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Original Research Articles: Original Clinical Research Report

Comparison of Monotherapy Versus Combination of Intravenous Ibuprofen and Propacetamol (Acetaminophen) for Reduction of Postoperative Opioid Administration in Children Undergoing Laparoscopic Hernia Repair: A Double-Blind Randomized Controlled Trial

Lee, Hye-Mi MD*,†; Park, Ji-Hoon MD; Park, Su-Jung MD*,†; Choi, Haegi MD*,†; Lee, Jeong-Rim MD, PhD*,†

Author Information
doi: 10.1213/ANE.0000000000005284
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Abstract

KEY POINTS

  • Questions: Is ibuprofen, acetaminophen, or their combination more effective in reducing pediatric postoperative opioid use?
  • Findings: The drug combination was found superior to acetaminophen monotherapy for the reduction of rescue opioid use immediately after surgery in children.
  • Meaning: Drug combinations should be considered and tested more extensively for pediatric pain management and may help to limit opioid use in these patients.

Pain is common but frequently undertreated following surgery in children.1,2 Opioid medications are often an essential component of pediatric postoperative pain management. However, given their well-known side effects of nausea, vomiting, sedation, and respiratory depression, as well as increasing concerns regarding opioid use disorder even after short periods of use,3,4 there is a practical need to reduce or eliminate pediatric patient exposure to opioids.3–7

Paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used systemic nonopioid agents. The analgesic and opioid-sparing effects of these drugs have been demonstrated in both adults8–10 and children following surgery.3,10 However, in most studies, individual drugs have only been compared to placebos. The efficacy of monotherapy versus a combination of drugs is not well-characterized, particularly in children. This study aimed to investigate whether paracetamol, an NSAID, or a combination of both drugs is the best option to effectively manage pain and reduce opioid administration during the acute postoperative period in children.

METHODS

Ethics

This prospective, randomized, double-blind trial was approved by the Institutional Review Board (IRB #4-2017-0869) of the Yonsei University Health System (Seoul, Republic of Korea) on October 27, 2017. The trial was registered before patient enrolment at ClinicalTrial.gov (NCT03352362, Principal investigator: Jeong-Rim Lee, Date of registration: November 24, 2017). The study protocol was explained to parents beforehand, and written informed consent was obtained on the day of surgery.

This manuscript adheres to the applicable Con-solidated Standards of Reporting Trials (CONSORT) guidelines.

Patients

Children aged 6 months to 6 years and classified as American Society of Anesthesiologists physical status I or II scheduled to undergo laparoscopic inguinal hernia repair were enrolled in this study from November 2017 to March 2019 (n = 159). Patients were excluded if they had clinical evidence or a past medical history of cardiopulmonary, renal, or hepatic dysfunction, or asthma, gastrointestinal bleeding, coagulation disorder, or hypersensitivity to either NSAIDs or paracetamol. Patients were randomly assigned to receive ibuprofen (group I), propacetamol (group P), or a combination of the 2 drugs (group I + P) in a 1:1:1 ratio based on a computer-generated list wherein randomization was achieved using a permuted 3-block strategy (Research Randomizer, version 4.0; SPN, Middletown, CT).

Anesthesia Protocol

General anesthesia was conducted according to the conventional hospital protocol for pediatric patients. Children were admitted early in the morning on the day of surgery, and intravenous cannulation was performed in the ward using a 24-gauge angiocatheter. When a patient arrived at the preoperative treatment room, the attending anesthesiologist confirmed the patient’s medical history and undertook a physical examination to ensure exclusion criteria were not present. Patients were transferred to the operating room, and routine monitoring, including pulse oximetry, electrocardiography, and noninvasive blood pressure measurements, was initiated. Capnography was monitored throughout the intraoperative period. Atropine (0.01 mg·kg−1), lidocaine (1 mg·kg−1), and propofol (2–3 mg·kg−1) were intravenously administered for anesthetic induction, and an attending anesthesiologist initiated assisted mask ventilation with a combination of 100% oxygen and 3%–4% sevoflurane. After confirming the lack of eyelash reflex and other signs of consciousness, rocuronium (0.4–0.6 mg·kg−1) and fentanyl (1 µg·kg−1) were administered. Two to 3 minutes after rocuronium administration, endotracheal intubation was performed. Anesthesia was maintained with a 0.8–1.2 minimal alveolar concentration of sevoflurane in an air/oxygen mixture (fraction of inspired oxygen 0.4). Ventilation was adjusted to target an end-tidal carbon dioxide concentration of 4.7–5.3 kPa, with a delivered tidal volume of 6–8 mL·kg−1.

An optical 5-mm trocar was introduced via an umbilical incision, and pneumoperitoneum was created with carbon dioxide insufflated to obtain an intraabdominal pressure of 10 mm Hg. Two 3-mm trocars were then inserted lateral to the rectus muscle, slightly below the level of the umbilicus. The surgeon approached the internal ring level and ligated it with a nonabsorbable purse-string suture.11 Once the trocars were removed, fentanyl (0.5 µg·kg−1) and dexamethasone (0.2 mg·kg−1) were administered for postoperative analgesia and antiemesis. At the end of surgery, sevoflurane was discontinued, and both atropine (0.01 mg·kg−1) and neostigmine (0.02 mg·kg−1) were administered for the reversal of residual muscle blockade, and the patient was ventilated with 100% oxygen at 6 L·min−1. Extubation was performed when the patient exhibited grimacing, eye-opening, signs of crying, spontaneous turning of the head, and purposeful movement of limbs. Patients were then transferred to the postanesthesia care unit (PACU) where standard monitoring was applied, and vital signs were checked every 10 minutes. If a child experienced separation anxiety, a parent was allowed to stay with the child during recovery.

Rescue fentanyl 1.0 µg·kg−1 was administered for face–legs–activity–crying–consolability (FLACC) scores ≥4,12 while ondansetron 0.1 mg·kg−1 was administered when a patient exhibited retching, vomiting, or nausea. After 30 minutes of recovery, the modified Aldrete score (respiration, saturation by pulse oximetry [SpO2], mental status, circulation, and reflex ability) was checked. Discharge from the PACU was permitted when the patients’ score was ≥9.13

Study Drug Administration Protocol

Concealment of the group allocation from primary physicians, nurses, patients’ parents, and designated researchers was ensured by using sealed, opaque envelopes. The principal investigator, who was the only person with knowledge of the group allocation, prepared and administered the drugs for each study arm,14,15 but was not involved in pain assessment or determination of the necessity of rescue analgesic administration. Anesthesia providers who monitored the patients in the operating room (staff anesthesiologist, nurse anesthetists, and/or anesthesia residents) may have been aware of group allocation, but they did not participate in the study.

Ibuprofen (Caldolor) was diluted to a final concentration of ≤4 mg·mL−1 in 0.9% normal saline to prevent hemolysis and administered intravenously as a 10 mg·kg−1 infusion over 30 minutes after the induction of anesthesia. Propacetamol (Denogan) was administered intravenously as a 30 mg·kg−1 infusion over 15 minutes after the trocars were removed. For group I + P, both infusions were administered as described. Differences in the start time of administration and the duration of drug infusion reflected the differences in the onset time of the drugs and possible side effects.14,16 The total volume of infusion fluids, including nonopioid analgesics, was controlled at 8–10 mL·kg−1·h−1.

Pain Assessment

The severity of postoperative pain was assessed using the FLACC scale. The FLACC scale is a measurement used for children between the ages of 2 months and 7 years who are unable to communicate their pain. The scale is scored in a range of 0–10 using 5 criteria.12 The pain scale was evaluated by a designated independent researcher who did not participate in the anesthesia during the surgery, and therefore, was unaware of which drug(s) was/were administered. The patients were assessed 4 times: on arrival at the PACU, 10 and 20 minutes after admission, and before discharge from the PACU. Fentanyl was administered as a rescue analgesic as needed according to the FLACC score, as described above.

Before discharge from the PACU, parents received instructions on the use of the parents’ postoperative pain measure (PPPM) scores,17 and were instructed to give their child 10 mg·kg−1 ibuprofen syrup for a PPPM score ≥6 or when a child complained of any discomfort.

After discharge, a follow-up phone call was made by the designated independent researcher at 4, 12, and 24 hours after surgery, and parents relayed their child’s pain score and the requirement for additional analgesia.

Outcomes: Postoperative Pain Measurement and Management

The primary outcome was the number of children who received rescue fentanyl in the PACU. Secondary outcomes included FLACC scores in the PACU and PPPM scores at 4, 12, and 24 hours after the operation. The incidence of postoperative nausea and vomiting (PONV) was recorded. The pain medicine requirement for a 24-hour postoperative period as well as adverse events (hypotension, bradycardia, and drug allergic reaction) were also recorded.

Statistical Analysis

The analysis was performed using SPSS 23.0 (SPSS Inc, Chicago, IL). Univariate statistical analysis was conducted to analyze baseline characteristics. We used the Shapiro-Wilk tests to assess the normal distribution. Continuous baseline variables were reported as medians with the interquartile range (IQR), and categorical variables were expressed as n (%). Standardized differences were computed to assess variations in baseline data among groups.

For the primary outcome analysis, the variable was expressed as n (%) and analyzed using the χ2 test among groups. Pairwise group comparisons were also performed using χ2 tests. The differences were reported as relative risk (RR) with a Bonferroni-adjusted 95% confidence interval (CI). For the secondary outcome analysis, FLACC and PPPM scores were analyzed using the Kruskal-Wallis test, and the results were expressed as medians (with the IQR). Pairwise post hoc comparison was performed using the Mann-Whitney U tests. Postoperative nausea, vomiting, and analgesic requirements were analyzed using χ2 tests. A P value <.05 indicated statistical significance.

In the pairwise group comparisons, significance was based on 0.05/3 = 0.017 using the Bonferroni correction.

Sample Size Calculation

Our sample size was calculated based on data obtained in a pilot study, which demonstrated that effect size Cohen’s F was 0.262 for the rescue opioid requirement in children undergoing laparoscopic inguinal hernia repair who were administered propacetamol, ibuprofen, or both as postoperative analgesia. Analysis of variance (ANOVA) indicated a required sample size of 48 patients per group when the significance threshold was 5% with 80% power. A final sample size of 159, with 53 patients per group, was selected to allow for a dropout rate of 10%. While we had calculated the sample size based on continuous pilot data, the primary outcome in this study was actually binary and was analyzed with a χ2 test. For this analysis, a priori calculated sample size of 53 patients per group provides a power of 80% to detect an effect size (Cohen’s w) of 0.246.

RESULTS

Table 1. - Patients Baseline Characteristics
Group I + P n = 47 Group I n = 49 Group P n = 48 Standardized difference
I + P – I I + P – P I – P
Men 29 (61.7%) 28 (57.1%) 21 (43.8%) 0.09 0.36 0.27
Age (mo) 28.0 (15.0–51.0) 31.0 (13.0−51.0) 41.5 (25.8–55.0) −0.01 −0.35 −0.33
Height (cm) 89.0 (79.3–103.9) 90.0 (76.0–103.5) 97.3 (89.9–107.0) 0.06 −0.41 −0.49
Weight (kg) 12.5 (10.5–18.0) 13.0 (9.7–15.9) 14.3 (11.8–17.4) 0.19 −0.18 −0.38
Duration of surgery (min) 41.0 (34.0–48.0) 36.0 (32.5–44.5) 39.0 (33.0–46.0) 0.21 0.14 −0.10
Duration of anesthesia (min) 70.0 (60.0–75.0) 65.0 (55.0–70.0) 65.0 (60.0–70.0) 0.20 0.11 −0.12
Values are expressed as medians (interquartile range) or percentages. Standardized difference = difference in means divided by SD; imbalance defined as absolute value >0.2 or <−0.2, respectively (small effect size).
Abbreviations: I, ibuprofen; P, propacetamol; SD, standard deviation.

F1
Figure 1.:
CONSORT flow diagram. CONSORT indicates Consolidated Standards of Reporting Trials; I, ibuprofen; P, propacetamol.

Among the 159 children enrolled, 144 patients were included in the analysis (Figure 1). The baseline characteristics of patients are presented in Table 1.

Primary Outcome Parameters

F2
Figure 2.:
Percentage of patients receiving postoperative rescue fentanyl (*P < .001, †P < .001). I indicates ibuprofen; P, propacetamol.

The number of children who received rescue fentanyl in the PACU was 14 (28.6 %) in group I, 32 (66.7 %) in group P, and 6 (12.8 %) in group I + P (P < .001) (Figure 2). Posthoc analysis indicated significant differences between group I + P and group P (P < .001, RR 0.19, Bonferroni-adjusted CI, 0.07-0.49), and between group I and group P (P < .001, RR 0.43, Bonferroni-adjusted CI, 0.23-0.78). Group I + P patients did not have a significant reduction in usage of rescue fentanyl as compared with group I (P = .057).

Secondary Outcome Parameters

The highest FLACC scores in the PACU were significantly different among the 3 groups (P < .001). The highest FLACC scores in group I + P were significantly lower than those of group I (P = .007) or group P (P = .001) (Table 2). In addition, ibuprofen monotherapy reduced the FLACC score significantly compared to propacetamol monotherapy (P = .002).

Table 2. - Highest FLACC Scores in the Postanesthesia Care Unit
Group I + P
n = 47
Group I
n = 49
Group P
n = 48
P a
FLACC 3.0 (1.0–3.0) 3.0 (3.0–4.0) 5.0 (3.0–6.0) <.001
P valueb
  Compared with group I + P NA .007c .001c
  Compared with group I NA NA .002c
Values are presented as medians (interquartile range) with P values.
Abbreviations: FLACC, face–legs–activity–crying–consolability; I, ibuprofen; NA, not applicable; P, propacetamol.
aP values were calculated using the Kruskal-Wallis test among 3 groups.
bP values are group comparisons using the Mann-Whitney U test.
cP < .017 with Bonferroni correction.

Immediately after arrival in the recovery room and again after 20 minutes, median FLACC scores were significantly different among the 3 groups (P < .001, .02, respectively). The pairwise comparison of FLACC scores in group I + P and group I was significantly lower than those in group P immediately after arrival in PACU (P = .001, .002; Table 3). After 20 minutes in the PACU, the FLACC score was significantly better in the combination group I + P than in group I and in group P (P = .015, .001, respectively) (Table 3).

Table 3. - FLACC Scores in the Postanesthesia Care Unit
Group I + P
n = 47
Group I
n = 49
Group P
n = 48
P a
Arrival 2.0 (0.0–3.0) 3.0 (2.5–3.0) 5.0 (3.0–6.0) <.001
P valueb
  Compared with group I + P NA .019 .001c
  Compared with group I NA NA .002c
10 min 1.0 (1.0–2.0) 2.0 (1.0–3.0) 1.0 (0.0–3.0) .14
20 min 1.0 (1.0–2.0) 2.0 (0.5–3.0) 1.5 (0.0–3.0) .02
P valueb
  Compared with group I + P NA .015c .001c
  Compared with group I NA NA .674
Discharge 1.0 (1.0–2.0) 2.0 (0.0–2.0) 1.0 (0.3–2.0) .28
Values are presented as medians (interquartile range) with P values.
Abbreviations: FLACC, face–legs–activity–crying–consolability; I, ibuprofen; NA, not applicable; P, propacetamol.
aP values were calculated using the Kruskal-Wallis test among 3 groups.
bP values for group comparisons using the Mann-Whitney U test.
cP < .017 with Bonferroni correction.

The median PPPM scores were significantly different between the 3 groups at 4 and 12 hours after surgery (P = .03, .01, respectively). Patients in group I + P showed significantly lower PPPM scores than group P at 4 and 12 hours after the operation (Table 4).

Table 4. - Parents’ Postoperative Pain Measurement Scores at Postoperative 4, 12, and 24 h
Group I + P
n = 47
Group I
n = 49
Group P
n = 48
P a
4 h 5.0 (2.0–7.0) 6.0 (4.0–8.0) 7.0 (4.0–8.0) .03
P valueb
  Compared with group I + P NA .038 .002c
  Compared with group I NA NA .065
12 h 2.0 (1.0–5.0) 4.0 (2.5–6.0) 5.0 (3.0–6.0) .01
P valueb
  Compared with group I + P NA .113 .001c
  Compared with group I NA NA .13
24 h 1.0 (1.0–5.0) 2.0 (0.0–4.0) 2.0 (1.0–5.0) .18
Values are presented as medians (interquartile range) with P values.
Abbreviations: I, ibuprofen; NA, not applicable; P, propacetamol.
aP values were calculated using the Kruskal-Wallis test among 3 groups.
bP values are for group comparisons using the Mann-Whitney U test.
cP < .017 with Bonferroni correction.

Six children manifested PONV in the PACU, including 1 in group I (2.0%), 2 in group P (4.2%), and 2 in group I + P (6.4%). There were no differences between groups, and there were no perioperative adverse events.

One patient in group I + P (2.1 %) required additional analgesia after discharge, compared with 5 in group I (10.2 %) and 4 in group P (8.3 %), but the differences were not significant.

DISCUSSION

The combination of ibuprofen and propacetamol reduced the frequency of rescue fentanyl administration by 80% compared with propacetamol alone in children aged 6 months to 6 years who underwent laparoscopic hernia repair. The combination also significantly reduced FLACC scores in the PACU as compared to monotherapy with either drug.

Since NSAIDs and paracetamol have different mechanisms of action, it is reasonable to assume that their combination would provide superior analgesia than either drug alone. This hypothesis is supported by animal studies.18–20 However, to show that the combination therapy is superior to monotherapy, it is important to clearly define the target effect and its timing. In this study, we evaluated 2 target effects: reduction in rescue opioid consumption and severity of postoperative pain. If the target effect is focused on reducing rescue opioid consumption after surgery, the combination is only better than propacetamol alone since the magnitude of opioid use reduction was not significant in comparison with the NSAID alone, similarly to what was previously reported.21–23 Meanwhile, if reducing the severity of pain is the target effect, previous studies and our results indicated that the combination therapy decreased the severity of pain to a greater extent than either propacetamol or NSAID alone.21–23 We found that the primary benefit of combining an NSAID with propacetamol is better postoperative analgesia rather than an opioid-sparing effect. Thus, clinicians need to make decisions regarding the use of combination therapy based on the importance of opioid sparing in their practice.

In pediatrics, rectal or oral routes of paracetamol or NSAID administration are more extensively studied than the intravenous route.3 Because of differences in the study methodology, we could not draw direct comparisons with previous studies. NSAIDs and paracetamol were compared in 2 previous studies for children undergoing open hernia repair surgery and in 1 study for children undergoing adenoidectomy, in which the drugs were orally or rectally and administered preoperatively.24–26 In another study that used orally-administered drugs, the mean pain score on arrival at the PACU indicated a need for immediate multiple opioid treatments, even under the most effective nonopioid treatment regimens.25 For children undergoing adenoidectomy for which the anesthetic duration was approximately 30 minutes, the time to the first dose of opioid was not significantly different compared with placebo, and the opioid-sparing effect of rectal acetaminophen and ibuprofen combination was only 28%, which was not different from that of acetaminophen alone (19%) and NSAID alone (27%). The above 3 studies indicate that the oral and rectal administration routes are not effective in maximizing the benefits of combined drugs administered at the appropriate time.

Here, we administered the drugs intravenously during laparoscopic surgery. Intravenous administration provides a higher maximum plasma concentration (Cmax) and a shorter time to Cmax for most drugs, providing faster and more reliable delivery than oral or rectal administration.27 The Tmax of intravenous acetaminophen and ibuprofen is 0.25 and 0.5 hours, respectively.28,29 The Tmax of intravenous acetaminophen is 4 and 10 times shorter than that of oral and rectal acetaminophen, respectively.28 The Tmax of intravenous ibuprofen is 3 times faster than that of oral ibuprofen.29 The Cmax of intravenous acetaminophen (21.6 µg·mL−1) is higher than that of oral (7.9 µg·mL−1) and rectal acetaminophen (12.3 µg·mL−1).28 The Cmax of intravenous ibuprofen is 1.33 times higher than oral ibuprofen.29 In our study, intravenous administration of the NSAID and propacetamol combination resulted in the lowest highest median FLACC scores among the 3 groups. Moreover, 87% of patients in the I + P group required no rescue opioids, compared with 71% and 33% patients in the I and P groups, respectively. These observations suggest that the prompt intravenous administration of propacetamol and an NSAID is required to achieve the desired pain reduction effect at the right time. Further studies making direct comparisons of the routes of administration should be conducted.

Laparoscopic hernia repair surgery induces significant pain, with a mean FLACC score of ≥5 during the acute postoperative period, even when opioids are administered at the end of surgery.30 Up to 80% of children undergoing this procedure require rescue analgesia.30,31 In addition, pain after this procedure is believed to be as intense as that after the open procedure, but of shorter duration. In the case of appendectomy, the pain lasted for a median of 2 days after the laparoscopic procedure, whereas 5 days after the open surgery.1 Therefore, the opioid-sparing effect needs to be tested as a pragmatic and meaningful end point for children suffering intense but short duration of postoperative pain.32 However, the effect of the combination therapy must be studied in various postoperative pain management settings because its efficacy may depend on specific characteristics and the severity of pain.33,34 Furthermore, the route of administration may also affect the analgesic effect.

This trial had several limitations. First, we used propacetamol, a prodrug form of paracetamol,15 because paracetamol was not available at our institute at the time of this study. We also used twice the usual dose based on the observation that 15 mg·kg−1 paracetamol and 30 mg·kg−1 propacetamol had similar outcomes in terms of their analgesic effects and durations.35 Second, no specific analgesia was recommended to patients after discharge from the PACU. Third, serious adverse events (SAEs) could not be observed because of the small sample size. However, in a previous study of 556 adults using a similar protocol, adverse event incidence did not differ among the 3 groups, and no patient developed a directly drug-related SAE.23 Finally, we defined the primary end point as rescue opioid use at the PACU and considered the pain scores as the secondary outcome. Testing hypotheses on these related outcomes in isolation can be problematic because it is difficult to reach a definite conclusion if results are discordant, and this approach requires post hoc decision making. A joint hypothesis testing framework would have avoided the aforementioned limitation.36

In conclusion, we showed that the combined intravenous administration of propacetamol and ibuprofen or ibuprofen alone is more effective than propacetamol alone in reducing acute postoperative opioid use in children undergoing laparoscopic hernia repair surgery. Furthermore, the highest FLACC score in PACU indicated the superiority of the combination over ibuprofen or propacetamol alone.

DISCLOSURES

Name: Hye-Mi Lee, MD.

Contribution: This author helped analyze and interpret the data and prepare the manuscript.

Name: Ji-Hoon Park, MD.

Contribution: This author helped design the study and acquire and analyze the data.

Name: Su-Jung Park, MD.

Contribution: This author helped design the study and review the manuscript.

Name: Haegi Choi, MD.

Contribution: This author helped review the manuscript.

Name: Jeong-Rim Lee, MD, PhD.

Contribution: This author helped design the study, interpret the data, and prepare the manuscript.

This manuscript was handled by: James A. DiNardo, MD, FAAP.

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