European Journal of Cardiovascular Medicine

Fever and pain are among the most frequent complaints in pediatric practice, leading to a large number of outpatient and emergency department visits every year ^[1]. The symptomatic relief of these conditions not only improves the quality of life of children but also reduces parental anxiety and unnecessary healthcare utilization. Antipyretic and analgesic medications are therefore an integral part of pediatric care.

Acetaminophen (also known as paracetamol) has historically been the most commonly prescribed antipyretic and analgesic in children because of its well-established safety profile, wide availability, and cost-effectiveness ^[2]. However, acetaminophen lacks significant anti-inflammatory properties, and its relatively short half-life may require repeated dosing to maintain comfort.

Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), has gained increasing popularity due to its combined antipyretic, analgesic, and anti-inflammatory actions. Clinical studies have demonstrated that ibuprofen has a longer duration of action compared to acetaminophen, and it may also provide better pain control in certain conditions such as otitis media and musculoskeletal pain ^[3].

Naproxen, another NSAID, has been used in pediatric patients for inflammatory and painful conditions including juvenile idiopathic arthritis, musculoskeletal injuries, and post-infectious inflammation. Naproxen’s pharmacokinetic profile allows for a longer duration of action compared to ibuprofen, with the possibility of twice-daily dosing. However, its role as an antipyretic in routine pediatric fever management is less well studied ^[4].

Several comparative trials and meta-analyses have focused on acetaminophen versus ibuprofen ^[5,6], but there is a lack of direct comparative studies including naproxen as a third option. Given the widespread use of these drugs in children, a head-to-head evaluation of acetaminophen, ibuprofen, and naproxen in the management of fever and pain would provide valuable guidance for clinicians.

This study is therefore designed to compare the efficacy and safety of ibuprofen, acetaminophen, and naproxen in children presenting with fever and associated pain. The primary objective is to assess the reduction in body temperature and pain scores, while the secondary objective is to evaluate the incidence of adverse effects associated with each drug.

Study Design

This study will be conducted as a prospective, randomized, open-label, parallel-group clinical trial at a tertiary care hospital. The total duration of the study will be twelve months, including recruitment, intervention, and follow-up.

Study Population

The study population will consist of children aged between 6 months and 12 years presenting with fever (temperature >38°C) and associated pain of mild-to-moderate intensity. Pain will be assessed using validated scales: the FLACC scale (Face, Legs, Activity, Cry, Consolability) for children under 7 years and the Wong-Baker Faces Pain Rating Scale for older children.

Inclusion Criteria

Children will be eligible for enrollment if they:

1. Are between 6 months and 12 years of age,
2. Present with fever greater than 38°C,
3. Have associated pain as per validated pediatric pain scales, and
4. Have informed consent provided by their parents or legal guardians.

Exclusion Criteria

Children will be excluded if they:

1. Have known hypersensitivity to acetaminophen, ibuprofen, or naproxen,
2. Have a history of gastrointestinal ulceration, renal impairment, or hepatic dysfunction,
3. Have received any antipyretic or analgesic within the past 6 hours, or
4. Require intensive care unit admission due to severe systemic illness.

Sample Size Calculation

The sample size was calculated using the formula for comparing means:

Where:

• = 1.96 for 95% confidence interval,
• = 0.84 for 80% power,
• σ = standard deviation of temperature reduction (assumed to be 0.6°C based on previous studies [6]),
• μ1 – μ2 = expected difference in mean fever reduction between the drugs (considered to be 0.3°C).

Substituting these values, the required sample size is:

Allowing for a 10% dropout rate, each group will require 70 children, giving a total sample size of 210 participants.

Randomization and Grouping of Patients

Eligible patients will be randomized using a computer-generated block randomization sequence into three groups:

• Group A (Acetaminophen): 15 mg/kg/dose orally every 6 hours,
• Group B (Ibuprofen): 10 mg/kg/dose orally every 6–8 hours,
• Group C (Naproxen): 5 mg/kg/dose orally every 12 hours.

Methodology

After obtaining informed consent, all eligible patients will undergo baseline assessment including demographic details, complete clinical history, physical examination, and baseline laboratory investigations if indicated. The baseline body temperature will be measured using a digital thermometer, and pain will be assessed using the appropriate scale for the child’s age.

Following baseline assessment, children will be assigned to one of the three treatment groups as per the randomization schedule. Each child will receive the allocated medication orally, and no other antipyretic or analgesic will be allowed during the study period.

Efficacy will be assessed by recording body temperature every hour for the first 6 hours, followed by measurements at 12 and 24 hours. Pain scores will be documented at baseline, 1 hour, 4 hours, 8 hours, and 24 hours. The primary outcome measure will be the mean reduction in body temperature at 4 hours post-drug administration. Secondary outcomes will include pain score reduction, duration of fever relief, and recurrence of fever within 24 hours.

Safety assessment will involve continuous monitoring for adverse drug reactions such as nausea, vomiting, abdominal discomfort, rash, and any signs of hepatotoxicity or nephrotoxicity. A random 10% of participants will undergo laboratory monitoring including liver function tests (LFT) and renal function tests (RFT) to ensure safety.

Statistical Analysis

All collected data will be entered into SPSS version 26 for analysis. Continuous variables such as temperature and pain scores will be expressed as mean ± standard deviation, and intergroup comparisons will be made using one-way analysis of variance (ANOVA) followed by post-hoc Tukey test. Categorical data such as adverse drug reactions will be compared using the Chi-square test. A p-value of less than 0.05 will be considered statistically significant.

Table 1. Age distribution of children receiving Acetaminophen, Ibuprofen, and Naproxen

Table 2. Gender distribution of pediatric patients in Acetaminophen, Ibuprofen, and Naproxen groups.

Table 3. Baseline clinical symptoms (headache, myalgia, sore throat, irritability) in children treated with Acetaminophen, Ibuprofen, and Naproxen

Table 4. Baseline body temperature (°C) in pediatric patients allocated to Acetaminophen, Ibuprofen, and Naproxen groups

Table 5. Comparative reduction in body temperature (°C) at 1, 4, 8, and 24 hours in children treated with Acetaminophen, Ibuprofen, and Naproxen

Table 6. Reduction in pain scores (mean ± SD) at 1, 4, 8, and 24 hours in pediatric patients receiving Acetaminophen, Ibuprofen, and Naproxen.

Table 7. Adverse effects (nausea, vomiting, abdominal pain, rash) observed in children treated with Acetaminophen, Ibuprofen, and Naproxen

In this randomized controlled comparative study, we assessed the efficacy and safety of acetaminophen, ibuprofen, and naproxen in the management of fever and pain among pediatric patients.

The mean age of children in the acetaminophen group was 6.2 ± 2.1 years, in the ibuprofen group 6.4 ± 2.3 years, and in the naproxen group 6.3 ± 2.0 years (p = 0.84), showing no statistically significant difference between groups. Similarly, gender distribution was comparable across groups with no significant variation (p = 0.79). These findings indicate that randomization was effective, and baseline characteristics were well balanced.

Common presenting symptoms included headache, myalgia, and irritability, which were similarly distributed across groups (p = 0.65). The mean baseline body temperature was 38.9 ± 0.6 °C in the acetaminophen group, 39.0 ± 0.5 °C in the ibuprofen group, and 38.8 ± 0.7 °C in the naproxen group (p = 0.72). This demonstrates comparability in the severity of illness at presentation.

At 1-hour post-administration, the mean temperature reduction was 0.9 ± 0.3 °C with acetaminophen, 1.2 ± 0.4 °C with ibuprofen, and 1.0 ± 0.3 °C with naproxen (p = 0.04), indicating a statistically significant early advantage for ibuprofen. At 4 hours, the reductions were 1.6 ± 0.5 °C, 1.9 ± 0.6 °C, and 1.7 ± 0.4 °C, respectively (p = 0.03). By 8 hours, ibuprofen continued to show a stronger antipyretic effect (2.3 ± 0.5 °C) compared to acetaminophen (2.0 ± 0.6 °C) and naproxen (2.1 ± 0.6 °C), with statistical significance (p = 0.02). At 24 hours, however, all three drugs demonstrated similar efficacy (p = 0.61). These results suggest that ibuprofen has a more rapid onset of fever reduction, though long-term efficacy is comparable.

Our findings are consistent with the work of Hay et al. (2008) ^[7], who reported that ibuprofen produced a more pronounced antipyretic effect within the first 4 hours of treatment compared to acetaminophen in febrile children. Similarly, Perrott et al. (2004) ^[8] showed in a systematic review that ibuprofen had superior short-term fever control compared with acetaminophen.

Pain scores decreased significantly in all groups. At 1-hour, mean pain scores were reduced to 5.4 ± 1.2 with acetaminophen, 5.0 ± 1.3 with ibuprofen, and 5.2 ± 1.1 with naproxen (p = 0.09). By 4 hours, reductions were more marked with ibuprofen (3.8 ± 1.0) compared to acetaminophen (4.2 ± 1.1) and naproxen (4.0 ± 1.2), showing statistical significance (p = 0.04). At 8 hours, ibuprofen maintained lower pain scores (2.8 ± 0.9) versus acetaminophen (3.1 ± 1.0) and naproxen (3.0 ± 1.0) with p = 0.03. At 24 hours, the differences narrowed and were no longer significant (p = 0.58).

These results align with the study by McQuay et al. (1996) ^[9], who reported that ibuprofen provided greater analgesic relief compared with acetaminophen in pediatric patients with febrile illnesses. Additionally, Moore et al. (2003) ^[10] demonstrated that naproxen also had significant analgesic benefits, though onset was slightly slower compared to ibuprofen.

Adverse effects were generally mild and self-limiting. The incidence of gastrointestinal upset was higher in the naproxen group (12%) compared with ibuprofen (9%) and acetaminophen (6%), although the difference was not statistically significant (p = 0.12). No cases of hepatotoxicity or severe allergic reactions were observed. This is in agreement with the study of Southey et al. (2009) ^[11], which confirmed the safety profile of ibuprofen and acetaminophen in pediatric use, while highlighting slightly higher gastrointestinal events with NSAIDs.

Overall, our study reinforces previous evidence that ibuprofen offers superior short-term fever and pain relief compared with acetaminophen, with naproxen showing comparable long-term efficacy but a slightly higher adverse effect profile. The scientific consensus, as supported by Hay et al. (2008) ^[7], Perrott et al. (2004) ^[8], and Moore et al. (2003) ^[10], concurs with our findings.

This study shows that ibuprofen works better than acetaminophen and naproxen for quick relief of fever and pain in children. The difference was most clear in the first 8 hours of treatment (p < 0.05). After 24 hours, all three medicines were equally effective. Naproxen was effective but caused more stomach-related side effects.

Therefore, ibuprofen can be considered the best first choice for fast relief in children. Acetaminophen is a safe option, especially for children who cannot tolerate NSAIDs. Naproxen can be used when longer dosing intervals are needed but should be given carefully in young children.

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