Analgesic effects of parecoxib following total abdominal hysterectomy{dagger}{ddagger}

A. Ng, G. Smith and A. C. Davidson1

University Department of Anaesthesia, Critical Care and Pain Management and 1 Department of Obstetrics and Gynaecology, Leicester Royal Infirmary, Leicester LE1 5WW, UK

{ddagger}Declaration of interest. The authors are grateful to Pharmacia for an educational grant for this trial.

Accepted for publication: February 27, 2003


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Forty-eight ASA I–II patients undergoing total abdominal hysterectomy (TAH) were studied in a double blind, randomized placebo controlled trial of parecoxib for postoperative analgesia.

Methods. All patients were given propofol 2–4 mg kg–1 i.v., a non-depolarizing muscle relaxant, morphine 10 mg i.v. and prochlorperazine 12.5 mg i.m. intraoperatively. Their lungs were ventilated with nitrous oxide and isoflurane 1–1.5% in oxygen. Morphine was self-administered for postoperative analgesia via a patient controlled analgesia (PCA) device. Patients were allocated randomly to receive either parecoxib 40 mg i.v. or normal saline on induction of anaesthesia.

Results. Twelve patients did not complete the study. Of the remaining 36 patients, there was no significant difference between the treatment groups in age, weight, ASA status, duration of surgery, or intraoperative dose of morphine. However, mean (95% CI) 24 h morphine consumption of 54 (42–65) mg in the parecoxib group was significantly (P=0.04) lower than that of 72 (58–86) mg in the placebo group. Pain intensity scores on sitting up were significantly lower (P=0.02) in the parecoxib group compared with placebo. There was no significant difference between the treatment groups in pain intensity scores at rest and on deep inspiration, or in nausea, total number of vomiting episodes, median number of rescue antiemetic doses, and sedation scores.

Conclusions. Parecoxib 40 mg i.v. may be recommended in patients having TAH as it provides morphine-sparing analgesia.

Br J Anaesth 2003; 90: 746–9

Keywords: analgesics anti-inflammatory, cyclooxygenase-2 inhibitors; analgesics non-opioid, parecoxib; analgesics opioid, morphine; vomiting, nausea, sedation


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Pain in the postoperative period is a critical factor that impedes recovery from surgery and anaesthesia.1 Total abdominal hysterectomy (TAH) is usually performed through a Pfannenstiel incision and patients experience considerable abdominal pain requiring administration of strong opioids during the first 24–48 h after surgery.

At our institution, the current management of postoperative pain following TAH involves the use of morphine administered by a patient controlled analgesia (PCA) device. The dose of morphine is high, particularly in the initial postoperative period.2 3 Administration of morphine is associated with adverse effects such as bowel immotility, and nausea and vomiting, in addition to sedation.1 Thus, other analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) are used to reduce the dose of morphine,4 and hence minimize postoperative morbidity. Currently available NSAIDs such as diclofenac and ketorolac,5 are non-selective inhibitors of both cyclo-oxygenase 1 (COX-1) and 2 (COX-2) enzymes. Parecoxib is the only currently available COX-2 selective inhibitor for i.v. administration and hence is suitable to use in the perioperative period.6

The primary aim of this study was to quantify the morphine-sparing effect of parecoxib. The secondary aim was to see if this analgesic effect leads to reductions in postoperative pain intensity, nausea, vomiting, consumption of rescue antiemetics, and sedation.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After obtaining local research Ethics Committee approval and informed patient consent, we studied 48 ASA I–II patients undergoing TAH via a Pfannenstiel incision. Patients with diagnosed malignancy or with chronic pain were excluded.

All patients were given a standardized general anaesthetic comprising i.v. propofol 2–4 mg kg–1, a non-depolarizing muscle relaxant i.v., morphine 10 mg i.v. and prochlorperazine 12.5 mg i.m.. Their lungs were ventilated with nitrous oxide, and isoflurane 1–1.5% in oxygen. At the end of surgery, residual neuromuscular block was antagonized with neostigmine 2.5 mg and glycopyrrolate 500 µg. For postoperative analgesia, patients received morphine by PCA delivering morphine 1 mg i.v. with a lockout time of 5 min. For escape analgesia, patients were given a bolus of morphine 5 mg i.v..

Patients were allocated randomly to receive either parecoxib 40 mg i.v. in 2 ml, or 2 ml of normal saline on induction of anaesthesia. Both solutions were colourless and were prepared from instructions enclosed in an opaque envelope, by an anaesthetist who was not involved further in the study. Using computer-generated random numbers, randomization of treatment was performed in blocks of six, so that additional patients could be recruited as necessary.

Hourly morphine consumption was recorded from the PCA device. In addition, pain assessments were made on awakening, and then at 1, 4, 8, 12, and 24 h, by a member of staff blinded to the treatment. Abdominal pain intensity at rest, on deep inspiration, and on sitting up was assessed using the visual analogue scale (VAS). Patients marked a point on the 100 mm horizontal line representing their pain ranging from ‘no pain’ on the left to ‘worst pain imaginable’ on the right.

Nausea and sedation were also assessed on VAS ranging from 0 mm for no nausea and fully awake to 100 mm for worst possible nausea and very drowsy, respectively. Patients who were too drowsy to assess themselves were scored at 100 mm for sedation and 0 mm for nausea. In addition, the number of instances of vomiting and number of doses of rescue antiemetic were recorded.

Previous work7 on patients having TAH has shown that mean 24 h morphine consumption would be expected to be 51 mg. From the data and a combined SD of 21 mg, we have estimated that to have an 80% chance of detecting a 35% or 18 mg reduction in 24 h morphine consumption in the parecoxib group compared with placebo, at a level of P<0.05, a population of 42 patients would be required. Data were analysed using Excel 2000 and SPSS 9.5. Data were assessed for normality using the Kolmogorov–Smironov test, and were analysed using the {chi}2 test, Student’s t-test, Mann–Whitney test, and analysis of variance for repeated measures. P<0.05 was considered statistically significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Of 48 patients, 12 did not complete the study for surgical and analgesic violations. Four patients had a midline incision after further examination under general anaesthesia, one patient had an abscess and so TAH was not performed, one patient had an abdominoplasty in addition to a TAH, and one patient had a subtotal abdominal hysterectomy. The PCA failed to work on the ward in one patient, the i.v. cannula tissued in another, and acetaminophen and meperidine were given to two and one patient, respectively.

Of the remaining 36 patients, there was no significant difference between the treatment groups in age, weight, ASA status, duration of anaesthesia (Table 1), and intraoperative dose of morphine (Table 2). However, mean (95% CI) 24 h morphine consumption of 54 (42–65) mg in the parecoxib group was significantly lower than that of 72 (58–86) mg in the placebo group (P=0.04) (Table 2). In addition, pain intensity scores on sitting up were significantly (P=0.02) lower in the parecoxib group than in the placebo group (P=0.02) (Table 3). There was no significant difference between the two groups in total number of vomiting episodes, number of rescue antiemetic doses (Table 2), pain intensity scores at rest and on deep inspiration, nausea, or sedation (Table 3).


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Table 1 Baseline characteristics. Age, weight and duration of anaesthesia are expressed as mean (95% CI)
 

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Table 2 Morphine consumption, episodes of vomiting and rescue antiemetic consumption. Data expressed as mean (95% CI). Unpaired, two-tailed t-test for analysis of morphine consumption. Mann–Whitney test for total vomiting and antiemetic consumption. Statistical significance when P<0.05
 

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Table 3 VAS (mm). Data expressed as mean (95% CI). ANOVA for repeated measures. Statistical significance when P<0.05
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In patients undergoing TAH, we found that parecoxib 40 mg i.v. was associated with significant reductions in 24 h morphine consumption and pain intensity on sitting up in comparison with placebo. However, there was no significant difference between the two groups in pain intensity at rest or on deep inspiration, nausea, number of vomiting episodes, rescue antiemetic consumption, or sedation. Of 48 patients studied, 12 had to be excluded for violations in protocol that were beyond our control. Despite this problem, we were able to show statistically significant results from 36 patients and thus it is unlikely that a type II error has occurred.

Our study is in agreement with another study of patients having TAH in which patients received two doses of parecoxib 40 mg i.v. in 24 h.7 Tang found a reduction in mean 24 h morphine consumption of 36% in the parecoxib group compared with the placebo group.7 This reduction was greater than that of 26% in our study, and is consistent with the lower dose (half maximum recommended daily dose) of parecoxib used in our study. However, in contrast to our study, there was no significant difference in pain scores between the two treatment groups in the study by Tang.7 It is unclear in the earlier study how pain was assessed, but it is likely that we were able to detect a difference in pain scores because our assessment of pain on sitting up was more sensitive than assessments made at rest or on deep inspiration.

Our results concur with another study of similar design, involving rectal diclofenac, a non-selective NSAID, administered to patients undergoing TAH.1 At its maximum recommended daily dose of 75 mg twice daily, diclofenac produced a 52% reduction in 24 h morphine consumption compared with placebo. Pain scores at rest and on movement, and sedation and nausea were also significantly reduced in the diclofenac compared with the placebo group. It is likely that the reduction in adverse effects was attributable to the large decrease in morphine consumption in the diclofenac group compared with placebo. The larger diminution in morphine consumption of 52% in the diclofenac study compared with 26% in our study may be attributable to the use of parecoxib at half its maximum recommended daily dose compared with diclofenac given in maximum recommended dosage.

COX enzymes are important physiologically for the formation of prostaglandins (PG). COX-1 is expressed constitutively in normal tissues as part of normal cellular function, whereas COX-2 is upregulated during inflammation. Traditional non-selective NSAIDs are associated with adverse effects that are related, in part, to COX-1 inhibition; these include gastrointestinal ulceration, renal failure, and bleeding.8 In the perioperative period, many patients are at risk of these problems owing to enforced starvation, dehydration, and tissue trauma. Whilst adverse effects are uncommon with non-selective COX inhibitors in healthy patients, their use in patients with peptic ulcer disease and renal impairment is contraindicated. A possible alternative in patients at risk of these problems is administration of COX-2 inhibitors.

The use of selective COX-2 inhibitors in comparison with non-selective NSAIDs has been investigated extensively in patients with arthritis. Two important randomized controlled trials, the CLASS9 and the VIGOR,10 have shown a significant reduction in upper gastrointestinal complications with celecoxib or rofecoxib compared with non-selective NSAIDs. This has been confirmed in a systematic review which showed that the relative risk (95% CI) of any upper gastrointestinal event with celecoxib compared with a non-selective NSAID was 0.54 (0.42–0.71) in patients treated for osteoarthritis or rheumatoid arthritis.11 In a recent placebo case controlled population based study, the adjusted risk ratios (95% CI) of gastrointestinal haemorrhage for non-selective NSAIDs, a combination of diclofenac and misoprostol, rofecoxib, and celecoxib were 4.0 (2.3–6.9), 4.6 (2.5–8.2), 3.5 (2.4–5.0), and 1.7 (1.1–2.6), respectively.12

In the VIGOR study, it was found that the rates of cardiovascular events and in particular myocardial infarction were significantly higher in patients having rofecoxib than in those having naproxen.10 The relative risk of myocardial infarction (95% CI) was 0.2 (0.1–0.7) in the naproxen group, suggesting a coronary protective effect presumably from sustained platelet inhibition. In an attempt to disprove the possibility of a higher cardiovascular event rate in patients taking rofecoxib, there has been an assessment of cardiovascular thrombotic events in 23 phase IIb to V rofecoxib studies.13 It was shown that the relative risk of an event between rofecoxib and placebo, between rofecoxib and non-naproxen NSAIDs, and between rofecoxib and naproxen was 0.84 (0.51–1.38), 0.79 (0.40–1.55), and 1.69 (1.07–2.69), respectively. Thus, it is possible to conclude that naproxen has no significant cardiovascular protective effect compared with rofecoxib. Also, it appears that rofecoxib may increase the risk of a cardiovascular event compared with naproxen. In a recent retrospective study, there was some evidence that any risk of a cardiovascular event with rofecoxib may be dose related.14 In comparison with non-users and celecoxib users, respectively, the relative risk (95% CI) of a serious cardiovascular event was 1.93 (1.09–3.43) and 2.20 (1.17–4.10) in patients taking rofecoxib in doses exceeding 25 mg. There was no increased risk of these events in patients receiving lower doses of rofecoxib, or in those receiving doses of celecoxib >300 mg, naproxen >=1000 mg or ibuprofen >=1800 mg.

The evidence for any sparing of renal function from selective COX-2 inhibitors compared with non-selective NSAIDs is sparse. The CLASS study did show that the incidence of increased serum creatinine concentration and hypertension was significantly lower in patients receiving celecoxib compared with those taking NSAIDs.9 However, these benefits were not detected in another RCT.15

The efficacy of celecoxib has been noted to be comparable with that of existing non-selective NSAIDs in a systematic review of patients with arthritic pain.11 For postoperative pain management, there is evidence that celecoxib and rofecoxib are effective after spinal fusion,16 and dental surgery.17 However, the disadvantage of celecoxib and rofecoxib in anaesthetic practice is that they are given orally, when patients may have PONV and delayed gastric emptying. Parecoxib may be administered intravenously or intramuscularly, and hence is more useful in this respect.

Despite the possible theoretical benefits of selective COX-2 inhibitors compared with non-selective NSAIDs, their role in postoperative pain management remains to be determined. They may be useful in patients at risk of gastroduodenal ulceration, or after procedures such as tonsillectomy when postoperative haemorrhage is an uncommon but significant problem. However, it seems unlikely that currently available selective COX-2 inhibitors will find a role in patients with renal dysfunction.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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