative pain following gynecologic laparotomy surgery. Anesthesiology 2002; 97: 30614[ISI][Medline]
9 Daniels SE, Grossman EH, Kuss ME, Talwalker S, Hubbard RC. A double blind, randomised 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]
10 Ogilvy AJ. The liver. In: Aitkenhead AR, Rowbotham DJ, Smith G, eds. Textbook of Anaesthesia. London: Churchill Livingstone, 2001; 25169