Authors: Gian Luigi de’Angelis, Francesca Vincenzi, Fabiola Fornaroli, Daniela Buonvicino, Alberto Chiarugi
Categories: Review, Pain, Fever, Children, Paracetamol, Acetaminophen, Ibuprofen
Source: Italian Journal of Pediatrics
Authors: Gian Luigi de’Angelis, Francesca Vincenzi, Fabiola Fornaroli, Daniela Buonvicino, Alberto Chiarugi
Fever and pain are common symptoms in pediatric patients, often presenting in a variety of clinical settings. Effective management of these conditions is essential to ensuring comfort and preventing complications. Paracetamol (acetaminophen) and ibuprofen are the most frequently used medications for treating fever and pain in children owing to their proven efficacy and safety profiles when used appropriately. However, despite their widespread use, both medications have the potential of having serious adverse effects if misused, highlighting the importance of therapeutic awareness among healthcare providers. A careful evaluation of current clinical guidelines for fever and pain management in children was carried out. A survey of recommendations regarding the dosing, timing, and combination of paracetamol and ibuprofen was also conducted in order to optimize treatment while minimizing risks. Recent evidence supports the combination of these two drugs as both effective and safe for managing moderate to severe pain in pediatric patients, offering enhanced symptom relief without significant increases in side effects. This combination has been shown to provide superior analgesic effects as compared to monotherapy, thus improving patient outcomes. However, it is critical that clinicians adhere to established guidelines to avoid potential complications, such as liver toxicity from excessive paracetamol dosing or gastrointestinal issues from ibuprofen. Overall, therapeutic awareness, guided by evidence-based practices and the careful application of clinical recommendations, is essential for optimizing fever and pain management in pediatric care, ensuring both efficacy and safety in treating these common yet distressing symptoms.
There has been an increasing use of medications, particularly anti-inflammatory and antipyretic drugs, especially following the COVID-19 pandemic. During the COVID-19 pandemic, there was a notable increase in the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Prior to the pandemic, only 12% of patients with gastrointestinal (GI) bleeding had a history of NSAID use. This percentage increased to 36.7% during and after the pandemic, marking a threefold increase. This trend could be attributed to several factors, including the use of NSAIDs during the pandemic, limited access to healthcare facilities, and, notably, self-medication [1].
As early as 2010, the Pediatric Working Group of the Italian Medicines Agency (AIFA) reported an increase in suspected adverse events related to ibuprofen and ketoprofen in conjunction with increased use (from 0.7 per 100,000 pediatric packages sold in 2005 to 1.7 per 100,000 packages sold in the first 9 months of 2010). The adverse events reported primarily involved the GI tract, particularly bleeding, and in some cases, renal damage [2]. The causes were primarily associated with the use of NSAIDs, along with dehydration resulting from fever and/or other concomitant conditions, such as vomiting and diarrhea, which are more frequent during the winter months. In line with these Italian data, the proportion of over-the-counter pediatric ibuprofen packages with respect to other NSAIDs increased from 28% in 2008 to 70% in 2015 [3]. Concurrently, there was an increase in publications regarding adverse events in patients who had used ibuprofen or other NSAIDs, in particular for fever control [3].
Fever is a physiological response to a pathological condition [4]. This definition immediately clarifies that considering fever as something dangerous, and thus to be fought, is deeply erroneous. The increase in body temperature caused by fever is therefore a beneficial event. Only when this increase is significant and associated with patient discomfort is antipyretic intervention advisable. While adults often report malaise discomfort (the so-called “sickness behavior”) even with mild fever, pediatric patients can tolerate marked increases in body temperature without manifesting signs of distress. This indicates that, in children with fever, the use of antipyretics is often contraindicated whether it occurs in a family setting or during hospitalization [2]. The situation is different in the case of hyperthermia. In this case, the increase in body temperature does not follow a physiological response but, instead, results from dysfunctions in the thermoregulatory centers which can be either primary or secondary to various pathophysiological conditions, including drug-induced hyperthermia, such as that caused by neuroleptics or general anesthetics. Hyperthermia, unlike fever, must therefore be carefully monitored and managed to prevent organ dysfunction (e.g., rhabdomyolysis with myoglobin release, precipitation in renal tubules, and the development of acute renal failure). In summary, fever is a response which can be equated to inflammation; it is a defensive response but, if excessive, it can have negative connotations and should be counteracted.
Given these premises, it is evident that there must be physiological mechanisms regulating the onset and resolution of fever. These are related to normal thermoregulation mechanisms. The increase in temperature during fever arises from a shift in the set point of the thermoregulatory systems. Specifically, within the preoptic area of the hypothalamus there are neuronal populations which form the thermoregulatory center [5]. This area can be compared to the “thermostat” of a home heating system. In fact, it is a “hypothalamic thermostat.” This hypothalamic thermostat, along with the complex neural networks which function as its counterpart, has evolved in homeothermic organisms, such as humans, to maintain body temperature within a range of 36.5 °C to 37.5 °C. This means that, when a child has a body temperature of 37.5 °C, the parent can be reassured that the child does not have “a slight fever” or “a temperature elevation,” but is instead in a completely physiological state [6, 7]. Conversely, in the presence of well-known conditions predisposing to fever, almost always characterized by a localized (e.g., abscess) or systemic (e.g., viral infection) inflammatory response, the release of pro-inflammatory cytokines triggers a signaling cascade which alters the hypothalamic thermostat set point, shifting it to higher temperatures. This shift is directly proportional to two fundamental parameters. The first is the intensity of the inflammatory response, which corresponds to a more or less intense cytokine production, and the second is the efficiency of the signaling cascade leading to fever. It is well known that in children, fever rises rapidly and can reach high temperatures, while in adults, the febrile response is less marked and more variable between individuals.
The action of plasma cytokines at the hypothalamic level activates specific receptors on the endothelial cell membrane of capillaries within the preoptic area. This activation leads to the release of arachidonic acid by phospholipase A2 which is then converted to prostaglandin E2 (PGE2) by cyclooxygenase-2 (COX-2). Cyclooxygenase-2 is an inducible isoform in immune cells; however, it is constitutively expressed in endothelial cells, including those in the preoptic area. As a lipid product of arachidonic acid, PGE2 is highly lipophilic and thus crosses the endothelium to reach the brain parenchyma, where it exerts its pyrogenic function [7]. However, before describing how PGE2 triggers fever, it is necessary to define the basic mechanisms of hypothalamic thermoregulation.
In homeothermic organisms, body temperature is determined by the balance of opposing signals generated by two populations of the Warm Insensitive (WI) neurons and the Warm Sensitive (WS) neurons. The WI neurons generate thermogenic signals, indicating that they activate physiological responses to generate and conserve body heat. An important characteristic of WI neurons is that their thermogenic signals maintain the same intensity regardless of body temperature. These thermogenic signals are antagonized by the thermolytic signals generated by WS neurons which reduce heat production and promote heat dissipation. A key feature of WS neurons is that, unlike WI neurons, the intensity of their thermolytic signals varies according to the temperature to which they are exposed. Thus, WS neurons represent the “hypothalamic thermostat”. Based on their “thermal sensitivity,” and a given hypothalamic temperature, they generate stronger or weaker thermolytic signals in opposition to the thermogenic signals of WI neurons [8].
Thanks to the intrinsic (i.e. innate) thermal sensitivity of WS neurons, body temperature is maintained at 37 °C since, at this temperature, the thermogenic signals of WI neurons balance the thermolytic signals of WS neurons. But what happens when WS neurons, while retaining their “thermal sensitivity,” are unable to function at some point in the course of an inflammatory/immune response? The answer is an increase in body temperature called fever. When fever exists, the PGE2 produced by the endothelium binds to the EP2 prostanoid receptors on WS neurons, inhibiting their activity. This inhibition, in turn, favors the thermogenic signals from WI neurons, leading to the accumulation of heat, an increase in body temperature, and the onset of fever. The degree of fever will depend on the number of pro-inflammatory cytokines synthesized systemically, the quantity of PGE2 produced, and the extent of the inhibition of the WS neurons [8, 9]. These neurons are, therefore, the primary regulators of fever onset and, as will be shown, are also the main target of antipyretic drugs [10].
Pain is a significant concern in pediatric patients and requires targeted management strategies. Pediatric pain can be acute (e.g., post-surgical, traumatic, or inflammatory) or chronic (e.g., juvenile arthritis or other rheumatic disorders). Pain in pediatric populations involves complex pathophysiological mechanisms which are not fully understood but are influenced by developmental, neurobiological, and psychological factors. At the molecular level, nociceptive signaling in children begins with the activation of nociceptors, specialized sensory neurons which detect harmful stimuli. It is well known that, in addition to the primary painful stimulus, classic pro-inflammatory mediators, such as prostanoids, leukotrienes, adenosine triphosphate (ATP) and bradykinin, among others, are released by immune cells and sensitize (i.e. reduce the activation threshold) nociceptor peripheral terminals. This peripheral sensitization triggers sustained firing of the primary sensory neurons which, in turn, prompts central sensitization. The latter is a phenomenon only in part deciphered at the molecular level and which is sustained by the “wind up” and “rewiring” plastic events which occur at the level of the dorsal horn of the spinal cord. A key role in central sensitization to pain is played by the deranged activation of NMDA (N-methyl-D-aspartate) receptors and the release of glutamate which enhances synaptic transmission and lowers pain thresholds. In addition, alterations in the expression of ion channels, such as sodium and calcium channels, contribute to a prolonged pain state. In pediatric patients, the maturation of the central nervous system plays a significant role in pain processing, with a more pronounced plasticity during early development which can amplify or modulate pain responses. Furthermore, genetic mutations, including those occurring at the SCN9A and SCN10A genes, which encode the Nav1.7 and Nav1.8 sodium channels, respectively can influence pain sensitivity and the susceptibility to certain pain conditions. Nav1.7 mutations can lead to the so-called “congenital insensitivity to pain”, a rare genetic disease characterized by the complete inability to feel pain throughout their entire lifespan. The role of the immune system is also critical since inflammatory cytokines (e.g., Interleukin-1β [IL-1β], tumor necrosis factor alpha [TNF-α]) and glial cell activation in the spinal cord contribute to both acute and chronic pain states. Psychosocial factors, such as emotional stress, family dynamics, and past pain experiences, also affect pain perception, emphasizing the importance of a multidisciplinary approach to pediatric pain management [11–17].
Fever is one of the most commonly observed signs/symptoms in pediatric clinical practice, responsible for over 30% of medical visit requests in childhood [18]. Fever management tends to be characterized by excessive treatment, often driven by anxiety and ‘fever phobia’ among parents. Fever is defined as an increase in the body’s central temperature above the normal range. According to the World Health Organization, the normal central temperature is considered to be between 36.5 °C and 37.5 °C.
Ideally, the central temperature should be measured, which requires the use of invasive techniques. For this reason, body temperature is measured at easily accessible sites, such as the axilla, under the tongue, in the rectum, or in the ear canal. There are various instruments available with varying accuracy for measuring body temperature. Mercury thermometers were previously the most commonly used; however, they have been banned due to concerns regarding mercury toxicity. Digital thermometers are reliable, low-cost, and fast; they require 2 min to record the temperature, which is displayed on a screen, and they also have an audible alarm. These thermometers can be used to measure axillary, rectal, or oral temperatures. Liquid crystal thermometers are not recommended due to their poor accuracy. Infrared thermometers with optical distance pointers are likely the best option since they are as accurate as electronic thermometers but much faster and better tolerated by children, and they can also be used while the child is asleep. Furthermore, the non-contact feature eliminates the need for disinfection when used by multiple individuals. Ear thermometers provide rapid measurements but are more invasive and can produce inaccurate readings if not properly positioned. Due to their low reliability, these thermometers are not recommended. Finally, there are infrared thermometers designed to measure the temperature of the forehead through direct contact [19].
Regarding measurement sites, rectal measurement seems to be the closest to central temperature measurement; however, it is not recommended due to the risk of rectal injury. Axillary measurement is easy and well tolerated by patients of all ages. Oral measurement is unreliable and influenced by many confounding factors, such as food temperature or mucosal conditions; the Italian Society of Pediatrics (SIP) Guidelines recommend avoiding it in all children. Tympanic measurement has several limitations, primarily related to the operator’s technique and the child’s age (e.g., curvature of the ear canal and distance to the tympanic membrane), especially in the early stages of life. The presence of erythema or earwax may also interfere with the measurement. Tympanic thermometers can be used in hospital or outpatient settings [20].
Pain is an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage. Each individual learns the application of the word pain through experiences related to trauma during early childhood [21]. From a clinical perspective, pain can be classified as acute, chronic, procedural, or terminal, while from an etiopathogenetic point of view, it can be nociceptive, neuropathic, nociplastic, or psychogenic. Pain is a common symptom in the course of numerous disorders; it is often an important sign which helps the initial diagnosis, a sensitive factor indicating either positive or negative disease evolution, and is present during diagnostic and/or therapeutic procedures.
From the end of the second trimester of gestation, the fetus has the anatomical and neurochemical structure necessary to perceive pain, and a “pain memory” exists starting with the neonatal period,. Given the same painful stimulus, neonates perceive pain more intensely than adults. Furthermore, evidence suggests that inadequately treated painful stimuli during childhood have significant effects on the current and future prognosis of the patient. Short-term (e.g., worsening clinical condition, complications, prolonged hospitalization) and long-term (e.g., chronic pain, altered pain threshold, psycho-relational problems) consequences follow chronic pain states during the neonatal-pediatric period, if inadequately managed with analgesic therapy [22].
Therefore, the assessment and proper management of pain in thec pediatric age is important. However, difficulties in assessing pain in the pre-verbal period, particularly the fear that analgesic medications might mask clinical symptoms and/or concerns regarding the adverse effects of analgesic drugs, make pain treatment in pediatric patients challenging and sometimes inadequate. Pediatric patients may receive fewer analgesic treatments than adults with the same diagnosis or those undergoing the same surgical procedure, and sometimes even inadequate dosages.
Pain measurement can be carried out by considering its subjective, behavioral, and physiological dimensions. The subjective dimension is considered the “gold standard”; however, behavioral and physiological dimensions are also important when the subjective condition cannot be assessed. The algometric methods used in pediatrics can be divided into four groups [23–25]:
Self-assessment scales. These constitute the gold standard. They are based on the description the child can provide of their own pain. The main limitations are patient age, and their cognitive and communicative abilities. These scales are used for children over 3 years of age. Multiple tools are available to help the child define the intensity of the perceived pain by using images, drawings, or predefined grids to assign a number to the pain;Hetero-assessment scales. These are used by individuals other than the child (parents/healthcare providers) to evaluate and measure the child’s pain. They are useful in assessing pain in children with cognitive delays. The tools used are the same as those for self-assessment;Physiological methods. These assess the effect of pain on physiological parameters. The most frequent indicators include an increase in heart rate, respiratory rate, blood pressure, palm sweating, and a decrease in transcutaneous oxygen saturation. These are not specific indicators of pain;Behavioral methods. These assess behavioral responses secondary to pain. They do not provide a direct evaluation of the qualitative and quantitative characteristics of the nociceptive stimulus but represent the overall (sensory and emotional) response to the painful experience. The most frequently used behavioral parameters include posture, facial expression, movement, crying, and changes in circadian rhythm (sleep, feeding, relationships). The assessment is carried out using appropriate scales which convert the overall behavioral data (and sometimes physiological data) into objective numerical items.
Three algometric scales are particularly suitable for measuring pain in competent children from 0 to 18 years of
Face, Legs, Activity, Cry, (FLACC) Scale for children under 3 years of age, or for children who cannot provide a subjective pain assessment due to motor or cognitive deficits [26];Wong-Baker Faces Scale for children 3 years of age or older [27];Numeric Scale for children 8 years or older.
For children with neuromotor disabilities, hetero-assessment by parents is used, and physiological parameters may also be determined.
The greatest difficulty in assessing pain is in neonates. There are also algometric scales available for neonates which
Premature Infant Pain Profile (PIPP) [28];FLACC [26];COMFORT Scale (behavioral and physiological parameters) [29, 30].
The drugs currently available as antipyretics for pediatric patients are paracetamol and ibuprofen. Paracetamol and ibuprofen are safe for use in children in different ways, as confirmed by the Food and Drug Administration (FDA) [31, 32]. In addition to their antipyretic properties, paracetamol and ibuprofen are core analgesics in pediatric pain management. Both agents are effective for mild to moderate pain; however, ibuprofen provides additional anti-inflammatory benefits. When monotherapy does not suffice, fixed-dose combinations offer an opioid-sparing alternative, ensuring optimal analgesic effects with reduced adverse events [3, 33–35].
Fever is a physiological increase in body temperature with a regulatory mechanism to control its upper limit, rarely exceeding 41 °C. There is no evidence that fever itself worsens the course of a disease or causes neurological complications; therefore, the primary goal of fever treatment should be to improve the child’s comfort rather than normalize the fever. Several reviews and randomized control trials (RCTs) have shown that antipyretics are ineffective in preventing febrile seizures [36].
Many physicians continue to encourage the use of antipyretics for improving comfort and enhancing recovery by resuming normal activities and feeding, with reduced irritability and general well-being [37].
Whether a temperature threshold should be set for antipyretic treatment is unclear due to insufficient studies. Although the majority of guidelines discourage antipyretic treatment based solely on temperature, studies in the general population have shown that many believe the risk of neurological adverse events increases with temperatures > 40 °C (104 °F), and more than 90% of physicians prescribe antipyretics for temperatures > 39 °C [38].
For fever control, NSAIDs should not be used as routine antipyretics in children. Their use is indicated only when fever is associated with significant discomfort or inflammatory conditions. However, NSAID use should always be avoided in dehydrated children, infants under 3 months of age, and in pediatric patients with asthma, GI disorders or renal impairment [3, 33].
To date, there are only a few studies which address the safety of analgesic drugs in the pediatric age, and often clinical practice is directly translated from adults to children. The clinical response in children is often different from that expected in adults due to differences in drug metabolism and other factors which are inevitably related to the patient’s age. Acute pain is a recurring symptom, and its treatment is often suboptimal as has been demonstrated by an Italian working group in numerous Italian Emergency Departments, the PIPER group (Pain In Pediatric Emergency Room). The group found that, despite the availability of national and international guidelines, pain management in Italian emergency departments remains inadequate and requires multifaceted strategies for improvement, including the development of local policies, staff educational programs, and parental involvement in pain assessment [39]. Effective pain management in pediatric populations is crucial for ensuring both the well-being and the comfort of children during medical procedures [40, 41].
The American Academy of Pediatrics’ consensus statement regarding the assessment and management of pain in children recommends paracetamol, ibuprofen, and opioids as drugs of choice for managing acute pain in pediatric patients [42]. The drugs used for acute pain are divided into opioids, reserved for moderate/severe pain, and non-opioids for moderate pain. The most commonly used drugs for managing mild to moderate pain in children are paracetamol and NSAIDs. There is consolidated experience with these medications which have been extensively studied for their safety and efficacy in pediatric care. Paracetamol is one of the most widely used analgesics in pediatrics, often regarded as the first-line treatment for mild to moderate pain. Paracetamol is often preferred due to its favorable safety profile when administered at recommended doses; NSAIDs, such as ibuprofen, are another cornerstone of pediatric pain management, and have analgesic, anti-inflammatory, and antipyretic effects. The SIP recommends ibuprofen as a first-line option for fever and pain in children, particularly for inflammatory conditions such as musculoskeletal pain [43]. Ibuprofen is typically preferred over other NSAIDs for pediatric patients owing to its safety profile; however, it should still be used cautiously in children with certain conditions, such as renal dysfunction or those having GI problems. Aspirin is contraindicated in children under the age of 12 due to the risk of Reye’s syndrome, a rare but life-threatening condition which causes acute encephalopathy and a fatty liver. The PIPER group emphasizes the importance of prompt pain assessment and management in pediatric emergency settings. They recommend starting with paracetamol for managing mild pain in children, followed by the use of NSAIDs, such as ibuprofen, for moderate pain [39]. For mild to moderate acute pain not relieved by ibuprofen or paracetamol alone, the fixed-dose combination of paracetamol/ibuprofen is indicated for children 2 to 12 years of age [3, 33–35]. By reducing the NSAID dose and leveraging the synergistic effect between the two molecules, it provides improved efficacy as compared to monotherapies, and has a good safety profile.
Although other NSAIDs are indicated in pediatrics, ibuprofen is the only one which can be used starting from 3 months of age, and ketoprofen after 6 years of age. Nimesulide is contraindicated in patients < 12 years of age, and ketorolac and acetylsalicylic acid in patients < 16 years of age [44].
In certain cases, when these medications are insufficient, stronger analgesics, such as opioids or regional anesthesia, may be considered, although these are typically reserved for more severe pain. The group also advocates for the use of combined analgesic therapy under specific circumstances, provided that the pharmacological agents do not interact negatively. The use of ibuprofen for pain control is steadily increasing, partly due to the growing evidence of potential adverse events associated with opioids (sedation, risk of respiratory depression, nausea, vomiting, constipation), especially in patients labeled as “rapid metabolizers”. The FDA has recommended not using codeine in adolescents 12–18 years of age who are obese or have conditions, such as obstructive sleep apnea or severe pulmonary diseases since they may experience serious respiratory problems in the case of the CYP2D6-dependent rapid conversion of codeine into morphine. Due to this pharmacogenetic risk, codeine use is restricted to children over 12 years of age [44].
Determining the appropriate analgesic medication for acute pain in pediatric patients is a complex decision influenced by multiple factors. An administration route also has to be chosen since the oral route for NSAIDs is associated with fewer adverse events than rectal route. A therapeutic decision must consider the duration of the pain (acute or chronic, episodic or recurrent), the pathophysiology (nociceptive, neuropathic, psychogenic, or mixed), and the associated clinical conditions and risk factors (e.g., dehydration, ongoing infection, asthma).
While paracetamol and NSAIDs are generally well-tolerated, it is important to consider the potential side effects and contraindications associated with their use. For example, the prolonged use of NSAIDs can lead to GI irritation, renal impairment, and bleeding risks, especially in children with pre-existing conditions. Moreover, careful attention should be given to ensuring that the correct dosage is followed, as overdosing on either medication can lead to severe adverse effects, such as liver failure in the case of paracetamol and GI bleeding in the case of NSAIDs. Proper education for both healthcare providers and caregivers is essential to ensure safe and effective pain management in pediatric patients. Parents should be informed regarding the importance of adhering to dosing recommendations and recognizing the signs of medication-related adverse events. Furthermore, healthcare professionals should monitor the efficacy of the pain relief and adjust treatment plans accordingly, especially in emergency settings [45].
Paracetamol is an analgesic and antipyretic agent and is the most prescribed analgesic in the world [46]. Paracetamol is a COX inhibitor acting at the peroxidase catalytic site of the enzyme, and therefore undergoes competition by endogenous peroxides (i.e. hydrogen peroxide). This specific type of inhibition is responsible for the inability of the drug to exert an anti-inflammatory effect. Immune cells typically produce the large amounts of peroxides necessary for their immunocompetence and anti-bacterial/fungal/viral activity, so that they inactivate the inhibitory effects of paracetamol on their COX. Conversely, both endothelial and neuronal cells produce very few peroxides to prevent oxidative stress, and in these cells, paracetamol can therefore prompt efficacious COX inhibition at the peroxidase site. The ensuing reduction of the prostanoid synthesis within the endothelia and the brain parenchyma exemplifies both the antipyretic and the analgesic effects of paracetamol. However, according to numerous studies, the analgesic effects of paracetamol are also due to various mechanisms in addition to COX inhibition. In particular, paracetamol is metabolized in the liver in a two-step process, with final production of N-(4-hydroxyphenyl) arachidonylamide (AM404) [46, 47]; AM404 inhibits fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of endogenous cannabinoids (anandamide and diacyl-glycerol). This inhibition prompts the accumulation of cannabinoids and the potentiation of their antinociceptive effects [46, 47].
Ibuprofen was developed in the 1960s and is widely used worldwide to relieve pain and inflammation in both acute and chronic conditions. Like other NSAIDs, ibuprofen inhibits both COX-1 and COX-2, with a weak selectivity towards COX-1. Ibuprofen inhibits the classic cyclooxygenase site of COXs by competing with arachidonic acid for entrance into the catalytic site, thereby blocking the synthesis of prostaglandins and thus downstreaming pro-inflammatory metabolites [48, 49].
In Italy, paracetamol can be used from birth, while ibuprofen is authorized starting from three months of age or 5.6 kg of body weight. The daily dose is chosen based on the child’s age and weight. The recommended dose of paracetamol is 15 mg/kg every 6 h. The optimal analgesic dose of ibuprofen, administered orally, is 10 mg/kg every 6–8 h; the cumulative daily dose should not exceed 30 mg/kg [43].
The majority of guidelines are against treatment aimed directly at fever, regardless of the temperature. In the guidelines which set a temperature threshold for antipyretics, there is little agreement on the specific value, with thresholds ranging from 37.5 °C to 40.5 °C, without a clear rationale [38].
There is no evidence which says that reducing fever decreases morbidity or mortality in febrile illness. The only exception could be in children with chronic conditions who may have reduced metabolic reserves, or critically ill children since these patients maypoorly tolerate the increased metabolic demand associated with fever [50].
A 2017 review of the guidelines emphasized that they all agreed on prescribing antipyretics solely to reduce the discomfort caused by fever, not to simply lower the temperature. All the guidelines agreed on the use of antipyretics, such as paracetamol and ibuprofen, according to the patient’s age, weight, and clinical characteristics [51–53].
The inappropriate use of antipyretics can be dangerous. Many scientific societies have practical guidelines for the management of fever in children with the aim of addressing the discrepancies between evidence and clinical practice, and of reducing the irrational fear of fever and the excessive attempts to suppress it. After numerous findings linking salicylates to Reye’s syndrome, paracetamol progressively replaced aspirin for the treatment of fever [51].
According to a review of 74 guidelines, paracetamol is recommended by all the guidelines, and in 17, it is preferred over ibuprofen thanks to its safety profile, although high-quality evidence has shown that both are effective in lowering temperature [3].
The oral administration of paracetamol remains the first-choice recommendation in pediatrics. Rectal administration should be used when oral administration is poorly tolerated, or in the presence of nausea and/or vomiting, in order to optimize compliance with the therapy [54]. The rectal administration of paracetamol does not guarantee the appropriateness of the dosage since a precise dose relative to weight cannot be administered, and there is uncertainty regarding the amount absorbed with a risk of non-response due to underdosing or overdosing. In fact, according to the American Academy of Pediatrics’ recommendation, rectal paracetamol therapy should be avoided due to the possibility of toxicity since peak drug levels may vary and often do not reach therapeutic targets after the recommended doses are administered [55, 56]. Furthermore, both rectal paracetamol and NSAIDs should be discouraged due to the potential psychological trauma and possible harm from the administration of the suppository via the rectal route.
Safety data regarding NSAID use in infants (< 2 years of age) remain limited. While ibuprofen is widely used in pediatric practice, its safety profile in younger infants has been less extensively studied. The risk of adverse effects, particularly renal impairment and GI bleeding, increases in this age group due to immature drug metabolism and clearance. High interindividual variability in NSAID metabolism in infants can lead to unpredictable drug levels, reinforcing the need for weight-based dosing and close monitoring. The pharmacokinetics of NSAIDs in infants differ significantly from older children and adults. Studies have indicated that ibuprofen undergoes slower clearance in infants under 6 months of age resulting in prolonged drug exposure. In addition, the rectal administration of NSAIDs is associated with highly variable absorption, leading to inconsistent plasma concentrations. This increases the chance of therapeutic failure, resulting in repeated dosing and higher cumulative NSAID exposure. It should be noted that rectal NSAIDs bypass first-pass metabolism differently than the oral forms which may exacerbate systemic adverse effects. Given these concerns, oral administration is preferred whenever possible in pediatric patients [3, 33].
When ibuprofen or paracetamol alone fails to provide sufficient pain relief, the use of a fixed-dose combination (FDC) therapy may be appropriate in children 2–12 years of age. By leveraging the synergistic mechanisms of ibuprofen (anti-inflammatory) and paracetamol (centrally acting analgesic), this approach enhances pain relief while reducing the total NSAID exposure, thereby minimizing GI and renal risks. However, the combination of the two therapies, paracetamol and ibuprofen, is under debate. There is no evidence that alternating the two drugs leads to improved clinical outcomes for fever. This practice provides a small, if any, benefit in temperature control, with a higher risk of supratherapeutic dosing [57, 58]. Paracetamol and ibuprofen should not be considered alternating drugs; instead, they should be used as alternative drugs in case one alone provides no clinical benefit. Notably, the clinically available fixed-dose combination indicated for pain in children 2–12 years of age can also be used when ibuprofen or paracetamol alone are ineffective, reducing the amount of NSAIDs (and therefore adverse events) with improved efficacy due to its synergistic action [3, 33–35]. The majority of fever guidelines discourage the alternation of the two antipyretics, except for the National Institute for Health and Clinical Evidence (NICE) guidelines and the South Australian Ministry of Health which permit the alternating use of the two drugs but only when the distress persists after administration of a single antipyretic [59, 60]. In a study involving over 40,000 cases 0–12 years of age reported to the national surveillance system, the risk of acute kidney injury was found to be significantly higher in patients who had received both drugs combined at full dosage as compared to those treated with ibuprofen alone or paracetamol alone for various indications [61].
Ibuprofen is contraindicated in children with varicella, particularly due to the potential increased risk of secondary skin and soft tissue infections, and invasive streptococcal infections (empyema) [62].
The use of NSAIDs in pediatric populations must be approached with caution due to several potential risks, including acute kidney injury (AKI) and asthma exacerbation; NSAIDs, such as ibuprofen, inhibit COX enzymes which can impair renal blood flow and the glomerular filtration rate, particularly in vulnerable children, such as those who are dehydrated or preterm. Dehydration, which can occur due to fever, vomiting, or inadequate fluid intake, increases the risk of AKI when NSAIDs are administered [63]. This is because NSAIDs can reduce prostaglandin synthesis, leading to vasoconstriction of the afferent arteriole of the nephron, additionally compromising renal perfusion. Studies have indicated that even a single dose of NSAIDs in dehydrated children can trigger significant renal complications, especially in infants and those with underlying renal conditions [64, 65]. Premature infants are particularly at risk due to their immature renal function which can lead to inadequate compensation for the reduced renal blood flow caused by NSAIDs, thus increasing the likelihood of AKI [66].
In addition to renal risks, NSAIDs have been shown to exacerbate asthma in children, with even a single dose potentially triggering an asthma attack in children with aspirin-sensitive asthma. This is due to the inhibition of COX-1 which can lead to an imbalance in the production of prostaglandins and leukotrienes, the mediators involved in the inflammatory response to the airways. Children with asthma, especially those who have been diagnosed with aspirin-exacerbated respiratory disease (AERD), are at an elevated risk of bronchoconstriction and severe asthma attacks following NSAID use [67, 68]. While this reaction is more commonly associated with the chronic use of NSAIDs, there is evidence suggesting that a single dose can cause an acute asthma exacerbation in susceptible children [69]. In fact, short-term NSAID use is definitely associated with asthma exacerbation, while its chronic or cumulative use is still a matter of debate [69]. In conclusion, NSAID use in children, especially in those who are dehydrated, premature, or have asthma/GI disorders, requires extreme caution and monitoring, and should be avoided to prevent serious, and in some cases, life-threatening untoward effects. Healthcare providers should assess the potential risks before prescribing NSAIDs, particularly in vulnerable populations, and explore alternative pain management strategies when necessary.
In recent years, the use of ibuprofen in children with upper respiratory tract infections (URTIs) has raised concerns due to a possible association with serious complications, such as pleural empyema. Several retrospective and prospective studies have indicated that pre-hospital ibuprofen use—especially at high cumulative doses—may predispose children to complicated pneumonia, including parapneumonic effusion, empyema, and lung abscess. A notable Polish study found that a cumulative dose exceeding 78 mg/kg was associated with a 2.5-fold higher risk of pulmonary complications [70]. The proposed mechanisms include ibuprofen’s ability to mask symptoms of bacterial infection, potentially delaying appropriate treatment and its modulation of the inflammatory response, which could promote bacterial proliferation [71]. Notably, in the case of Streptococcus pyogenes or Pneumococcus, the use of ibuprofen may favor invasive infections, such as severe sepsis/toxic shock, pleuropneumopathy, meningitis/meningoencephalitis and necrotizing dermohypodermatitis. This could also be due to the specific intrinsic effect of NSAIDs on the enhancement of streptococcal diffusion via vimentin [72]. Finally, a retrospective multicenter cohort study suggested that taking ibuprofen can be a risk factor for intracranial or orbital complications of acute fronto-ethmoidal sinusitis in children [73]. While ibuprofen remains a common treatment for fever and pain, cautious use is advised in children with respiratory infections, particularly when signs of potential pulmonary complications are present. In such cases, paracetamol may be considered a safer alternative.
While NSAIDs are well tolerated in many cases, their GI risks may be often underestimated. Many believe that a single NSAID dose or rectal administration poses no harm; however, studies have shown that NSAID-induced GI damage can occur after even a single dose, particularly in children with predisposing conditions (e.g., dehydration, infections, chronic diseases). Unlike adults, pediatric patients have a more permeable gut mucosa and a lower gastric prostaglandin synthesis, making them more vulnerable to NSAID-induced injury. Moreover, NSAID-associated GI complications, such as bleeding or ulceration, have been reported even in short-term pediatric use, especially when dehydration or fever coexists [3, 33]. The GI safety of NSAIDs is outlined below.
Gastrointestinal bleeding in pediatric patients is a condition which could necessitate admission to intensive care in 6–20% of cases; if massive GI bleeding could be life-threatening with a worldwide mortality rate of 15% [74]. Bleeding typically involves the proximal GI tract, up to the Treitz ligament, and may present as hematemesis, melena, or hematochezia. The potential causes of GI bleeding vary significantly between geographic regions and may be influenced by factors, such as the prevalence of Helicobacter pylori, the incidence of hepatitis, and the demographic age of a population having associated comorbidities. Liver disease is associated with GI bleeding owing to portal hypertension with variceal bleeding, portal hypertensive gastropathy and acquired coagulopathy. Helicobacter pylori infection and NSAID use are among the primary causes of proximal GI tract bleeding [75].
According to the guidelines of the American College of Gastroenterology, the main risk factors for NSAID-induced GI toxicity include the concomitant use of other medications (corticosteroids, anticoagulants, antiplatelet drugs), previous peptic ulcers, Helicobacter pylori infection, and prolonged or high-dose NSAID therapy. In particular, the risk concerns specific patient critically ill patients at risk for underlying stress ulcers or hypoxemia, reduced gastric pH, and reduced organ perfusion. In these patients, NSAID use may be a trigger for massive GI bleeding [76–78]. Of note, Helicobacter pylori infection independently increases the risk of GI bleeding in NSAID users, even in the absence of overt ulcers or GI symptoms which probably cause mucosal damage and act synergistically with NSAIDs [79]. In addition, prolonged and cumulative NSAID use in chronic patients, particularly those with rheumatological conditions, significantly increases the risk of GI bleeding. This risk is influenced by factors, such as dosage, concurrent medications, age, and previous GI history [80].
Few data exist regarding the incidence of GI bleeding in the pediatric age. Based on a study conducted in France in 2010, the incidence is 1–2 per 10,000 children [81].
Studies in adults indicate that the relative risk (RR) of proximal GI bleeding or perforation depends on the type of NSAID molecule; COX-2 selective inhibitors are less toxic than non-selective NSAIDs (RR 1.9).
A 2017 study noted that, in the past decade, there had been a progressive increase in GI complications, such as bleeding and perforation, with a decrease in upper GI complications and an increase in lower GI complications, including the duodenum, ileum, and colon. The ratio of upper to lower complications changed from 4.1 in 1996 to 1.4 in 2005 [82].
It has been observed that NSAID-induced enteropathies manifest with various symptoms, particularly anemia, protein loss with hypoalbuminemia, malabsorption, and nonspecific abdominal pain. Severe complications, such as perforations and strictures, may also occur [83]. The advent of new endoscopic techniques, such as video capsule ileoscopy and double-balloon enteroscopy, has permitted the detection of lesions in this tract. Lesions in the small intestine are incidentally detected in approximately 71% of patients who chronically use NSAIDs, even though only 10% report dyspeptic symptoms. Therefore, the difficulty in being aware of the prevalence of NSAID-induced enteropathy is due to the poor correlation between NSAID damage and evident symptoms. Until the introduction of these new technologies, the importance of NSAID-induced enteropathy was underestimated when compared to NSAID-induced gastropathy [83]. Some studies have suggested that NSAID damage to the small intestine occurs with the same frequency and severity as damage to the proximal GI tract [83]. Aspirin appeared to be less harmful to the small bowel as compared to other NSAIDs. However, even low-dose aspirin can cause bowel damage with short-term administration [84, 85].
In adults, the use of NSAIDs and proton pump inhibitors (PPIs) increases the risk of developing microscopic colitis [83]. As a matter of fact, NSAIDs hamper the mechanism by which prostaglandins maintain mucosal integrity, thus favoring intestinal permeability to pathogens and inflammation. Long-term or high-dose NSAID use appears to carry a higher risk, although even short-term use has been associated with the above in susceptible individuals. There is no clearly defined threshold dose; however, repeated or chronic use increases the risk [83]. Similarly, PPIs significantly reduce gastric acid secretion which can disrupt the normal gut microbiome, promoting dysbiosis. This may contribute to immune dysregulation in the colonic mucosa, probably also increasing intestinal permeability and promoting mucosal inflammation. In this case, a high dose and chronic use are associated with a higher risk [86].
Video capsule ileoscopy and double-balloon enteroscopy allow for direct visualization of the mucosa. Video capsule ileoscopy is a technique also used in pediatric patients. It was first used in 1999 and was approved by the FDA in 2001. In 2004, it was approved for children over 10 years of age, and then in 2009, it was approved for children as young as 2 years of age. Several studies have demonstrated the effectiveness of the technique in GI diseases, particularly in cases of anemia and occult bleeding [87–89].
Calprotectin, which is a protein in the cytosol of neutrophils, monocytes, and macrophages, can be used as an inflammatory marker of the small intestine. By checking the amount of fecal calprotectin, small bowel injuries caused by NSAIDs could be easily estimated. However, fecal calprotectin has low specificity since it could be elevated in inflammatory bowel disease (IBD), colon cancer, and other inflammatory conditions [83].
In general, GI bleeding is associated with long-term NSAID use. However, a study regarding children revealed that the average duration of NSAID use and bleeding was almost 4 days. Moreover, these manifestations appear to be age-related, being more frequent in younger children. Children under the age of 3 years had more lesions in the proximal tracts (esophagus and stomach), while older children had mainly duodenal lesions [77].
Gastrointestinal damage and bleeding can even be reduced by limiting the use of ibuprofen at appropriate dosage indications and only for few days, even if many studies have reported adverse events after even a single use.
When long-term full-dose NSAID use is required, only for patients with troublesome symptoms, combination therapy of a traditional non-selective NSAID and a PPI reduces the incidence of dyspepsia.
Patients with a history of a bleeding ulcer or a perforation are, however, at the highest risk of NSAID-related (re-)bleeding, and therefore, the decision to prescribe NSAIDs should be considered carefully [83].
In the case of small intestine involvement, the drug should be discontinued to prevent NSAID-induced enteropathy. Moreover, there are no medications which can prevent or treat damage from NSAIDs. Drugs, such as H2 antagonists, sucralfate, and PPIs, which may be effective in treating upper GI damage, cannot prevent damage to the small intestine [83]. In addition, the inappropriate use of PPIs may have some side effects, such as an increase in infections and dysmicrobiosis. Long-term NSAID use can disrupt the gut microbiota, leading to dysbiosis-associated diarrhea. This is particularly concerning in pediatric patients in whom diarrhea may exacerbate dehydration, especially in febrile children [90, 91]. Furthermore, NSAID-induced gut inflammation increases the risk of infectious colitis and enterocolitis, necessitating careful monitoring. Monitoring NSAID-related colitis should start with clinical and biochemical tools (symptoms, calprotectin), followed by stool studies to rule out infection, and then escalate to imaging or endoscopy if the diagnosis remains uncertain or the symptoms are severe. Clinical studies have highlighted a higher incidence of antibiotic-resistant diarrhea in NSAID-exposed children, additionally complicating treatment. Moreover, NSAID rectal administration is contraindicated due to the risk of severe GI side effects, including mucosal damage and unpredictable absorption, which may lead to toxicity. An increased incidence of rectal ulcers and delayed drug metabolism in children may occur, emphasizing the preference for oral formulations when possible [3, 33].
Since these drugs have a wide range of applications, the US FDA issued a health advisory which stated that NSAIDs should be used at the lowest effective dose and for the minimum possible duration consistent with individual patient treatment goals.
Multimodal analgesia is a pharmacological method of pain management which combines various groups of medication for pain relief with fewer side effects than single analgesics. According to the International Association for the Study of Pain (IASP), multimodal analgesia is one of the possible approaches to manage acute pain [92].
An ibuprofen and paracetamol fixed-dose combination for pain management represents an area of growing interest and focus, and is appealing for several practical reasons. The individual components in this combination have established efficacy and safety profiles, providing pain relief thanks to the complementary mechanisms of action of the drugs. It is a potential first-line pain therapy for the management of acute pain. The effect of the combination, which would have a superior analgesic effect, could be ascribed to an enhancement of the efficacy of the single drugs, the greater inhibitory effect on COX, the inhibition of the inflammatory component by ibuprofen, and the activation of the various analgesic mechanisms by paracetamol. It allows effective treatment at lower doses than those used for either treatment when administered alone. Ibuprofen and paracetamol do not share metabolic pathways which decreases the likelihood of drug–drug interaction. Pharmacokinetic studies have demonstrated a lack of drug–drug interaction between ibuprofen and paracetamol [93]. The combination would allow the use of lower doses of both molecules, reducing the safety issues associated with higher doses of either drug, while meeting the need for more effective analgesics. It consistently demonstrated pain relief similar to or better than opioids [93], suggesting that it could be a viable alternative to opioids in the most common types of acute pain. Moreover, there are some suggestions of a more rapid onset of action with the combination than with ibuprofen alone due to the faster onset of the analgesic effect of paracetamol and the longer duration of action of ibuprofen [94, 95].
The American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists strongly recommend that clinicians offer multimodal analgesia and postoperative pain treatment also in the pediatric age by using these molecules. For the treatment of acute mild-to-moderate pain in children, the use of oral paracetamol and ibuprofen in fixed-dose combination should be a 3.3:1 dose ratio [93].
In 2022, an expert consensus paper obtained by Nominal Group Technique (NGT) agreed that the fixed-dose combination of paracetamol and ibuprofen can be used as a first-choice treatment in moderate (score 4–6) pain in children 2–12 years of age. The Board was favorable to switching to the fixed combination when paracetamol or ibuprofen in monotherapy was ineffective in treating mild-to-moderate pain, especially in the case of headache, earache, odontalgia, and musculoskeletal pain. Similarly, the combination is beneficial in postoperative pain management when both analgesic and anti-inflammatory effects are required, especially in cases where monotherapy with paracetamol proves ineffective. The oral suspension facilitates optimized dosage based on the child’s weight, reducing dosing errors, and ensuring faster absorption, leading to faster pain control [34].
Other studies have confirmed the efficacy of the combination in pediatric use. However, there are reservations regarding its use in chronic pain, partly due to limited experience and its primary indication for acute pain. The administration of multiple analgesics at home can be challenging, and fixed combinations improve patient adherence to therapy, enhancing analgesic efficacy and reducing dosing errors [35].
The management of fever and pain in pediatric patients remains a critical aspect of clinical practice, requiring careful consideration of both efficacy and safety. Paracetamol and NSAIDs are the cornerstone therapies, each with specific indications and limitations. Evidence has indicated that, while ibuprofen demonstrates the same efficacy in many pain models, its GI safety profile warrants cautious use, especially in younger children and those with comorbidities. In fever management, NSAIDs, such as ibuprofen, are not routinely recommended but may be considered when fever is associated with significant discomfort or inflammatory conditions. Unlike paracetamol, ibuprofen provides anti-inflammatory effects, making it preferable in select cases such as otitis media, tonsillitis, and post-vaccination fever. However, caution is required for children at risk of dehydration since NSAID use can exacerbate renal dysfunction in these patients.
The widespread misuse of antipyretics, often fueled by parental anxiety, underscores the importance of education and adherence to the guidelines which prioritize symptom relief over temperature normalization. The concurrent or alternating use of paracetamol and ibuprofen at full doses for pain and fever, although practiced in clinical settings, raises concerns about potential toxicity, necessitating additional evidence to clarify its benefits and risks. An FDC may be useful in limiting NSAID usage and reducing te adverse events of ibuprofen.
Emerging insights into NSAID-induced GI and renal complications, along with the potential role of gastroprotective agents, highlight the need for individualized therapeutic approaches. Pediatric-specific strategies, including the use of non-invasive diagnostic tools and adherence to age-appropriate guidelines, can mitigate risks while ensuring effective symptom management.
Future research should focus on optimizing dosing strategies, exploring alternative therapies, and improving the evidence base for managing pain and fever in pediatric populations. A balanced approach, integrating safety, efficacy, and education, will ensure better outcomes and enhance the quality of care for children.