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Effect of intraoperative intravenous acetaminophen vs. intramuscular meperidine on pain and discharge time after paediatric dental restoration

Alhashemi, J. A.*; Daghistani, M. F.*

European Journal of Anaesthesiology: February 2007 - Volume 24 - Issue 2 - p 128–133
doi: 10.1017/S0265021506001232
Original Article

Background and objective: Enteral acetaminophen (paracetamol) has limited analgesic efficacy due to its delayed absorption and sub-therapeutic plasma concentration. Intravenous (i.v.) acetaminophen solves this issue and could thus provide adequate analgesia as a single agent. We compared intraoperative i.v. acetaminophen with intramuscular (i.m.) meperidine with regard to postoperative analgesia and readiness for discharge in paediatric patients undergoing day care dental restoration.

Methods: Forty children were randomized, in this double-blind study, to receive acetaminophen 15 mg kg−1 i.v. (Group A) or meperidine 1 mg kg−1 i.m. (Group M) after anaesthesia induction and before surgery. All patients received midazolam 0.5 mg kg−1 orally 30 min preoperatively and fentanyl 1 μg kg−1 i.v. immediately after induction. Anaesthesia was induced with either sevoflurane inhalation or propofol 3 mg kg−1 i.v. and was maintained with sevoflurane. Postoperatively, the objective pain scale, Ramsay sedation score, and Aldrete score were determined every 5 min until readiness for recovery room discharge (defined as achieving an Aldrete score of 10).

Results: Group A had slightly higher pain scores during early recovery compared with Group M (estimated marginal means: 3 ± SEM 0.4 vs. 2 ± SEM 0.4, respectively (95% CI for difference: 0.4, 2.6), P = 0.012 for F-test). In contrast, Ramsay scores were higher in Group M than in Group A during assessment period (estimated marginal means: 4 ± SEM 0.3 vs. 2 ± SEM 0.4, respectively (95% CI for difference: −2.3, −0.3), P = 0.013 for F-test). Group A patients achieved an Aldrete score of 10 sooner than those in Group M (5 ± SEM 2 vs. 16 ± SEM 4 min, respectively (95% CI for difference: −9, −14), P = 0.009).

Conclusion: Compared with i.m. meperidine, intraoperative i.v. acetaminophen resulted in slightly higher pain scores but earlier readiness for recovery room discharge in paediatric patients undergoing dental restoration. The potential economic benefit of early recovery room discharge needs to be further explored.

*King Abdulaziz Medical City, Department of Anesthesia, Jeddah, Saudi Arabia

Correspondence to: Jamal A. Alhashemi, Department of Anesthesia and Critical Care, King Abdulaziz University Hospital, P.O. Box 31648, Jeddah 21418, Saudi Arabia. E-mail:; Fax: +966 2 6408015

Accepted for publication 25 June 2006

First published online 8 August 2006

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Pain after dental surgery under general anaesthesia has been identified as the most prevalent and long-lasting symptom of postoperative morbidity among paediatric patients [1]. Opioids and non-steroidal anti-inflammatory drugs are commonly used to treat postoperative pain [2], however, these drugs may increase the risk of respiratory depression and postoperative bleeding, respectively [3]. In contrast, acetaminophen (paracetamol) is a non-opioid analgesic that is devoid of these risks [3], and its enteral formulation has been used alone [4] and as an adjunct to other agents in the management of postoperative pain [5]. However, the efficacy of enteral acetaminophen as a stand alone analgesic has been hampered by its delayed absorption [6] and sub-therapeutic plasma concentrations [3,7] which have made this form of analgesia less than ideal in the immediate postoperative period [3,4]. Recently, an intravenous (i.v.) formulation of acetaminophen has been introduced, and its safety and pharmacokinetic properties have been established in children as young as 1 yr of age [8]. This new formulation may confer added analgesic benefit over that of enteral acetaminophen, as it solves the bioavailability issue associated with the latter formulation, and may thus prove effective as monotherapy in patients undergoing ambulatory dental surgery.

A randomized, double-blind, double-dummy, clinical study was undertaken to compare the postoperative analgesic effects of intraoperatively administered i.v. acetaminophen with those of intramuscular (i.m.) meperidine in children undergoing dental restoration under general anaesthesia.

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Study population

After institutional Ethics Committee approval, we asked 50 parents/guardians to have their children participate in this randomized, double-blind, double-dummy, clinical trial (Fig. 1). Children were considered for inclusion if they were 3–16 yr of age, ASA I or II and scheduled for elective dental restoration under general anaesthesia. Patients were not enrolled in the study if they had any of the followings: planned dental extraction, delayed mental development, neurological dysfunction, renal insufficiency or allergy to any of the study medications. Parents/ guardians of 40 children gave informed consent for participation in the study and their children were randomized to one of two treatment groups; i.v. acetaminophen (Group A) or i.m. meperidine (Group M).

Figure 1.

Figure 1.

Randomization of study medications was performed by the hospital's pharmacy using a computer-generated random list and study drugs were delivered in an infusion bag labelled ‘drug 1’ and a 3-mL syringe labelled ‘drug 2’ for each patient to ensure blinding. All study patients were premedicated with midazolam 0.5 mg kg−1 orally 30 min before the procedure and received fentanyl 1 μg kg−1 i.v. immediately after induction of general anaesthesia, which was performed with either sevoflurane inhalation or propofol 2–3 mg kg−1 i.v. Subsequently and before surgery was started, Group A patients received acetaminophen 15 mg kg−1 i.v. (premixed with normal saline to a total volume of 60 mL) and normal saline 1 mL i.m., whereas those in Group M received meperidine 1 mg kg−1 i.m. (premixed with normal saline to total volume of 1 mL) together with normal saline 60 mL i.v. Anaesthesia was maintained, in both groups, with sevoflurane in oxygen/nitrous oxide mixture at a total fresh gas flow of 1L min−1, titrated to keep mean arterial pressure within 20% of baseline values. Other than the single dose of fentanyl administered on anaesthesia induction and the study drugs, no additional opioids or non-steroidal analgesics were administered intraoperatively. In addition, none of the patients received dental local anaesthesia, dexamethasone, or anti-emetic drugs perioperatively. At the end of surgery, sevoflurane and nitrous oxide were discontinued and the patient was put on 100% oxygen at 8L min−1 to rapidly wash out the anaesthetic gases while the lungs were still being mechanically ventilated.

Oxygen saturation (SPO2) (Dinamap Plus; Critikon Inc., Tampa, FL, USA), the objective pain scale (best to worst: 0–10) [9], Ramsay sedation score [10] and Aldrete score [11,12] were determined on admission to the postanaesthesia care unit (PACU) and every 5 min thereafter until patients were ready for discharge, which was determined by achieving an Aldrete score of 10. Rescue analgesia with morphine 0.05 mg kg−1 i.v., as needed, was administered postoperatively for a pain score ≥5 or if the patient requested analgesia during pain assessment. All adverse events including, but not limited to, nausea, vomiting, respiratory depression (respiratory rate ≤10 breaths min−1) and oxygen desaturation (SPO2 ≤ 92%) were documented. The anaesthesiologist who administered the anaesthetic, recovery nurses and the observer who recorded study parameters were all blinded to patients' group assignment.

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Statistical analysis

Study sample size was calculated using a two-sided alpha of 0.05, a population variance of (2)2, and a power of 90% to detect a difference of 2 in objective pain scale (OPS) scores between study groups [13]. All statistical analyses were performed on an intention-to-treat basis. Pain and Ramsay scores were analysed using repeated measures analysis of variance, proportions were compared with Fisher's exact test, and Aldrete scores data were analysed using the log-rank test after constructing Kaplan–Meier survival curves for times to achieving an Aldrete score of 10. Sample size calculation was performed using PS Power and Sample Size Calculations Program®, version 2.1.30 (Copyright © 1997 by Dupont and Plummer) [14], whereas other statistical procedures were performed using SPSS® statistical software (SPSS Inc., Chicago, IL, USA), version 13.0 for Windows®. Results throughout the text and tables are presented as mean ± SD unless otherwise indicated, and statistical significance was defined as P < 0.05.

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All children underwent dental restoration of their primary teeth without extraction, completed the study protocol without deviations, and were analysed for primary and secondary outcomes in the group to which they were randomized. Baseline characteristics were similar between study groups (Table 1). Group M patients had lower pain scores during early recovery (P = 0.012 for the overall F-test of between-subject effects; Fig. 2, Panel A) and were more sedated in recovery (P = 0.013 for the overall F-test of between-subject effects; Fig. 2, Panel B) compared with those in Group A. These results did not change after adjusting for the type of anaesthesia induction used. Three (15%) patients in Group A required a single dose of rescue morphine compared with one (5%) in Group M (P = 0.342). Median (Q1, Q3) time to administering rescue morphine was 5 (2.5, 15) min in Group A compared with 10 min in Group M (P = 0.655). Nine (45%) patients in Group A had an Aldrete score of 10 on admission to recovery and were ready for discharge compared with 4 (20%) in Group M (P > 0.176). Furthermore, Kaplan–Meier survival curves demonstrated that Group A patients achieved an Aldrete score of 10 earlier than those in Group M (P = 0.009, Fig. 3). Accordingly, time to readiness for discharge was shorter in Group A compared with Group M (5 ± SEM 2 vs. 16 ± SEM 4 min, respectively (95% CI for difference: −9, −14), P = 0.009). In contrast, there was no difference between groups with regard to discharge time (32 ± 12 vs. 34 > 10 min for Groups A and M, respectively, P = 0.519). Furthermore, there were no episodes of desaturation, respiratory depression, or other major adverse effects in either group. Postoperative nausea and vomiting occurred in one (5%) patient in each group, but none of the children experienced delayed discharge or unplanned hospital admission.

Table 1

Table 1

Figure 2.

Figure 2.

Figure 3.

Figure 3.

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This is the first randomized, double-blind study that compared the analgesic effects of i.v. acetaminophen with that of i.m. meperidine in paediatric patients undergoing day care dental restoration under general anaesthesia. The study demonstrated that, when administered intraoperatively, i.m. meperidine provided lower pain scores in the immediate postoperative period compared with i.v. acetaminophen; however, i.v. acetaminophen administration was associated with earlier readiness for discharge.

In this study, pain was assessed by the (blinded) nurse using pain scores which have been used to evaluate acute postoperative pain in children 1–12 yr of age [9,15], an age range that is wider than the one observed in this trial (Table 1). This was done in view of the limitation of using the traditional visual analogue scale in very young children. All children studied had restorative surgery of their primary (milk) teeth without extraction and, thus, there were no differences between patients in the magnitude of pain inflicted by surgery. Nevertheless, pain scores were statistically different between the study groups in the early recovery period. This could be attributed to the deeper level of sedation observed in Group M (Fig. 2, Panel B) which had likely resulted from the synergistic effects of midazolam premedication and intraoperative meperidine administration. In support of this are the findings of Patel and colleagues [16] who demonstrated that deeper sedation than intended occurs when meperidine and midazolam are co-administered during endoscopy. On the other hand, it is also possible that i.m. meperidine truly resulted in better postoperative analgesia compared with i.v. acetaminophen. Nevertheless, the facts that the requirement for rescue analgesia and the time to its administration were similar in both study groups together with the observed trend towards decreasing pain scores over time in Group A (Fig. 2, Panel A) suggest that the observed differences in pain scores between study groups were probably clinically minor. In support of this argument are the findings of Farrar and colleagues [17] who demonstrated that the best cut-off point for a patient-determined clinically important analgesic response is a change of ≥2 on a 0–10 numeric rating scale. In this study, the difference in pain scores between groups was <2 throughout recovery (Fig. 2, Panel A). Furthermore, propacetamol (an i.v. prodrug of paracetamol) has been demonstrated to have similar analgesic effects to i.m. morphine and better analgesic properties than placebo in patients undergoing third molar surgery [18]. It is unlikely that the route of meperidine administration had an impact on the outcomes of this study since i.m. meperidine results in peak plasma concentrations 20 min after administration [19], which is well below the average anaesthesia time observed in this study. It is also unlikely that the age distribution of the study patients had an effect on the observed results. This is based on the similar age distribution of the study groups and the fact that it falls within the age limits of the children studied to develop and validate the pain scores [9].

In the current study, sedation levels were assessed using the Ramsay scale which has been used in children of different age groups, ranging from few months to 16 yr of age [20,21]. In addition, the Ramsay sedation scale has been demonstrated to have good correlation with bispectral index in this patient population [20,21]. In this study, i.m. meperidine resulted in deeper levels of sedation in Group M throughout recovery (Fig. 2, Panel B). This could be explained, in part, by the inherent sedative effects of meperidine and their lack thereof in acetaminophen and, in part, by the synergistic effects of midazolam premedication and meperidine administration in Group M [16]. It is unlikely that the observed differences in Ramsay sedation scores were related to the anaesthetic technique itself since patients in both groups were managed equally intraoperatively and had received similar amounts of preoperative midazolam and intraoperative fentanyl. Furthermore, the age of the children studied falls within the age range in which Ramsay sedation scale has been previously used, which makes it unlikely that the age distribution of the study groups had an effect on the observed differences in sedation scores.

An important finding of this study is the earlier readiness for discharge from the recovery unit defined as achieving an Aldrete score of 10, among patients who received i.v. acetaminophen. This was likely due to the lighter levels of sedation observed in Group A compared with Group M. Although an Aldrete score of ≥8 has been described as being adequate for discharge in all age groups [12], we used the optimal score of 10 in this trial. Based on these results and the observation that 45% of patients in Group A had an Aldrete score of 10 and were, thus, ready for discharge on admission there might be an economic benefit if such patients could bypass the recovery unit and be admitted straight from the operating room to a level II recovery area. In support of this proposal is the low incidence of postoperative adverse effects in this patient population as reported by Enever and colleagues [22] who observed a 20% incidence of postoperative nausea and vomiting, and 13% rate of unexpected drowsiness among paediatric patients undergoing ambulatory dental procedures under general anaesthesia. Furthermore, other investigators have identified pain as the most prevalent symptom of postoperative morbidity in paediatric dental surgery patients [1]. Nevertheless, the safety of this proposal would have to be determined first in this patient population before it is implemented and its economic benefit is explored. The observation that actual discharge times were comparable between study groups is in keeping with other studies [23] and reflects the fact that factors other than readiness for discharge affect patients discharge. A common example of such factors is the availability of porters to transfer patients out of the unit. Postoperative adverse events were rare in this study and the occurrence of nausea and vomiting was in keeping with previous reports [1].

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Study limitation

One possible limitation of the current study is the lack of postoperative pain follow-up after discharge. This was not done because the need for pain relief at home after dental restoration is fairly low (13%) [22]. Another potential limitation of this study is the lack of a placebo group. This, however, was foregone based on the fact that children in a placebo group would wake up in pain, and postoperative analgesia would have to be administered in the form of rescue analgesia, which would potentially compromise the quality of pain relief in these children. One may also criticize the lack of dose response curves for the study drugs. However, the dose of i.v. paracetamol used in this study (15 mg kg−1) is a standard dose that has been demonstrated to result in mean plasma concentration of 10 mg L−1 and a mean reduction of 2.6 out of 10 in visual analogue scale in children 2–15 yr of age [8]. In addition, the meperidine dose of 1 mg kg−1 is also a standard dose for postoperative analgesia.

In conclusion, when compared with i.m. meperidine, i.v. acetaminophen was associated with slightly higher pain scores in the early recovery period but earlier readiness for recovery room discharge among paediatric patients undergoing restoration of their primary teeth under general anaesthesia. Based on these findings, i.v. acetaminophen appears to be a reasonable alternative to i.m. meperidine in this patient population. Further studies are required to evaluate the role of i.v. acetaminophen as an adjunct to other analgesic agents in this patient population.

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Conflict of interest

The authors have no conflicts of interest to disclose.

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The authors acknowledge Ms Priya McDonald, RN, of the Post Anesthesia Care Unit and Dr Razaz H. Mujallid of the Department of Anesthesia for the help in collecting and entering the study data. This study was supported, in part, by Bristol Meyer Squibb, Saudi Arabia, solely in the form of providing free study drug.

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