Surgical trauma induces nociceptive sensitization, leading to amplification and prolongation of post-operative pain. Pre-emptive analgesia may prevent nociceptive inputs generated during surgery from sensitizing central neurons and, therefore may reduce postoperative pain [1,2]. Non-steroidal antiinflammatory drugs (NSAIDs), opioids and local anaesthetics have been used for pre-emptive analgesia [1–4]. The mechanism of action of NSAIDs is through their inhibition of prostaglandin biosynthesis by cyclo-oxygenase (COX) . COX is now known to exist as two isoforms, COX-1 and −2 . NSAIDs have been shown generally to inhibit both COX isoforms [6,7]. It has been proposed that the therapeutic activity of NSAIDs was primarily the result of inhibition of COX-2, whereas the toxicity of NSAIDs primarily may result from inhibition of COX-1 . Recently, compounds have been developed that are highly selective COX-2 inhibitors with little or no effect on COX-1 [6,7]. Celecoxib and rofecoxib, two novel COX-2 selective inhibitors, have relative COX-2:COX-1 selectivity ratios of approximately 375:1  and >800:1 , respectively. Previous data from studies on pain after dental surgery have suggested that both celecoxib [6,9,10] and rofecoxib [8,11,12] have analgesic effects similar to those of the non-selective NSAIDs. However, the analgesic efficacy of celecoxib and rofecoxib on postoperative pain is still unclear . The aim of this randomized placebo-controlled study was to compare analgesic efficacy and safety of preoperatively administered single-dose oral celecoxib and rofecoxib in patients undergoing thyroid surgery.
The study was approved by our local Ethics Committee and written informed consent was obtained from all patients. We studied 90 ASA I-II patients undergoing elective thyroid surgery. Exclusion criteria were a known allergy, sensitivity, asthma, a contraindication to any NSAID, renal insufficiency, a history of peptic ulcer, a history of a bleeding diathesis and pregnancy.
Patients were randomized to one of three groups of 30 patients each according to a computer-generated randomization list. As a premedication, midazolam 0.07 mg kg−1 and atropine 0.01 mg kg−1 were administered intramuscularly 45 min before the surgical procedure. When the patients arrived in the operating room, an intravenous 20-G cannula was inserted and a crystalloid infusion was started, and heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR) and peripheral oxygen saturation were monitored (Cato® PM 8040; Dräger, Lübeck, Germany).
The study drugs were prepared by the pharmacy and a code number was assigned to each treatment. Patients in the placebo group received a placebo capsule, those in the celecoxib group received one celecoxib 200 mg capsule (Celebrex® Fort; Pfizer, Istanbul, Turkey), and those in the rofecoxib group received two rofecoxib 25 mg tablets (Vioxx®; Merck Sharp & Dohme Pty, South Granville, NSW, Australia). Study medications were given to the patients by a nurse – who was not involved in the study – 1 h before induction of anaesthesia.
Anaesthesia was induced with propofol 2 mg kg−1 and was maintained with 50% O2/N2O and 1.5–2.5% sevoflurane. Intubation of the trachea was facilitated with atracurium 0.5 mg kg−1. Ventilation of the lungs was mechanically controlled (Cato®; Dräger, Lübeck, Germany) and adjusted to maintain the end-expiratory CO2 between 4.5 and 4.8 kPa. Following the induction of anaesthesia, all patients received fentanyl 0.5 μg kg−1 intravenously and muscle relaxation was maintained with atracurium 0.2 mg kg−1. At the end of surgery, residual neuromuscular blockade was antagonized with neostigmine.
Intraoperative blood loss was determined by measuring the blood volume in the suction canister and by estimating the amount of blood present in the surgical sponges. Assessment of postoperative pain was made based on a visual analogue scale (VAS: 0 = no pain; 10 = worst pain imaginable). Sedation was assessed using a score ranging from 0 to 2 (0 = alert; 1 = drowsy but rousable to voice; 2 = very drowsy but rousable to shaking). For postoperative analgesia, all patients received acetaminophen (paracetamol) 2 g rectally every 6h for the first 24 h after surgery. If additional analgesia was required (VAS > 4), intravenous meperidine (pethidine) 1 mg kg−1 was administered. Both VAS and rescue analgesia were explained to the patients during the preoperative visit. The VAS scores, sedation scores, HR, MAP and RR were recorded at 0, 1, 2, 4, 6, 12 and 24h. The total dose of meperidine and the cumulative doses for the time periods were also recorded. These measurements were recorded by the same anaesthesia resident who was unaware of the treatment allocation. Patients were asked about the occurrence of any adverse effects during the first 24h. All patients received intravenous ondansetron 4 mg at the end of surgery. Patients who experienced severe nausea and/or vomiting were given additional ondansetron. The number of patients receiving ondansetron and the number of doses for each patient was recorded.
Data on patient characteristics (ASA classification, age, weight, height, gender), surgery (intraoperative blood loss, duration of anaesthesia, operation), haemodynamics (HR, MAP), respiration and meperidine requirements were analysed by one-way ANOVA. The Bonferroni and Tamhane post hoc tests were applied to determine the significance of differences in means.
Pain (VAS) scores and sedation scores were analysed with a Kruskal-Wallis test. If a significant result was obtained, a Bonferroni post hoc test was performed for multiple comparisons. Fisher's exact test was used for the analysis of adverse effects. Data are the means ± SD. P < 0.05 was considered as significant.
A previous study compared the analgesic efficacy of a single preoperative dose of rofecoxib 50 mg and of celecoxib 200 mg with placebo in patients undergoing major surgery . In that study, a significant analgesic benefit of the COX-2 inhibitors with regard to postoperative pain relief and a decrease in opioid requirements were reported. Based on data from this study, a power analysis suggested that a sample size of 30 patients in each group was sufficient for a 80% chance (Type II error = 0.2) of detecting a similar difference in postoperative pain scores at a 95% (Type I error = 0.05) significance level.
The three groups were similar with regard to demographic and surgery data (Table 1). There were no statistically significant differences in HR, MAP and RR (Figs 1–3). Sedation scores were also similar at all time points.
VAS scores were significantly different among the three groups at all time points postoperatively (P < 0.001). The scores were significantly lower in the rofecoxib group compared with the placebo group at all times (P < 0.05). At 0, 1, 2 and 4h, but not thereafter, VAS scores were significantly lower in the celecoxib group compared with the placebo group (P < 0.05). The VAS scores were significantly lower in the rofecoxib group than in the celecoxib group at 6, 12 and 24 h postoperatively (P < 0.05) (Table 2).
For all seven periods, the cumulative doses of meperidine were similar among the groups (Table 3). However, the average 24 h meperidine dose was significantly different among the groups (P < 0.001). The meperidine dose was significantly decreased in both the celecoxib and the rofecoxib groups compared with the placebo group (P < 0.01 and < 0.001, respectively). There were no statistically significant differences between the celecoxib group and the rofecoxib groups concerning the meperidine doses (Table 3).
Adverse effects were not significant among the groups (Table 4). Adverse effects were reported in 6 (20%), 9 (30%) and 8 (26.6%) patients in the placebo, celecoxib and rofecoxib groups, respectively. The most frequent adverse effects in the celecoxib and rofecoxib groups were nausea and dry mouth. None of the patients suffered from hypotension, respiratory depression, bronchospasm or an allergic reaction. One patient who experienced severe nausea in the two COX-2 groups was given ondansetron.
NSAIDs are useful analgesic adjuncts for a multimodal management of postoperative pain . Most, but not all, studies comparing the postoperative analgesic effect of different non-selective NSAIDs have shown a decrease in opioid requirements, pain intensity or both, despite using a variety of drugs, dose regimens and surgical procedures . The use of COX-2-selective inhibitors may represent a therapeutic advance in the management of acute pain. Preliminary data from animal studies have revealed that selective inhibition of COX-2 produces analgesia with substantial safety advantages over non-selective NSAIDs . Although selective COX-2 inhibitors have demonstrated analgesic efficacy in mild to moderate pain after dental surgery [8,10–12,17], their efficacy in more severe pain has yet to be established.
Compared with placebo, rofecoxib 50 mg was effective for pain relief during the 24 h observation, while celecoxib 200 mg was effective for the first postoperative 4 h only. Our results are similar to those of a previous study in dental pain where rofecoxib 50 mg had an analgesic duration of >24h compared with 5.1 h only for celecoxib 200mg . Additionally, we found that the average 24 h meperidine requirement was significantly decreased with both rofecoxib and celecoxib compared with placebo. However, there was no statistically significant difference between the celecoxib and rofecoxib groups for the meperidine doses.
Celecoxib and rofecoxib have different dosing regimens. It is recommended that celecoxib be taken once or twice daily by patients with osteoarthritis and twice daily by patients with rheumatoid arthritis, and that rofecoxib be taken once daily by patients with osteoarthritis or acute pain [8,12]. The recommended dose of rofecoxib for the treatment of acute pain is 50 mg. At this dose, the analgesic efficacy of rofecoxib is comparable with ibuprofen 400 mg [8,11,12] and with naproxen sodium 550mg  in pain after dental surgery. The efficacy of celecoxib in providing relief of acute postoperative pain seems to be limited and there is no general agreement for its use in the acute pain setting . In dental surgery, celecoxib 100–400 mg was superior to placebo  and similar to aspirin , and celecoxib 200 mg was less effective than ibuprofen 400 mg .
Chang and colleagues observed that a single dose of rofecoxib 50 mg was superior to codeine plus acetaminophen (60/600 mg), and fewer patients experienced adverse effects . This provides support for the use of rofecoxib as an alternative to opioid analgesia for the treatment of acute pain. Morrison and colleagues found that in patients with primary dysmenorrhoea, the analgesic efficacy of a single daily dose of rofecoxib 50 mg was better than placebo, but that there was no difference compared with naproxen sodium 550mg . Reicin and colleagues showed that rofecoxib 50mg was superior to placebo and similar to naproxen sodium 550 mg for pain after orthopaedic surgery . In the same study, patients receiving rofecoxib needed less supplemental narcotic analgesia compared with those receiving a placebo.
Reuben and Connelly compared the efficacy of a single oral dose of rofecoxib 50 mg and celecoxib 200 mg given before spinal fusion surgery . Average pain scores were significantly less with rofecoxib compared with celecoxib after 12 and 16h, and with both COX-2 inhibitors were less compared with placebo group after 8, 12 and 16 h. Additionally, the average cumulative 24 h dose of morphine was significantly increased with placebo compared with both rofecoxib and celecoxib, and was significantly less with rofecoxib compared with celecoxib.
In yet another study, a single oral dose of rofecoxib 50 mg – given 1h before induction of anaesthesia for radical prostatectomy – was similar to placebo for VAS scores at 1, 2, 4, 6, 8 and 24 h, and there was no difference in the postoperative morphine consumption .
At therapeutic doses, non-selective NSAIDs non-specifically inhibit both COX-1 and -2. The antiinflammatory and analgesic effects mediated through COX-2 inhibition – gastrointestinal toxicity and platelet dysfunction – are due to COX-1 inhibition . Thus, the theoretical benefits of selective COX-2 inhibitors are a reduced incidence of gastric ulceration, including perforation and bleeding, and a reduced effect on platelets [6,7,9,23]. In previous studies, a similar frequency of adverse events was found with placebo and celecoxib [12,24] or with rofecoxib [8,11]. Since both celecoxib and rofecoxib do not inhibit platelet function , they may be safer analgesics in the perioperative period. Celecoxib 1200 mg daily had no effect on serum thromboxane or platelet function . Similarly, rofecoxib 1000mg day−1 had no effect on platelet aggregation or bleeding time . Our study suggested that a single oral dose of celecoxib 200 mg or rofecoxib 50 mg administered before surgery did not lead to increased intraoperative bleeding.
Previous studies have demonstrated that the most frequent adverse effects of celecoxib are severe abdominal pain, headache, dyspepsia, nausea and vomiting [12,24], and of rofecoxib are headache, fatigue, nausea, dizziness, dyspepsia and dry mouth [8,11, 12,20]. In our study, adverse effects were not different among the groups during the first 24 post operation. The most common drug-related adverse effects in the celecoxib and rofecoxib groups were nausea and dry mouth.
In conclusion, in patients undergoing thyroid surgery, a single preoperative dose of rofecoxib 50mg and less so of celecoxib 200 mg enhanced postoperative analgesia and decreased opioid requirement. Both regimens were well tolerated.
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