Non-steroidal anti-inflammatory drugs (NSAID) are frequently used for pain control after surgical procedures in order to reduce opioid administration and their adverse effects [1–5]. A newer class of NSAIDs, cyclooxygenase-2 (COX-2) specific inhibitors, is thought to be advantageous over the previous generations in terms of safety, since they have significantly less gastrotoxicity and no effects on platelet aggregation [6–10]. Several studies have documented their efficacy for the management of postoperative pain [2,11–14].
We performed a double-blinded, randomized, placebo-controlled trial to compare an NSAID of the oxicam class (lornoxicam) with a COX-2 inhibitor (parecoxib) for the management of pain after laparoscopic cholecystectomy. Lornoxicam is formulated for parenteral administration for the management of moderate postoperative pain. It has received approval from the National Organization for Medicines of Greece for the treatment of mild postoperative pain, and has been used routinely for pain management after laparoscopic cholecystectomy in our department since 1999. Parecoxib sodium is a parenterally administered amide, that has been studied for use as an adjunct, or alternative, to parenteral opioid analgesics in treating and preventing moderate to severe postoperative pain. The primary interest of our trial was to study differences in pain scores at rest and movement, and the potential opioid sparing with these two compounds.
Patients and methods
The Ethics Committee of our hospital approved the study and informed consent was obtained from all patients. No grants or funds from pharmaceutical companies were acquired for this study.
Patients who underwent laparoscopic cholecystectomy in our Department were included in this study between June and November 2004. Seventy-six ASA I and II patients were randomized to receive parecoxib 40 mg i.v. (Dynastat; Pfizer Hellas, Athens, Greece), lornoxicam 8 mg i.v. (Xefo; Nycomed Hellas, Athens, Greece), or placebo (saline). The doses of parecoxib and lornoxicam were regarded as equipotent. To ensure blinding (lornoxicam has a yellow colour), the study drugs were prepared in non-transparent syringes. All patients received antithrombotic prophylaxis.
Thirty minutes before induction of anaesthesia, all patients received 2.5 mg of midazolam intravenously (i.v.). Then, the study drugs were administered i.v. according to group assignment.
All patients received ondansetron 4 mg i.v. before induction. Induction was with propofol 2 mg kg−1 and remifentanil 1 μg kg−1 min−1; rocuronium 0.6 mg kg−1 was administered for muscle relaxation. In all patients, meperidine 1 mg kg−1 i.v. was administered after induction. Maintenance was with sevoflurane in an O2 –air mixture (FiO2 0.5) and remifentanil as a continuous infusion (0.15–0.2 μg kg−1 min−1). No local anaesthetics were given. Intraoperative monitoring included electrocardiogram, heart rate, non-invasive arterial pressure, end-tidal CO2, O2 saturation, tidal volume, respiratory rate, airway pressure, and minimal alveolar concentration of sevoflurane. Ventilation was adjusted to keep the end-tidal CO2 between 35 and 40 mmHg. Blood pressure and heart rate were maintained within 20% of preoperative values by adjusting anaesthetic depth, fluid replacement, and vasoactive drugs. Adductor pollicis stimulation over the ulnar nerve at the wrist was used to monitor neuromuscular function. Atropine 1 mg and neostigmine 1 mg were administered for reversal of neuromuscular blockade.
Standard laparoscopic cholecystectomy with a 4-port technique was performed in all patients in the anti-Trendeleburg position with left tilt (10 degrees). CO2 pneumoperitoneum at a maximum pressure of 14 mmHg was maintained.
All patients were extubated on the operating table and were admitted to the recovery room. Pain was measured with a 0 to 10 cm visual analogue scale (VAS) at rest and on movement (cough), immediately after admittance to the recovery room (time 0), and at 6 and 12 h postoperatively. Rescue analgesia constituted of meperidine 12.5 mg i.v. On the ward, trained staff nurses recorded the VAS. If the VAS was superior to 5, meperidine 50 mg i.m. were administered, maximally every 4 h. All patients were inquired for postoperative epigastric pain, nausea or vomiting.
The primary end-point was the difference between groups in pain scores at rest and on movement. Secondary end-points were meperidine consumption and adverse effects. Statistical analysis was performed using χ2-test for categorical variables, and analysis of variance (ANOVA) or ANOVA on ranks (Friedman's test) for numerical variables. Kruskal–Wallis test was used for post hoc comparisons. The level of statistical significance was set at P < 0.05. Sample size was calculated in order to allow for non-inferiority testing. With α 0.05 and β 0.20, 23 patients were needed per group to identify a significant difference in VAS scores of 1.5 (SD 2); these data were based on previous retrospective data in our hospital. We decided to include 28 patients per group (n = 84) to allow for drop-outs. Power analysis calculations were performed with computer software (Hintze J. NCSS and PASS Number Cruncher Statistical System, Kaysville, Utah, USA, 2005).
At 12 h, VAS scores at rest and on movement were significantly lower with parecoxib and lornoxicam compared with control (P = 0.047) (Table 1, Fig. 1). The percentage of patients needing meperidine and the average dose of meperidine administered was significantly lower with parecoxib and lornoxicam compared with control (P < 0.001 and P = 0.018). There was no difference between parecoxib and lornoxicam in pain scores or meperidine consumption. One patient receiving lornoxicam vomited. We did not observe bleeding episodes.
NSAIDs are potent analgesics for the control of postoperative pain [1–5]. The main mechanism of action is the inhibition of cyclooxygenase which is found to exist in at least two isoenzymes. Cyclooxygenase 1 (COX-1) has a role in the regulation of normal cell activity while COX-2 is induced in inflammatory states. The development of specific COX-2 inhibitors is an alternative for the selective inflammatory-pain control without the COX-1 inhibition-related adverse effects of the older NSAIDs [2,11,12]. Since the principal advantage of this class of drugs over previous generations is the theoretical reduction of gastro-intestinal adverse events, large scale studies were launched addressing this issue. The VIGOR study and a report comparing parecoxib to ketorolac suggested that there was less gastrointestinal toxicity with the COX-2 [8,15].
However, the reported increase of cardiovascular adverse events noted during the VIGOR study raised concerns about the potential inherent thrombotic risk of COX-2 inhibitors . Subsequent studies verified these observations and concluded that COX-2 inhibitors should be avoided in patients at high risk for thrombotic events but that they posed little, if any, risk in patients with no preexisting risk factors [16–18]. Current recommendations suggest that an assessment of the risk of thrombotic events should be performed for patients in whom COX-2 inhibitors are considered for postoperative pain management . The effect COX-2 inhibitors on kidney function in postoperative patients is another reason for concern. Until further studies address that issue, it should be assumed that COX-2 and NSAIDs have a similar risk for renal toxicity .
The specificity of COX-2 inhibitors for the COX-2 isoenzyme with concurrent reduction of the adverse effects in the gastrointestinal tract is a significant advantage in the treatment of chronic pain. Despite that, the selection of the appropriate treatment for postoperative analgesia in an ambulatory setting has rather been a matter of choice than an issue addressed by specific studies. The issue is whether the advantages of the COX-2 drug are important for (short) postoperative pain treatment. NSAIDs have been implicated in postoperative bleeding due to platelet aggregation inhibition [19–21]. COX-2 inhibitors lack such effect on platelet function; also, they do not affect blood coagulation parameters in patients receiving low molecular weight heparins for postoperative prophylaxis for deep vein thrombosis [8–10,22].
The aim of our study was to evaluate the efficacy of a selective COX-2 inhibitor, parecoxib, compared with a non-specific NSAID, lornoxicam, in patients undergoing ambulatory laparoscopic surgery. Pain after laparoscopic cholecystectomy has a specific pattern. It can be subdivided into three components: incisional pain from the port traumas, visceral pain from peritoneal irritation and shoulder pain from the irritation of the diaphragmatic peritoneum . Effective pain control in this setting requires an analgesic with rapid onset and long duration of action. Meperidine and other opioids are satisfactory regimens with rapid onset of action but their use is frequently accompanied by adverse effects such as respiratory depression, nausea and vomiting leading to slower patient recovery . NSAIDs have an opioid sparing effect when used postoperatively but they tend to show a slower onset of action due to the time required to achieve blockade of the COX enzymes [11–13]. Our data showed that both NSAID and COX-2 inhibitor reduced the percentage of patients requiring opioid administration and the total amount of opioid consumption compared with placebo (Table 1). They also reduced pain at rest and on movement at 12 h postoperatively. However, rescue analgesia with meperidine was still required in a high percentage of patients in both NSAID and COX-2 groups.
In conclusion, parecoxib 40 mg i.v. and lornoxicam 8 mg i.v. were equianalgesic and both were more efficacious than placebo for the management of pain after laparoscopic cholecystectomy. The theoretical advantages of COX-2 inhibitors over NSAIDs should be balanced against the increased costs and the risk of cardiovascular adverse events.
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