The efficacy of intravenous paracetamol versus tramadol for postoperative analgesia after adenotonsillectomy in children

Journal of Clinical Anesthesia (2011) 23, 53 57 Original contribution The efficacy of intravenous paracetamol versus tramadol for postoperative analgesia after adenotonsillectomy in children Hale Yarkan Uysal MD (Specialist in Anesthesiology), Suna Akin Takmaz MD (Specialist in Anesthesiology), Ferda Yaman MD (Resident in Anesthesiology), Bülent Baltaci MD (Specialist in Anesthesiology), Hülya Başar MD (Associate Professor and Head of Department) Anesthesiology and Reanimation Clinic, The Ministry of Health, Ankara Training and Research Hospital, Ankara, Turkey Received 29 September 2009; revised 14 May 2010; accepted 3 July 2010 Keywords: Adennotonsillectomy; Children; Paracetamol; Postoperative analgesia; Tramadol Abstract Study Objective: To evaluate the efficacy and the quality of recovery with intravenous (IV) paracetamol versus tramadol for postoperative analgesia after adenotonsillectomy in children. Design: Prospective, randomized, double-blinded clinical trial. Setting: Operating room and Postanesthesia Care Unit (PACU) of a university-affiliated hospital. Patients: 64 ASA physical status I and II children, aged 6 to 16 years, scheduled for adenotonsillectomy. Interventions: All patients were premedicated with oral midazolam 0.5 mg/kg 30 minutes before surgery. Patients were randomized to two groups following induction of general anesthesia. The paracetamol group (n = 32) received 15 mg/kg of IV paracetamol and the tramadol group (n = 32) received 1.0 mg/kg of IV tramadol. Measurements: Modified Hannallah pain scores, emergence agitation, Aldrete scores, sedation scores, time to first administration of analgesic, heart rate, and mean arterial blood pressure were recorded for each patient. Data were recorded every 5 minutes for the first 30 minutes and every 10 minutes for the remaining 30 minutes in the PACU, then at 2, 3, 4, 5, 6, 8, 12, and 24 hours in the ward. The frequency of postoperative nausea and vomiting also was noted. Satisfaction of parents and nurses was determined on a 4-point scale at the end of the study. Main Results: No significant demographic differences between groups were noted. No statistically significant difference was found in postoperative pain scores in either group. Agitation scores, Aldrete scores, sedation scores, and number of patients who received rescue analgesia and time to administration of rescue analgesia were similar in both groups. Conclusions: The IV formulation of paracetamol was associated with similar analgesic properties and early recovery to that of IV tramadol after adenotonsillectomy in children. 2011 Elsevier Inc. All rights reserved. Corresponding author. Ç. Emeç Bulv., C. Atıf Kansu Cad., 11.Sok., 8/7 Balgat, Ankara, Turkey. E-mail address: haleuysal@gmail.com (H.Y. Uysal). 0952-8180/$ see front matter 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2010.07.001

54 H.Y. Uysal et al. 1. Introduction Adenotonsillectomy is a common surgical procedure in children. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in reducing postoperative pain, with a lower risk of postoperative nausea and vomiting (PONV). However, they also introduce the possibility of increased bleeding due to their antiplatelet effect [1,2]. Opioids provide satisfactory analgesia and better emergence in children undergoing ear, nose, and throat (ENT) surgery, but prolonged sedation due to opioid use is one of the reasons for delayed discharge from the hospital after day-case surgeries [3]. The efficacy of tramadol in relieving post-tonsillectomy pain has been well documented [4,5]. Due to its negligible effect on respiration, tramadol may be preferable to traditional opioids, but side effects such as PONV occur [2]. Paracetamol is a non-opioid analgesic that is devoid of these risks. Its analgesic action is assumed to be mediated by a serotonergic mechanism, and the antipyretic action is via inhibition of cyclooxygenase-3 in the hypothalamus [6]. Paracetamol also has little antiplatelet activity and does not affect bleeding time, unlike NSAIDs [7]. Although enteral formulations of paracetamol are the most commonly used analgesics for management of pain in children, their analgesic efficacy is weak after ENT surgery [8,9]. An intravenous (IV) formulation of paracetamol recently has become available, and it achieves target plasma concentration more rapidly with reduced variability compared with the rectal and oral formulations [10,11]. This randomized, double-blind, clinical study was undertaken to evaluate the effectiveness of IV paracetamol on postoperative pain and its effect on the quality of recovery versus IV tramadol in children after adenotonsillectomy. Comparison of the frequency of PONV and satisfaction of the nurses and parents with the study drugs were secondary objectives of the study. 2. Materials and methods The study protocol was approved by the Institutional Ethics Commitee of Ankara Training and Research Hospital. Written, informed consent were obtained from the parents and from the children over 8 years of age. A total of 66 healthy, ASA physical status I and II children, aged between 6 and 16 years, and scheduled for adenotonsillectomy operation, were enrolled in the study. Exclusion criteria were a known history of allergy to the study drugs; active and severe renal, hepatic, respiratory, or cardiac disease; and neurological or neuromuscular disorders. Children were fasted from solid foods for 6 hours before the procedure; clear liquids were permitted until two hours prior to surgery. All study patients were premedicated with oral midazolam 0.5 mg/kg 30 minutes before surgery. In the operating room: electrocardiography (ECG), noninvasive blood pressure, and pulse oximetry monitors were attached. Anesthesia was induced with IV fentanyl 1.0 lg/kg and IV propofol 2.0 to 3.0 mg/kg. Vecuronium bromide 0.1 mg/kg was given for muscle relaxation. After tracheal intubation, the lungs were mechanically ventilated with the pressure-controlled mode (pressure-controlled ventilation at 15 cm H 2 O), and end-tidal carbon dioxide (ETCO 2 ) tension was maintained at 30-35 mmhg. Intravenous fluid management included administration of lactated Ringer's solution. Fluid deficit was calculated to be replaced over three hours, and maintenance fluid was calculated according to patients' weights. Anesthesia was maintained with 1.5k to 2.5k sevoflurane and 50k nitrous oxide in oxygen at a total fresh gas flow of 2.0 L/min. No additional opioids were given intraoperatively. At the end of the operation, residual neuromuscular block was reversed with neostigmine 0.04 mg/kg and atropine 0.02 mg/ kg, and the endotracheal tube was removed when respiration was regular and adequate in rate and depth. Heart rate (HR), systolic (SBP) and diastolic (DBP) arterial blood pressures, oxygen saturation (SpO 2 ), and ETCO 2 were monitored continuously during the procedure. After induction of anesthesia and before the surgical incision, the children were randomized to one of the two groups using a computer-generated random numbers table, with 33 patients in each group. Patients in the paracetamol group received 15 mg/kg of IV paracetamol (Perfalgan) and the tramadol group patients received 1.0 mg/kg of IV tramadol (Tramadolor) over 15 minutes. The medications were diluted with saline to a total volume of 75 ml. All study drugs were prepared by an anesthesiologist who was blinded to the details of the study. After patient arrival at the PACU, postoperative observational pain scores, emergence agitation, Aldrete scores [12], HR, and mean arterial blood pressure (MAP) were recorded every 5 minutes during the first 30 minutes, then every 10 minutes for the remaining 30 minutes of the PACU stay. Patients were then transferred to the ward. At the ward, observational pain scores, HR, and MAP were recorded at 2, 3, 4, 5, 6, 8, 12, and 24 hours postoperatively. All postoperative observations and scores were performed by the same anesthesiologist who was unaware of the patients' group assignment. Pain was assessed using a modification of the pain score scale originally described by Hannallah et al [13]. This assessment allowed for a maximum score of 10 and a minimum of 0. This scale has been validated in infants and children and has been used to score pain after ENT surgery [3,14]. Duringthe first 6 hours, patients with a pain score of 4 or more received rescue analgesia with IV meperidine 0.5 mg/kg, to a total dose of 1.0 mg/kg until the pain score was b 4. Thereafter, oral paracetamol 20 mg/kg was administered every 6 hours. Any patient with a pain score of 4 or more, in spite of having received oral paracetamol, received oral ibuprofen 10 mg/kg.

IV paracetamol in children post-tonsillectomy Table 1 Patient characteristics and duration of anesthesia and surgery Variable Paracetamol Tramadol P-value group (n = 32) group (n = 32) Age (yrs) 10 (6-16) 10 (6-15) 0.551 Weight (kg) 34 (33-58) 35 (33-70) 0.443 Gender 15/17 19/13 0.316 (women/men) Duration of 55.7 F 17.13 52.3 F 17.27 0.108 anesthesia (min) Duration of surgery (min) 44.6 F 16.89 39.3 F 15.59 0.056 Data are medians (minimum-maximum) for age and weight, absolute numbers for gender, and means F SD for duration of anesthesia and surgery. The Pediatric Anesthesia Emergence Delirium (PAED) Scale devised by Sikich and Lerman was used to assess emergence agitation [15]. At the same time points, adverse effects such as PONV, sedation, and rebleeding were recorded. Nausea was defined as an unpleasant feeling associated with an inclination to vomit, and vomiting was defined as the forceful ejection of gastric contents through the mouth. Sedation was assessed using a 4-point scale, where 0 = fully awake, 1 = awake but drowsy, 2 = sleeping, but arousable by light touch or speech, and 3 = sleeping, not arousable). At the end of the study, parents and ward nurses were asked to assess the quality of postoperative analgesia using the following satisfaction scale: 1 = bad, 2 = poor, 3 = good, 4 = excellent. A power analysis based on a previous article [16] showed that a sample size of 20 patients per group was required to achieve a power of 90k and an a of 0.05 for detection of a difference of 2 in objective pain scale (OPS) scores between study groups. All statistical analyses were performed using SPSS for Windows, version 11.5 (SPSS, Chicago, IL, USA). Data are shown as means (SD) and medians (minimummaximum) for continuous variables and frequencies with percentages for categorical variables, respectively. Means were compared using the Mann Whitney U test. The Bonferroni correction was applied for all possible comparisons. For categorical comparisons, Chi-square analysis or Fisher's Exact test were used where appropriate. A P-value less than 0.05 was considered statistically significant. 3. Results Although 66 children were enrolled in the study, one child was excluded from the paracetamol group because of rebleeding that required reoperation one hour after surgery, and one child was excluded from the tramadol group because of early discharge to home. Therefore, the number of patients entered into analysis was 32 in each group. No statistical differences in age, weight, duration of surgery, duration of anesthesia (Table 1), or observational pain scoring at specific time intervals were noted between the two groups (Fig. 1). There were also no significant differences between groups in the number of patients who received rescue analgesia. Intravenous meperidine was given to 10 (31.25k) paracetamol group patients and to 9 (28.1k) tramadol group patients (P = 0.784) (Table 2). The mean time to administration of rescue meperidine analgesia was 10.5 F 6.0 minutes in the paracetamol group and 18.9 F 20.1 minutes in the tramadol group (P = 0.968) (Table 2). One child receiving IV paracetamol and two children receiving tramadol needed two doses of meperidine postoperatively (P = 0.313). At the ward, two children in the paracetamol group and none in the tramadol group received oral ibuprofen (P = 0.492). Eighteen (56.2k) patients in the paracetamol group had an Aldrete score of 10 at admission to the PACU compared with 16 (50k) in the tramadol group (P = 0.616) (Table 2). The median Aldrete scores at PACU admission were 10 (6-10) in the paracetamol group and 10 (8-10) in the tramadol group (P N 0.05) (Table 2). The mean (SD) time to reach an Aldrete score of 10 was 10.6 F 17.8 minutes in the paracetamol group and 18.1 F 22.6 minutes in the tramadol group (P = 0.444) 55 Observational Pain Scores 5 4 3 2 1 0 0 5 10 15 20 25 30 40 50 60 120 180 240 300 360 480 720 1440 Time (minutes) Paracetamol Group Tramadol Group Fig. 1 Mean observational pain scores in the two groups throughout the study period.

56 H.Y. Uysal et al. Table 2 Recovery and analgesic requirements in the study groups Variable Paracetamol Tramadol P-value group (n = 32) group (n = 32) Aldrete score 10 (6-10) 10 (8-10) 0.767 at PACU admission No. of patients 18 (56.2) 16 (50.0) 0.616 with an Aldrete score of 10 at PACU admission (k) Time to reach an 10.62 F 17.85 18.12 F 22.6 0.444 Aldrete score of 10 (min) No. of patients 10 (31.2) 9 (28.1) 0.784 requiring rescue analgesia (k) Time to first rescue analgesia (min) 10.5 F 5.98 18.88 F 20.12 0.968 Data are medians (minimum-maximum), means F SD, or absolute numbers of patients (k). PACU = Postanesthesia Care Unit. (Table 2). The two groups were comparable regarding emergence agitation scores at the PACU. Sedation scores did not change significantly over the course of the assessment period in any group (P = 0.270). No differences in mean HR or MAP were noted between the two groups during the study period (P N 0.05). The frequency of nausea was not significantly different between the two groups (22k in the paracetamol group and 38k in the tramadol group) (P = 0.171). Postoperative vomiting occurred in 19k of paracetamol group patients and 34k of tramadol group patients (P = 0.157). Parents' and nurses' satisfaction scores regarding the quality of pain management were similar in both groups (P = 0.779, P = 0.385) (Table 3 and Table 4). 4. Discussion Table 3 Parent satisfaction scores. Satisfaction Paracetamol group Tramadol group P-value scores * (n = 32) (n = 32) 1 0 (0) 0 (0) 0.779 2 4 (12.5) 3 (9.4) 3 23 (71.9) 22 (68.8) 4 5 (15.6) 7 (21.9) Data are absolute numbers of patients (k). 1 = bad, 2 = good, 3 = very good, 4 = excellent. Table 4 Nurse satisfaction scores Satisfaction Paracetamol group Tramadol group P-value scores * (n = 32) (n = 32) 1 2 (6.3) 0 (0) 0.385 2 9 (28.1) 8 (25) 3 20 (62.5) 23 (71.9) 4 1 (3.1) 1 (3.1) Data are absolute numbers of patients (k). 1 = bad, 2 = good, 3 = very good, 4 = excellent. The analgesic efficacy of IV paracetamol 15 mg/kg and tramadol 1.0 mg/kg in children undergoing adenotonsillectomy was evaluated, and no statistical difference was found between groups regarding postoperative pain scores, rescue analgesic consumption, or PONV. We also failed to show a significant difference in recovery characteristics between the groups. There are conflicting results about the efficacy of IV paracetamol for postoperative analgesia after tonsillectomy in children. According to Pendeville et al, IV proparacetamol 30 mg/kg resulted in higher postoperative pain scores than did IV tramadol 3.0 mg/kg given before surgical incision [17]. Administration of high doses of tramadol 3.0 mg/kg may have contributed to the pronounced low postoperative pain scores in their study. However, in another study, Alhashemi and Daghistani reported that IV paracetamol 15 mg/kg was an efficient analgesic similar to intramuscular (IM) meperidine 1.0 mg/kg for children undergoing tonsillectomy [18]. Evaluation of recovery characteristics and rescue analgesic medication were the other objectives of our study. Alhashemi and Daghistani found earlier readiness for recovery room discharge in pediatric patients undergoing dental restoration with IV paracetamol when compared with IM meperidine [16]. Similarly, in the present study, although statistically no difference was detected in recovery characteristics of both drugs, the mean (SD) time to reach an Aldrete score of 10 in the PACU was shorter in the paracetamol group (10.6 F 17.8 min vs. 18.1 F 22.6 min in the tramadol group). Early readiness for PACU discharge was clinically, not statistically, different in this study, suggesting that IV paracetamol may offer the advantage of early recovery and early discharge from hospital, which leads to beneficial economic aspects for day-case surgeries in children. Despite the high number of patients receiving rescue analgesia, pain scores in both groups were lower over the course of the assessment period in this study. The meperidine rescue analgesia may have influenced the subsequent low pain scores in both groups. These data were in disagreement with the results of Alhashemi and Daghistani [18], who reported a high percentage of patients requiring rescue morphine analgesia in the IV paracetamol group versus the meperidine group. This may be due to the fact that meperidine was more effective than tramadol for pain relief after tonsillectomy in children [19]. Vomiting occurred in 40k to 65k of children after tonsillectomy due to swallowed blood and oropharyngeal

IV paracetamol in children post-tonsillectomy irritation [20-22]. Tracheal intubation and use of opioids and nitrous oxide all have been implicated as anesthetic factors increasing the rate of PONV [23]. The administration of tramadol for postoperative analgesia also may have an additive effect on the incidence of PONV [24,25]. In our study, the frequency of PONV was not as high as has been stated in previous reports. These data may result in part from the anesthetic regimen that we used in both groups. Another explanation for the discrepancy in vomiting data may be the intraoperative administration of tramadol as an IV infusion over 15 minutes, which reduces the frequency of PONV compared with postoperative administration [5,25]. One limitation of our study was the lack of a true placebo group. 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