Background

Acute pain is a common symptom in pediatric age. The underlying cause of pain can be medical (e.g., headache, earache, trauma) or surgical (e.g. postoperative pain) [1]. Regardless of its origin, pain can weaken the child’s physical and psychological integrity, and ultimately be a cause of stress for parents. If left untreated, pain may impact the quality of life and determine short- and long-term effects, with patients becoming more sensitive and getting more pain with less provocation in their lifetime [2].

Therefore, pain should always be evaluated with age-appropriate scales and treated adequately in each patient [3].

Despite the availability of guidelines [1, 4], pain in children is often underestimated, and as a consequence undertreated [4, 5] both in patients seen in emergency departments and in patients admitted to hospitals [3].

According to the International Association for the Study of Pain (IASP), multimodal analgesia is one of the possible approaches to manage acute pain [1].

Multimodal analgesia is a pharmacologic method of pain management which combines various groups of medication for pain relief with fewer side effects than single analgesics [1].

Ibuprofen and paracetamol which are commonly used as first-line treatment for acute pain with the same level of evidence, and a comparable efficacy and safety profile, are both recommended for multimodal analgesia [2].

The aim of this research was to share experts’ opinions about the most appropriate use of oral paracetamol and ibuprofen in fixed-dose combination (3.3:1 dose ratio) for the treatment of acute mild-to-moderate pain in children.

Methods

We conducted a Nominal Group Technique (NGT) investigation on the use of oral paracetamol and ibuprofen fixed-dose combination for the treatment of acute mild-to-moderate pain in children.

The NGT is a suitable method for generating ideas and consensus in a virtual format [6]. It represents a direct and structured technique based on experts’ opinion. This study used a modified NGT which included three different phases: initial phase, pre-meeting phase, final meeting phase (Fig. 1).

Fig. 1
figure 1

Scheme of modified NGT method

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Initial phase

The initial phase included the Board identification and the literature search.

Board identification and sharing of objectives

A medical content factory identified a Board composed of nine clinicians with experience in pediatric pain management and one pharmacologist based on their institutional affiliations and if satisfying two of the following selection criteria: documented clinical experience in one of the branches of pediatrics, being active member of scientific societies dealing with pediatric patients and pain management, publications with pediatric pain as topic (at least five in the last five years), and different background (e.g., general practitioner vs hospitalist, size of the hospital, geographic location in the country).

The survey objectives were identified by reviewing the most recent publications [7, 8] and guidelines [1, 4] on acute pain. Objectives were shared with the Board in order to collect valuable opinions and suggestions for the next step.

Literature research

We performed a five-year (April 2017-April 2022) literature search within the PubMed database to identify the topics of the survey. The search was focused on the following keywords: paracetamol, ibuprofen, children, postoperative, headache, rheumatic pain, fixed dose, earache, musculoskeletal pain.

Filters applied during the PubMed search: in the last 5 years, Preschool Child: 2–5 years, Child: 6–12 years; Observational Study (prospective cohorts or retrospective cohorts), Review, Meta-Analysis, Systematic Reviews, Clinical Trial, Classical Article, Humans, English.

The search terms are reported in Additional file 1.

Duplicates were removed from the list of publications. Articles were screened by title and abstract to check the appropriateness of the contents with respect to the research objective. References of the selected articles were screened to search for other possibly missing articles, left out by our research.

Relevant publications on the effecacy, pharmacokinetics, and safety of the paracetamol/ibuprofen fixed-dosecombination for the treatment of acute pain [7,8,9] were analysed. National and international guidelines for the management of pain in children [1, 4] were also reviewed. The analysis also focused on even more critical aspects related to the use of ibuprofen and paracetamol in clinical practice: pain undertreatment, appropriateness of dosage regimen, compliance with guidelines by healthcare professionals, and parents [10, 11].

Pre-meeting phase and questionnaires

Based on the results of the literature research, a first semi-structured open (non-anonymous) survey consisting of ten questions was developed (Table 1). The questionnaire was emailed to the Board members on May 2022 with a copy of the bibliographic search.

Table 1 First questionnairea administered to the Board
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Once collected, the results of the first questionnaire were analysed. Questions were validated if there was an agreement of ≥ 7members. On the other hand, questions were not validated if ≤ 3 members reached the agreement.

The questions and/or options that received an agreement of 4 to 6 Board members were reviewed, amended, and proposed again in a second questionnaire of the NGT survey, after an evaluation phase that involved the Board members and/or the acquisition of supporting literature. All the answers to the open questions provided by the Board were raised as multiple-choice questions.

The second questionnaire included a new multiple-choice question on the willingness of board members to use the fixed-dose combination of paracetamol and ibuprofen for the treatment of acute pain (Table 2). The second open (non-anonymous) survey was administered to the Board, starting on July 2022. Once the responses to the second questionnaire were acquired, they were processed in the form of a descriptive statistical analysis and the materials for the final meeting with the Board were prepared. The final remote meeting, on 31 August 2022 was conducted by a facilitator. All Board members were present at the meeting.

Table 2 Second questionnairea administered to the Board
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The meeting started with a summary of the results obtained from the NGT survey, followed by a brainstorming session. The debate concerned both the already validated questions and those which did not reach a qualified majority. In the final meeting the results of the two questionnaires were shared to confirm the questions validated or to reach the highest possible consensus for those with intermediate score (i.e. agreement 4–6 members). The aim of the meeting was to share experts’ opinions about the most appropriate use of oral paracetamol and ibuprofen in fixed-dose combination for pain management in children.

Results

At the end of this NGT survey, our Board has reached a consensus on 12 questions (Table 3). Among these, questions n. 1, 3, 5, 6, 7, 8, 10 and 12 have been approved in the second round (agreement ≥ 7) and confirmed at the final meeting; the questions n. 1, 5, 8 and 10 had already been validated at the first round. Instead, the questions n. 2, 4, 9 and 11 have been discussed by the Board during the final meeting, because some of their response options had not reached a qualified majority at the second questionnaire.

Table 3 Questions approved at final meeting and clinician' responses
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A summary of the main final statements agreed by the Board is reported below. The full results with the clinicians’responses to the each question of second questionnaire are provided in Table 3.

  • The Board, almost unanimously, has reached a consensus on the use the fixed combination for the treatment of postoperative pain when both anti-inflammatory and analgesic effects are desired or when paracetamol alone is not sufficient to control a postoperative pain.

  • The use suitability of the fixed-dose combination of almost all the post-operative setting with the exclusion of Ear, Nose and Throat (ENT), and abdominal surgery was confirmed, following brainstorming at the final meeting.

  • The oral formulation (suspension) of the fixed combination of paracetamol and ibuprofen was judged suitable in pediatrics being able to optimize the dosage in relation to the weight of the child, reduce parental dosing errors as compared to the combined administration of two separate drugs, and allow for quick pain control with greater effectiveness.

  • The complementarity of the mechanisms of action, as well as the synergy between the effects of the two substances, were deemed as important factors for the efficacy of the fixed combination by the majority of the Board.

  • Greater analgesic power was considered to be the pharmacodynamic advantage of the fixed combination.

  • The fixed combination of paracetamol and ibuprofen was deemed suitable when both drugs used in monotherapy are not efficacy, especially for headache, earache, odontalgia, and musculoskeletal pain.

  • The majority of our Board members reported their willingness to use the fixed combination of paracetamol and ibuprofen for acute moderate (score 4–6) pain.

Discussion

The results of this NGT survey highlighted some key points regarding the use of the combination of paracetamol and ibuprofen in the 3.3:1 dose ratio in pediatric age.

The Board agreed that the fixed-dose combination of paracetamol and ibuprofen could be used as a first-choice treatment in moderate (score 4–6) pain in children (assessment pain with Face, Legs, Activity, Cry, Consolability (FLACC) Scale, WONG-BAKER Scale, Numerical Rating Scale (NRS)).

In agreement with the literature [7], the Board agreed on the greater analgesic potency as the main pharmacodynamic advantage of the fixed-dose combination of ibuprofen and paracetamol. The analgesic efficacy of ibuprofen and paracetamol is well known also when used in monotherapy [9]. The superior analgesic effect of the combination of paracetamol and ibuprofen could be ascribed to an enhancement of the efficacy of the single drugs, the greater inhibitory effect on cyclooxygenase (COX) the inhibition of the inflammatory component by ibuprofen, and the activation of the various analgesic mechanisms by paracetamol [12].

The Board was favorable to switching to the fixed combination when paracetamol or ibuprofen in monotherapy is ineffective in treating mild-to-moderate pain, especially in case of headache, earache, odontalgia, and musculoskeletal pain.

In fact, clinical studies in adults on fixed-dose combination of paracetamol and ibuprofen have shown greater efficacy in pain control with better and lasting analgesic effect, and faster onset of action without compromising tolerability, compared to monotherapy [8, 13]. Moreover, the fixed-dose combination of ibuprofen and paracetamol was found to be significantly more effective in preventing persistent pain in pediatrics [14].

The Board reached a consensus on the use of the fixed combination of ibuprofen and paracetamol in the treatment of postoperative pain. ENT surgery, with specific reference to tonsillectomy, was left out from this indication, due to the risk of Post-Tonsillectomy Hemorrhage (PTH) which is a potentially life-threatening complication. Nonetheless, a recent systematic review of the literature and a meta-analysis reported that when ibuprofen is prescribed at the low or high range of commonly used clinical dosages no statistically significant increased risk of PTH [15].

The Board speculate that the low dose of ibuprofen contained in the combination could result in a safer drug profile that could warrant the use in ENT surgeries. On the other hand, further studies are needed to determine if there is a clinically relevant dose-dependent difference in PTH with ibuprofen [15].

The Board did not agree on the use of the paracetamol and ibuprofen combination in postoperative abdominal surgery, as its superior analgesic effect could hide the causes of the pain. Finally, the combined administration of the two drugs, according to the Board, allows for an appropriate dosage based on body weight, thus achieving greater efficacy, and reducing potential dosing errors both on the part of parents and emergency department [5].

Conclusions

The results of our NGT suggest that the use of the fixed-dose combination of paracetamol and ibuprofen may be a useful option for mild to moderate acute pain control in pediatrics. However, the limited evidence available highlights the need for future well designed studies to better define the advantages of this formulation in the various therapeutic areas.