Non-steroidal anti-inflammatory drugs (NSAIDs) are often administered as adjuvants in the management of postoperative pain because these drugs have analgesic properties comparable to opioid compounds but without opioid-related side-effects . Laparoscopic cholecystectomy is a procedure which causes moderate postoperative pain and is increasingly performed under a day case setting. NSAIDs are routinely used for post-laparoscopic pain control and opioids are often needed as a rescue medication , but the side-effects of opioids may delay the hospital discharge .
Tenoxicam has the advantages of an intravenous (i.v.) formulation and a long half-life of plasma concentration (60–75 h) . After administration, maximum plasma concentrations are reached within 0.5–2 h, which indicates that tenoxicam may be suitable for the treatment of postoperative pain .
Lornoxicam is a relatively new NSAID belonging to the enolic acid chemical class shared by piroxicam and tenoxicam . In animal pain models, its analgesic potency exceeds that of tenoxicam and piroxicam approximately 12- and threefold, respectively . In the treatment of postoperative pain, lornoxicam has been shown to be as effective as morphine , pethidine (meperidine)  and tramadol [8,9]. Moreover, in the postoperative setting, lornoxicam has been well tolerated [7-11].
A review of the literature written in English revealed no study on the comparison of the effects of lornoxicam and tenoxicam in laparoscopic cholecystectomy. In this double-blind, randomized, controlled study, the efficacy, tolerability and morphine-sparing effects of lornoxicam were compared with those of tenoxicam in patients undergoing laparoscopic cholecystectomy.
Materials and methods
After approval of the Medical Faculty Drug Research Ethics Committee, and written informed consent of the patients, 60 ASA physical status I–II patients between 18 and 65 yr of age scheduled for elective laparoscopic cholecystectomy were enrolled.
Exclusion criteria were: hypersensitivity to NSAIDs, history of peptic ulceration, gastrointestinal bleeding or any bleeding disorder, presence of severe renal (creatinine > 0.2 mg mL−1), hepatic, cardiac or blood disease, morbid obesity, any possibility of pregnancy, any patient with bronchial asthma, chronic pain disorder, any psychiatric illness and use of NSAID, opioids, diuretics, angiotensin-converting enzyme inhibitors, warfarin, digoxin, methotrexate, cimetidine, glibenclamide or lithium in the 24 h preceding surgery.
During the preoperative visit, patients signed the informed consent and were informed about the visual analogue score (VAS) for pain scoring and how to use the patient-controlled analgesia (PCA) device.
Patients were randomized prospectively to two groups in a double-blind fashion. Randomization was done using a sealed envelope method.
Patients were not premedicated. Group T (n = 30) received 40 mg tenoxicam and group L (n = 30) received 16 mg lornoxicam i.v. prior to the induction of anaesthesia. During the operation, all patients were monitored with electrocardiography (ECG), peripheral oxygen saturation (SPO2), non-invasive systemic blood pressure (NIBP), end-tidal carbon dioxide partial pressure. Haemodynamic and ventilatory parameters were recorded every 5 min. Anaesthesia was induced with thiopental 3–5 mg kg−1, fentanyl 2 μg kg−1 and vecuronium 0.1 mg kg−1. Maintenance of anaesthesia was achieved with 1–2% inspiratory concentration of sevoflurane in a mixture of 50% oxygen and 50% nitrous oxide. Sevoflurane was discontinued at the end of skin closure. Any residual muscle relaxation was antagonized with atropine and neostigmine at the end of the operation, if necessary. All patients were extubated in the operating room. The time to extubation was recorded.
Laparoscopic cholecystectomy was performed with a 4-port technique in all patients in the anti-Trendelenburg position (20°) with left tilt (20°). CO2 was insufflated to an abdominal pressure of 14 mmHg. At the end of dissection of the gall bladder, the operation field was irrigated with normal saline. After the termination of pneumoperitoneum, CO2 was removed as much as possible via an umbilical trocar with the help of brief pressure on the abdomen.
In the recovery room, the PCA device (Abbott Life Care PCA Plus Infuser; Abbott Laboratories, North Chicago, IL, USA) was set to deliver morphine sulphate 50 μg kg−1 as a loading dose and 20 μg kg−1 bolus doses with a lockout of 10 min without any background infusion. A loading dose was administered according to the patients' demands and the time from extubation and administered loading dose was recorded as a first morphine demand time. During the recovery period, all patients received 4 L min−1 oxygen via face-mask and were monitored with ECG, SPO2 and NIBP. Pain intensity was assessed with a VAS from 0 to 10 (0 = no pain, 10 = worst possible pain). At the end of 2 h, the patients were discharged from the recovery room to the ward. Postoperative pain scores, localization of pain and cumulative morphine consumption were assessed at 15 and 30 min and 1, 2, 4, 6, 12 and 24 h following the extubation, and data were recorded. When the VAS score was ≥5, 20 μg kg−1 morphine was given as rescue medication. Nausea (0 = none, 1 = mild, 2 = moderate, 3 = severe), vomiting (none, existing), sedation (1 = aware, 2 = sleep and easily awake, 3 = sleep and strongly awake, 4 = not awake) and patient satisfaction (1 = bad, 2 = moderate, 3 = good, 4 = excellent; (A) Do you prefer to take this analgesic management if you will undergo an operation again? (B) Do you recommend this analgesic management if your relatives will undergo an operation?) were assessed. Antiemetic treatment was prescribed (10 mg metoclopramide) to patients who had ≥2 postoperative nausea scores. An investigator, blinded to the group to which the patient belonged, recorded the pain scores and analgesia requirements.
Statistical analyses were performed using SPSS 11.0 for Windows. For the comparison between groups, t-test for parametric data and χ 2-test for non-parametric data was used. A value of P < 0.05 was considered statistically significant for all analyses. Data are expressed as mean ± standard error of the mean (mean ± SEM). Sample size was calculated by power analysis. Initial sample size estimation showed that 26 patients were needed in each group to detect a clinically relevant decrease in cumulative morphine consumption by 5 mg with a power of 0.80 and level of significance 0.05. During the study design, a pilot study was performed comprising 10 patients, three of whom received tenoxicam 40 mg, and seven lornoxicam 16 mg. Standard deviation of the pilot study was 5.7. Therefore, 30 patients in each group was preferred in order to compensate for any drop-outs and also to enable the use of parametric tests for the statistical analysis.
Fifty-seven patients completed the study; one patient of Group L and two patients of Group T were withdrawn from the study because the surgery proceeded to laparatomy. The mean body weight of the patients was different between two groups (P = 0.002). The other patient characteristics data and the duration of surgery did not differ (Table 1).
Although pain levels were not significantly different, there was an important difference in the first morphine demand times between groups (P = 0.037). The first morphine demand time was 18.79 ± 3.02 min in Group L, whereas it was 11.89 ± 0.98 min in Group T.
The mean VAS were higher in Group T at 15 min, 1, 2 and 4 h after extubation (P < 0.05) (Table 2). Although the cumulative morphine consumptions were higher in Group T, no statistically significant difference was found between the groups. Cumulative morphine consumption was 23.04 ± 2.81 and 22.66 ± 2.03 mg in Groups L and T, respectively, at the end of 24 h. The comparison of the calculated cumulative morphine consumptions on a per kilogram basis showed a statistically significant difference between the two groups at 15 and 30 min, 1 and 2 h (Table 3). During the study design, the morphine dose per kilogram was not considered for the power analysis. Therefore, the post hoc power was calculated with the morphine doses per kilogram and with 0.05 α error, the power was found to be 87%.
In the postoperative period, there was no difference in the severity of nausea in both groups, but nausea occurred between 15 min and the first hour in Group L, whereas it occurred between 30 min and 2 h in Group T. Thirteen patients had vomiting in Group T and five patients in Group L (P = 0.018). The injection pain was noticed in four patients in Group T (P = 0.035). Six patients in each group experienced shoulder pain. The distribution of side-effects according to the groups is presented in Fig. 1. The patient satisfaction was excellent (n = 13) or good (n = 16) in Group L, and excellent (n = 17), good (n = 9), moderate (n = 1) or bad (n = 1) in Group T. All patients in both groups answered ‘yes' to the questions assessing the patient satisfaction. There was no significant difference in patient satisfaction between the groups while discharging from hospital.
The authors studying the pathophysiology of acute pain have implied that pain does not arise from the activation of a unique system, but it is an expression of dysfunction in the somatosensory system. According to experimental data, the nociceptive impulses that are brought to the central nervous system by the C fibre afferents produce long-lasting changes of the dorsal horn neurons . A noxious stimulus can change the excitability of these neurons and alter their receptive field properties. High doses of analgesics are required in order to suppress this state, whereas small doses of analgesics administered before central sensitization, termed pre-emptive analgesia, may be effective in reducing the subsequent pain effectively [13,14]. Bisgaard  stated that postoperative pain treatment after laparoscopic cholecystectomy should be initiated shortly before or at induction of anaesthesia or during surgery and continued for 3 or 4 days.
Laparoscopic approach for cholecystectomy is being preferred increasingly in day case setting because of its advantages of causing less severe postoperative pain and allowing early discharge . White  determined ambulatory postoperative analgesic management as effective, with minimal side-effects, intrinsically safe and easily manageable away from the hospital. Standard opioid analgesia may result in over sedation, nausea and vomiting in mobile patients. Bisgaard , in a systematic review, emphasized that NSAIDs were used widely as adjuvant in reducing opioid requirements, and their postoperative analgesic efficacy has been demonstrated in many studies in laparoscopic operations. NSAIDs inhibit the synthesis of prostaglandins and thromboxane by inhibition of the enzyme cyclo-oxygenase. Although the use of NSAIDs for postoperative pain control is greatly accepted, the drug of choice is still controversial [1,3].
Tenoxicam is an oxicam class NSAID which is suitable for i.v. administration . Although this drug's pre-emptive role in surgery has been demonstrated by Colbert and colleagues  and O'Hanlon and colleagues , the optimal dose, the timing of the administration and the role of the postoperative analgesia of this drug are still controversial. Merry and colleagues  showed that a single i.v. dose of tenoxicam 20 mg, after thoracotomy, was associated with a reduction in opioid consumption, when compared with placebo. They concluded that tenoxicam reduced the opioid consumption during the first 12 h, but for a better analgesia higher doses were needed. In a recent study, with a multimodal analgesia design, the same authors compared tenoxicam 20 and 40 mg with placebo, after thoracotomy, and concluded that any additional advantage of high dose of tenoxicam was achieved . However, Merry and colleagues  emphasized that the exclusion of the benefit of the larger doses of tenoxicam was not possible with their data, but the additional advantage was more between tenoxicam and placebo. The preoperative administration of 40 mg tenoxicam proved superior to post-incision administration in patients undergoing laparoscopic surgery . Salman and colleagues  found no significant reduction in postoperative pain when 20 mg of tenoxicam was used pre-emptively in laparoscopic surgery. These findings are consistent with the study of Windsor and colleagues . The authors of those studies suggested that a 40 mg dose of tenoxicam given i.v. would produce superior analgesia in the immediate postoperative period [19,22,23].
Lornoxicam is a new NSAID that has been shown to be effective and well tolerated in the treatment of pain associated with a variety of conditions, including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and postoperative dental pain . The short plasma half-life (approximately 4 h) may provide advantages over other NSAIDs, which have been linked to a high incidence of adverse events . In the studies comparing the analgesic properties of lornoxicam with those of opioids, the authors concluded that equipotent analgesia was obtained. In a randomized, double-blind study with 66 gynaecological patients, Trampitsch and colleagues  investigated the pre-emptive analgesic effect of lornoxicam. They administered 8 mg of lornoxicam pre-emptively or intraoperatively, followed by 8 mg every 8 h for a total dose of 24 mg in the first 24 h. They concluded that lornoxicam administered pre-emptively improved the quality of postoperative analgesia and led to reduced postoperative opioid consumption. Visalyaputra and colleagues  and Straunstrup and colleagues  showed that intramuscular 16 mg of lornoxicam offered a useful alternative to 100 mg of tramadol for the treatment of moderate to severe postoperative pain. Lornoxicam 8 mg i.v. has produced analgesic activity equivalent to that of i.v. pethidine 50 mg in patients who underwent laminectomy .
Few studies exist comparing the analgesic effects of lornoxicam with the other NSAIDs in the postoperative setting [25,26]. Papadima and colleagues  compared the analgesic effects of lornoxicam 8 mg and parecoxib 40 mg with placebo in laparoscopic cholecystectomy, and concluded that lornoxicam 8 mg was more efficacious than placebo for the management of pain after laparoscopic cholecystectomy. However, in that study, meperidine 1 mg kg−1 was used following the anaesthesia induction.
In our study, 40 mg tenoxicam or 16 mg lornoxicam was administered just before the induction of anaesthesia. Laparoscopic cholecystectomy is increasingly performed in a day case setting and it is not advisable to use opioids for postoperative analgesia because of their side-effects. On the other hand, the results of many studies suggested that lornoxicam has produced analgesic activity equipotent to that of opioids. The second end-point of this study was to examine whether lornoxicam was effective in ambulatory laparascopic cholecystectomy without opioids. For this aim, the doses of the study medications were based on the literature data and recommended effective daily doses. Since no data were available for the equipotent doses of these two NSAIDs, the recommended daily doses were compared, and this may be considered as a limitation of the study.
The first morphine demand in Groups L and T was 19 and 12 min, respectively. Similar pain scores were obtained in the first morphine demand time. These findings suggested that lornoxicam was more potent than tenoxicam, and its analgesic effect lasted longer. Pain scores were lower in Group L throughout the study, but this difference was statistically significant only at 15 min, 1, 2 and 4 h. The significant lower pain scores in Group L during the first 4 h were consistent with the findings of Visalyaputra and colleagues , and can be explained with the high analgesic potencies of lornoxicam.
Cumulative morphine consumption was not significantly different in the first 4 h, although pain levels were significantly lower in Group L. Therefore, cumulative morphine consumption per kilogram was computed, because the mean body weight was higher in Group L in this randomized study. When the cumulative morphine consumption per kilogram was compared, the consumption in Group L was significantly lower during the first 2 h with the power of 0.87.
Postoperative nausea and vomiting (PONV) are frequently observed complications of laparoscopic surgery. Since opioids are known to be associated with higher incidences of PONV, care must be taken in order to reduce this complication. NSAIDs are associated with less PONV in the perioperative use . In our study, we observed a higher incidence of vomiting in Group T as compared with Group L, while the incidence of nausea was similar in the two groups. This is consistent with the findings of better gastrointestinal tolerability of lornoxicam compared with that of the other NSAIDs . Sedation and respiratory depression were not developed during the study period. No patient complained of injection pain associated with NSAIDs in Group L. This is a great advantage in favour of lornoxicam compared to tenoxicam. Shoulder pain incidence did not show any significant difference between the groups during the 24 h postoperatively. Even though the incidence of shoulder tip pain is reported from 35% to 63% by Dobbs and colleagues  after laparoscopic surgery, the reduced incidence of shoulder pain was found in our study. This may be associated with administered analgesic management and active removal of intra-abdominal carbon dioxide.
One patient in Group T did not obtain satisfactory analgesia from this method. When the postoperative chart was reviewed, it was found that the cumulative morphine consumption was only 0.21 mg kg−1, which was lower than the mean morphine consumption of this group. Another reason for dissatisfaction was that they vomited three times during the study period. Apart from this patient, patient satisfaction did not differ significantly between the two groups.
In conclusion, the pre-emptive use of lornoxicam, in 16 mg doses, was found to be superior to the 40 mg of tenoxicam in increasing time to first morphine demand and reducing postoperative morphine consumption and causing less adverse effects. Since lornoxicam was not found to be superior to tenoxicam after 4 h in this study, further studies comparing repeated doses of both these drugs in the 4 and 6 h following laparoscopic cholecystectomy are needed.
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Keywords:© 2007 European Society of Anaesthesiology
ANTI-INFLAMMATORY AGENTS; NONSTEROIDAL, lornoxicam, tenoxicam; ANALGESIC, OPIOID, morphine; CHOLECYSTECTOMY, LAPAROSCOPIC