Early analgesic effects of parecoxib versus ketorolac following laparoscopic sterilization: a randomized controlled trial{dagger}

A. Ng*, A. Temple, G. Smith and J. Emembolu1

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
{dagger}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
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. The aim of this prospective double blind randomized controlled trial was to compare the effects of ketorolac and parecoxib on early postoperative pain.

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 (46–74) min in the parecoxib group was not significantly shorter than that of 100 (70–130) 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: 846–9

Keywords: analgesics anti-inflammatory, cyclooxygenase-2 inhibitors; analgesics non-opioid, ketorolac; analgesics non-opioid, parecoxib


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Laparoscopic sterilization is a minimally invasive gynaecological operation that is performed on a day case basis. Effective, non-sedating pain relief in the postoperative period is essential to minimize the risk of delayed recovery and discharge from hospital. The routine use of strong opioids is undesirable because of adverse effects such as nausea, vomiting and sedation. However, non-steroidal anti-inflammatory drugs (NSAIDs) are useful because of their lack of sedative properties and their opioid-sparing effects.13

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
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After obtaining local research Ethics Committee approval and informed patient consent, we studied 36 ASA I/II patients in a prospective double blind randomized controlled trial. Patients who were aged 20–50 yr and undergoing laparoscopic sterilization were invited to participate. Patients with a chronic pain syndrome or receiving regular analgesics were excluded.

All patients were given a standardized general anaesthetic comprising propofol, 2–4 mg kg–1 i.v., fentanyl 1.5 µg kg–1 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 ml–1 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 Bland–Altman repeatability plots that the repeatability coefficients over three assessment periods were 13.5–23.0 mm.5

Data were processed in Excel 2000, Prism 2.0 and SPSS 11.0. The Kolmogorov–Smirnov test was used to test for normality, and the Student’s t test, {chi}2 test, Mann–Whitney U-test and multivariate analysis of variance for repeated measures were used to test for significance. In addition, the Kaplan–Meier survival analysis was used to obtain the time to first analgesia; the log rank test was used to test for its significance.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Of 36 patients, one was excluded for a protocol violation. Of the remaining patients, the age, height, weight, ASA status, and duration of surgery were similar for the ketorolac and parecoxib groups (Table 1). However, the abdominal pain scores at rest and on inspiration (Table 2) were significantly higher in patients who received parecoxib compared with those who had received ketorolac.


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Table 1 Baseline characteristics, rescue analgesic, and antiemetic consumption. Age is expressed as mean (interquartile range). Duration of surgery and time to rescue cocodamol are expressed as median (interquartile range). Height and weight are expressed as mean (95% CI). ASA status, cocodamol, morphine, and antiemetic consumption are expressed as number of patients
 

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Table 2 Pain scores. Pain scores in mm are expressed as median (interquartile range). ANOVA for repeated measures for comparison of pain scores at 0, 1, 2, and 3 h. *P<0.05 for pairwise comparison. #P<0.05 for parecoxib vs ketorolac at time 0 h using Mann–Whitney U-test. {ddagger}P<0.01 for parecoxib vs ketorolac at time 0 h using Mann–Whitney U-test
 
Despite this initial difference, we found no significant difference in number of patients needing rescue analgesia and time to rescue analgesic consumption (Fig. 1). The majority of patients in each group required cocodamol for rescue analgesia and only one patient in the parecoxib group received morphine. There was no significant difference in rescue cocodamol or morphine consumption between the two groups (Table 1). In addition, there was no significant difference between the two treatment groups in rescue antiemetic consumption (Table 1), nausea, or sedation (Table 3).



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Fig 1 Time to rescue cocodamol postoperatively. Kaplan–Meier survival analysis. Log Rank test. No significant difference between two groups.

 

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Table 3 Adverse effects. Data expressed as median (interquartile range). No significant difference between ketorolac and parecoxib
 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
On awakening after laparoscopic sterilization, we found that parecoxib 40 mg i.v. was associated with significantly higher abdominal pain scores at rest and on inspiration, compared with ketorolac 30 mg i.v.. In addition, over the 3 h period, patients in the parecoxib group experienced significantly more pain than patients who received ketorolac; on inspiration, this difference was attributable to the significantly higher pain on scores on awakening and at 1 h postoperatively, in patients who received parecoxib. However, median (interquartile range) time to rescue cocodamol consumption of 60(46–74) min of the parecoxib group was not significantly shorter than that of 100(70–130) min of the ketorolac group. Furthermore, the proportion of patients requiring rescue cocodamol consumption was not significantly different between the two groups.

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 20–40 mg 6–12 hourly..6 The initial recommended i.v. dose of ketorolac is 10 mg, followed by 10–30 mg, 4–6 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 litre–1 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 0–100 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(9–28) min after parecoxib 40 mg i.v. and of 10(9–14) 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
 
We are grateful to Pharmacia for a grant for this study.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Ng A, Parker J, Toogood L, Cotton BR, Smith G. Does the opioid-sparing effect of rectal diclofenac following total abdominal hysterectomy benefit the patient? Br J Anaesth 2002; 88: 714–6[Abstract/Free Full Text]

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3 Pavy TJ, Paech MJ, Evans SF. The effect of intravenous ketorolac on opioid requirement and pain after cesarean delivery. Anesth Analg 2001; 92: 1010–4[Abstract/Free Full Text]

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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: 102–6[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

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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: 306–14[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: 1018–31[CrossRef][ISI][Medline]

10 Ogilvy AJ. The liver. In: Aitkenhead AR, Rowbotham DJ, Smith G, eds. Textbook of Anaesthesia. London: Churchill Livingstone, 2001; 251–69