Effective treatment of postoperative pain is extremely important in children, as pain can cause long-lasting behavioral changes (1). Opioids may be associated with side effects such as sedation, respiratory depression, and vomiting. Meta-analyses in adults have shown that the combination of acetaminophen with a nonsteroidal antiinflammatory drug (NSAID) provides better postoperative analgesia than either drug alone (2–3). It is surprising that, although they are widely used in clinical practice, there is very little evidence to support the use of NSAIDs with acetaminophen in children.
Korpela et al. (4) compared acetaminophen and placebo and found that rectal acetaminophen ≤20 mg/kg does not differ from placebo and that a dose of ≥40 mg/kg is superior to placebo with respect to postoperative pain and need for rescue opioid. Anderson et al. (5) compared acetaminophen 40 mg/kg given orally or rectally. They found that children who received acetaminophen orally had lower pain scores and a smaller requirement for supplemental opioids for 24 h than did children after receiving rectal acetaminophen. When acetaminophen was compared with a NSAID, five of the six pediatric studies found similar visual analog scale (VAS) pain scores with both single drugs (2). Four pediatric studies have compared acetaminophen or a NSAID to a combination of acetaminophen and NSAID (6–9). Three of these studies used very small acetaminophen doses of 15–20 mg/kg (6–8), wherefore the plasma acetaminophen concentration had to be less than the analgetic range (5,10,11). In the study by Viitanen et al. (9) rectal acetaminophen was given only 30 min before the end of anesthesia, which may explain the lack of an additive effect of acetaminophen and NSAID.
The aim of this randomized, double-blind study was to examine the analgesic efficacy and plasma concentration of the currently recommended doses of acetaminophen, ketoprofen, or their combination in children undergoing orthopedic or soft tissue (mainly urologic) inpatient surgical procedures. Ketoprofen is a traditional NSAID that belongs to the same group of phenylpropionic acid derivatives as ibuprofen and naproxen.
One-hundred-twenty children between 1–9 yr of age were included in the study. They were ASA physical status I-II and underwent elective inpatient orthopedic or soft tissue (mainly urologic) surgery. The study was approved by the Institutional Ethics Committee and the National Agency for Medicines. The parents of the children gave written informed consent. Patients were excluded if they had kidney or liver dysfunction or a hemorrhagic diathesis.
All children were premedicated with oral midazolam 0.4–0.5 mg/kg. General anesthesia was induced with IV thiopental or facemask inhalation with sevoflurane in nitrous oxide and oxygen. Before endotracheal intubation a bolus of remifentanil 1 μg/kg was given IV followed by a continuous infusion of remifentanil 0.25 μg · kg−1 · min−1. Endotracheal intubation was facilitated with rocuronium 0.5 mg/kg IV.
After induction of anesthesia the children were randomized by a sealed-envelope method to 3 groups of 40 children each. In the acetaminophen group, the children received rectally lipid-soluble acetaminophen 60 mg/kg (SmithKline Beecham Liquides Industrie, Herouville, France). In the ketoprofen group, the children received ketoprofen 2 mg/kg IV (Orion Pharma, Espoo, Finland). In the combination group, the children received acetaminophen 60 mg/kg rectally and ketoprofen 2 mg/kg IV. The drugs were given by an anesthesia nurse who did not participate in postoperative care. Investigators were blinded regarding the patients' study medications.
Anesthesia was maintained with sevoflurane 1–1.5 minimum alveolar concentration (MAC) in nitrous oxide and oxygen 2:1. Hemoglobin oxygen saturation, end-tidal carbon dioxide, electrocardiogram, and arterial blood pressure were monitored during anesthesia. The infusion rate of remifentanil was increased if there was an increase of ≥20% in heart rate or mean arterial blood pressure. No other opioids or local anesthetics were given. Remifentanil infusion and sevoflurane were discontinued at the end of operation. Thereafter, the inspired gas mixture was switched to 100% oxygen and the child was tracheally extubated and transferred to the postanesthesia care unit (PACU).
One blinded investigator followed each child for 2 h in the PACU. Postoperative pain was assessed using the behavioral Objective Pain Scale (OPS) (12). OPS is an observer assessment based on facial expression, vocalization, movement or rigidity of the limbs and body, response to handling and irritability, and measured cardiorespiratory variables. In the OPS score, 0 = no pain, 1–3 = mild pain, 4–5 = moderate pain, 6–8 = severe pain, and 9 = worst possible pain. Because of the young age of most of the children, self-assessment of pain was not used. OPS scores were recorded at 10 min intervals after arrival at the PACU as the highest score during the preceding 10-min period. Rescue pain medication in the PACU and on the ward was morphine 0.05 mg/kg IV.
Eight hours after the administration of the first study drugs, the children received the second doses of the study drugs. Children of the acetaminophen group received acetaminophen effervescent tablet 40 mg/kg (Smith Kline Beecham Liquides Industrie, Herouville, France) dissolved in 100 mL of water and a 10-mL injection of saline 0.9% IV. Children of the ketoprofen group received ketoprofen 2 mg/kg dissolved in 10 mL of 0.9% saline and a 1-gram vitamin C effervescent tablet (Orion Pharma, Espoo, Finland) dissolved in 100 mL of water. Children of the combination group received acetaminophen 40 mg/kg orally and ketoprofen 2 mg/kg IV. Study drugs were individually packed in the PACU by a nurse who administered the first drug doses. The ward nurse who gave the drugs to the children was blinded regarding the content (placebo or active drug) of the drugs provided to them (the two effervescent tablets were of the same size and color). On the ward, pain was assessed hourly as the highest OPS score during the preceding hour. The observation time was 24 h.
Four hours after the administration of first the study drugs, a venous blood sample was drawn from each child for the analysis of acetaminophen and ketoprofen plasma concentrations. Plasma was separated by centrifugation and stored at −20°C until analysis. Plasma concentration of acetaminophen was measured colorimetrically using an enzymatic reaction. The detection limit was 4.6 μmol/L and the inter- and intra-assay coefficients of variation were 6.3% and 0.6%, respectively. Ketoprofen was analyzed with high-performance liquid chromatography by a modification of that described by Upton et al. (13), as ibuprofen was used as an internal standard. The detection limit was 0.02 μg/mL and the inter- and intra-day coefficients of variation were 7.3% and 3.4%, respectively.
In this study the primary outcome variable was morphine consumption in the first 24 h. Secondary outcome variables were time to first postoperative analgesia and behavioral OPS. In addition side effects (nausea and vomiting, antiemetic use, urinary retention, and itching) and acetaminophen and ketoprofen plasma concentrations were assessed.
The meta-analysis by Hyllested et al. (2) made comparisons between acetaminophen and NSAIDs according to the type of surgery. We also made another analysis comparing the children undergoing orthopedic or soft tissue surgery.
Analysis of variance, the χ2 test, correlation analysis and survival analysis were used for statistical analysis when appropriate. In the analysis of variance the homogeneity of variances was checked by Levene's test. No violations were detected. Multiple comparisons were done by Tukey's HSD test. Survival analysis tests included comparisons of multiple groups and plots of cumulative proportions of surviving (Kaplan-Meier). Power analysis showed that a group size of 34 would be needed to detect a 30% decrease in morphine consumption in the combination group compared with the groups receiving acetaminophen or ketoprofen alone (α = 0.05, β = 0.80). Between-group comparisons were made at 30, 60, 90, and 120 min after children arrived at the PACU and at 6, 12, 18, and 24 h in the ward. A P value of <0.05 was considered statistically significant.
Based on a box plot analysis one child in each group was regarded as an outlier because of morphine requirement that exceeded 3 sd from the mean of the group. Thus 117 children were available for the analysis of recovery room data. A further 8 patients were excluded from the 24-h data analysis for the following reasons: 3 children in the acetaminophen group and 3 in the combination group refused to take acetaminophen orally, 1 child in the acetaminophen group had an early reoperation for a surgical reason, and 1 child in the ketoprofen group did not receive ketoprofen because of a malfunctioning IV-line. Thus complete 24-h analysis was successful in 109 children. Demographic data of the patients and the type of surgery are summarized in Table 1. There were no significant demographic differences among the groups.
Analysis of variance showed that at specific time points in the PACU the number of morphine doses per child was significantly smaller in the combination than in the acetaminophen or the ketoprofen group (P < 0.05) (Fig. 1A, Table 2). There was no difference between the single drug groups with respect to the cumulative morphine requirement in PACU. On the ward, there were no intergroup differences in morphine requirement during the time period of 2–24 h after the end of anesthesia (Table 2). However, the cumulative number of morphine doses per child remained significantly smaller in the combination group than in the acetaminophen group (P < 0.05) (Fig. 1B).
Survival analysis showed that the mean time to the first morphine request was significantly longer in the combination group (46 min) compared with the acetaminophen (21 min, P < 0.01) or the ketoprofen (31 min, P < 0.05) groups. The difference between acetaminophen and ketoprofen groups was not statistically significant.
The percentage of children who experienced severe pain (OPS scores of 6–9) at any time in the PACU was less in the combination than in the acetaminophen or the ketoprofen group (44% versus 64%–67%) (P < 0.05) (Fig. 2A). In all groups, 70%–73% of the OPS scores in PACU and 78%–86% of the scores on the ward showed no pain or the child was sleeping (not significant). On the ward the percentage of children whose maximal pain score was mild was significantly larger in the combination than in the acetaminophen group (Fig. 2B).
Kaplan-Meier analysis showed that after orthopedic surgery children of the combination group required less rescue morphine than children of the acetaminophen or ketoprofen groups. The average number of morphine doses per child during the 24-h postoperative period among orthopedic patients was 3.5 versus 5.7 and 5.5 doses in the combination, acetaminophen, and ketoprofen groups, respectively (P < 0.05) (Table 3) (Fig. 3A). After soft tissue surgery there were no differences in opioid requirement among the three groups (Table 3) (Fig. 3B).
In the orthopedic patients the percentage of children whose maximal pain was mild was larger in the combination than in the ketoprofen or the acetaminophen groups in the PACU and larger in the combination than in the acetaminophen group on the postoperative ward (P < 0.05) (Fig. 4A). In the PACU the orthopedic patients in the combination group experienced less severe pain than children of the acetaminophen group (P < 0.05). In soft tissue surgical patients there were no between-group differences in OPS scores neither in PACU nor on the ward (Fig. 4B).
The acetaminophen plasma concentration at 4 h after the administration of the drug was 125.1 (53.8) (range, 8.8–263.5) μmol/L. Eighty-four percent of children had a plasma acetaminophen concentration of more than the antipyretic threshold concentration of 67 μmol/L. The ketoprofen plasma concentration was 2.6 (1.7) (range, 0.9–9.1) μg/mL. There were no differences in acetaminophen or ketoprofen concentrations if the drugs were given alone or in combination.
Nausea and vomiting were the most frequent side effects recorded. The incidence of nausea was 56%, 51%, and 42% in the combination, the acetaminophen, and the ketoprofen groups, respectively (not significant). The corresponding figures for vomiting were 56%, 63%, and 47% (not significant). One third of the children in each group received antiemetic medication postoperatively. Urinary retention occurred in 5 of the 66 children (8%) who did not have a urinary catheter. One child in the combination and one in the ketoprofen group experienced significant itching. No patient experienced signs of abnormal bleeding.
Our results show that relatively large doses of acetaminophen and ketoprofen provided equal analgesia in children undergoing orthopedic or soft tissue inpatient surgery performed under general anesthesia with remifentanil. The combination of acetaminophen with ketoprofen provided better analgesia than acetaminophen or ketoprofen alone in the PACU, but the clear difference persisted only among the orthopedic children in the postoperative ward.
In the present study, cumulative morphine consumption in the combination group was reduced approximately 30% compared with the parent drug groups. This is in agreement with the review of Hyllested et al. (2), in which reductions varying from 33%–46% were reported in adults when the combination of acetaminophen and NSAID was compared with acetaminophen. Even through the morphine requirement of the single drug groups did not differ from each other, only the acetaminophen group differed from the combination group statistically. Morphine consumption in the ketoprofen group did not differ significantly from the combination group, probably because of large individual variation within the ketoprofen group.
The doses of acetaminophen (60 mg/kg rectally plus 40 mg/kg orally) and ketoprofen (2 mg/kg IV twice) we used were based on published data (5,10,14,15). In the study of Birmingham et al. (13) acetaminophen 40 mg/kg rectally was followed every 6 hours by acetaminophen 20 mg/kg. Anderson et al. (5) found that acetaminophen 40 mg/kg orally provided longer lasting analgesia than 40 mg/kg rectally. In our study, the second dose was given late in the evening to allow sufficient basic analgesia for the night. With these relatively large doses of acetaminophen and ketoprofen, the parent drug groups did not differ from each other in morphine requirement or pain scores.
In this study after orthopedic surgery the combined use of acetaminophen and ketoprofen provided better analgesia than either parent drug alone during the 24-hour postoperative period. Earlier studies in adults undergoing orthopedic surgery have shown either reduced morphine consumption (16) or better analgesia (17) after combined use of acetaminophen and a NSAID, but this result is the first in children.
Acetaminophen and ketoprofen have different mechanisms of action. Acetaminophen inhibits brain cyclooxygenase (18) whereas ketoprofen inhibits prostaglandin synthesis, mainly peripherally but also centrally (19–20). Acetaminophen exerts its antinociceptive effect also through the opioidergic system, modulating dynorphin release in the central nervous system (21). Given that remifentanil induces hyperalgesia, it is likely that acetaminophen's impact on dynorphin in the brain inhibited this opioid tolerance. NSAIDs are thought to be effective for relieving postoperative pain after orthopedic surgery when prostanoid activity is enhanced. A recent adult study by Sinatra et al. (22) also showed that IV acetaminophen alone provided rapid and effective analgesia after major orthopedic surgery. Because there were no differences in analgesia between acetaminophen and ketoprofen alone, acetaminophen 60 mg/kg rectally plus 40 mg/kg orally seems to provide effective pain relief in children when there are contraindications to NSAIDs.
After other types of surgery, e.g., thyroidectomy, the combination of propacetamol and ketoprofen did not improve analgesia compared with ketoprofen alone (23). This is corroborated by our results in children undergoing soft tissue surgery, among whom the combination of acetaminophen and ketoprofen did not show a great difference from the single drugs. Therefore, pain relief from the combination of acetaminophen and NSAIDs may depend on the type of surgery. Further studies are needed in children to compare analgesia between the combination of acetaminophen and NSAID and parent drugs after major orthopedic surgery.
In the present study the acetaminophen daily dose was 100 mg/kg. Nahata et al. (24) gave oral acetaminophen 66–81 mg/kg for 3 days to febrile children and found no evidence of hepatotoxicity. Earlier studies suggest that a dose of 80–100 mg/kg acetaminophen per day can be given postoperatively for 2–3 days (25–26). Acetaminophen plasma concentrations obtained 4 hours after the first drug administration were within or over the antipyretic range in 84% of the children. All individual acetaminophen plasma concentrations were well below levels associated with potential liver toxicity (800 μmol/L) (27). It is noteworthy that the combination of acetaminophen and NSAIDs may cause interstitial papillary necrosis when large doses are used over a prolonged period (28).
The most common side effect among our children was postoperative nausea and vomiting (PONV), occurring in 42%–63% of the children in all study groups. Recent meta-analysis in adults showed that when acetaminophen or NSAIDs were given with patient-controlled analgesia morphine, morphine consumption was reduced, but only NSAIDs reduced PONV (29–30). However, as the incidence of PONV was similar in all groups, it is likely that the most important reason for PONV was perioperative and postoperative opioid treatment. Even a single dose of morphine at the induction of anesthesia can increase PONV in children (30).
We conclude that the combination of acetaminophen and ketoprofen reduced postoperative opioid requirements by 30% compared with single drug administration. This effect was especially enhanced after orthopedic surgery.
The authors thank the nursing staff and pain consultant nurses Saimi Rauhala, Anette Lemström, and Tuula Hartikainen for their help with the conduct of this study, Hannu Iso-Aho for statistical analyses, and Professor R. J. Rintala for his valuable remarks in the preparation of the manuscript.
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