Overall, 55 relevant publications were identified, including reviews, randomised clinical trials, observational clinical studies and case reports. In detail, 12 focused on gastrointestinal tolerability, 11 on renal tolerability, 7 on pulmonary tolerability, 12 on ibuprofen and asthma, 5 on the use of the drug in patients with varicella, 4 on Stevens–Johnson syndrome, and 4 on hepatic tolerability. Single studies are presented below, grouped according to system, organ or condition.
2.1 Gastrointestinal Tolerability
Epidemiological studies and controlled clinical trials have demonstrated that ibuprofen is among the NSAIDs associated with the lowest risk of severe gastrointestinal adverse events [
10].
NSAIDs can cause damage to both the epithelium and the micro-vessels of the digestive tract. There are two main mechanisms of gastrointestinal damage due to NSAIDs: a local effect related to an alteration of the mucosal barrier and a systemic effect due to the inhibition of COX with a consequent reduction in the synthesis of prostaglandins.
Prostaglandins play an important role in protecting the gastric mucosa from acid-related damage by inhibiting the production of hydrochloric acid by the gastric parietal cells and increasing the production of a protective mucus by the epithelial cells lining the stomach. High doses or repeated, prolonged treatment with an NSAID can, on the one hand, remove the inhibition of activation of parietal cells by gastrin, histamine and acetylcholine and, on the other hand, decrease the barrier effect of the mucus that protects the gastric mucosa [
27]. In more detail, NSAID-induced gastric lesions are caused by a gradual deterioration of the superficial layer of muco-phospholipids, which is followed by damage to the mucosal cells, local microcirculation and acid-secreting parietal cells. Damage to endothelial cells of blood vessels is thought to be the consequence of the release of free radicals, protein oxidation, and inhibited production of nitric oxide and prostaglandins. These phenomena translate clinically into gastrointestinal tract bleeding, peptic ulcer and erosive gastritis. In addition, in the small intestine several mechanisms take place: the enterohepatic cycle of the NSAIDs conjugated with bile acids, and their deconjugation by intestinal bacteria with the release of active molecules and consequent stimulation of local immunological reactions [
28]. The lack of acid, but presence of both bacteria and bile in this part of the gastrointestinal tract, favour the development of ulcers.
From a clinical point of view, the administration of NSAIDs can hesitate in the onset of a broad spectrum of symptoms and in organic lesions.
Although the aim of this paper is not specifically focused on symptoms caused by NSAIDs, it is well known that vague and nonspecific manifestations are often referred to by patients of any age, including dyspepsia, heartburn and nausea [
29].
Overall, the side effects of NSAIDs can be divided into minor and serious [
29].
Complications of the upper gastrointestinal tract are well-recognised problems, whereas the less common but potentially more severe complications of the lower gastrointestinal tract are often overlooked, by patients and physician, even though the more widespread use of technologies, such as video capsule endoscopy and balloon endoscopy, has increased the feasibility of documenting mucosal damage throughout the entire digestive tract [
30].
The spectrum of possible NSAID-induced lesions is broad and includes increased intestinal permeability, anaemia, inflammation, diarrhoea, perforation, diverticulitis, ulcers and stenosis of the gastrointestinal tract [
31].
Furthermore, there is clear evidence that prostaglandin production is increased in patients with active inflammatory bowel disease. Prostaglandin levels correlate with disease activity and decrease with successful medical intervention. Disease activity has also been correlated with COX expression, especially COX-2. In fact, prostaglandins seem to play a protective role and be involved in tissue repair processes. Consequently, NSAIDs are contraindicated in chronic inflammatory bowel disease, being potential co-causes of exacerbations of the disease [
32].
Although there are fewer studies on the effects of NSAIDs on the gastrointestinal tract in children than in adults, there is substantial body of evidence on this issue in the paediatric population.
Bianciotto et al. [
33] evaluated the risks of upper gastrointestinal complications associated with the use of various drugs (NSAIDs, oral steroids and antibiotics) in paediatric age. Their study included children admitted to the emergency room of eight clinical centres for upper gastrointestinal complications (with endoscopically confirmed gastroduodenal lesions or clinically diagnosed haematemesis or melena); children admitted for neurological disorders formed the control group. In the period 1999–2010, 486 children with upper gastrointestinal complications and 1930 children with neurological disorders were enrolled. Recent use of drugs (for brief periods: 1–8 days) was greater in the group with upper gastrointestinal complications than in the controls (73 vs. 54%;
p < 0.001). The complications were related to the use of NSAIDs, oral steroids and antibiotics. The mean duration of the use of ibuprofen in this study was 4 days, showing that upper gastrointestinal complications can occur even during short courses of treatment [
33].
Grimaldi-Bensouda et al. [
34] studied 177 children (aged between 2 months and 16 years) with upper gastrointestinal tract bleeding. Among these 177 children, 83 were prescribed at least one NSAID in the 7 days preceding the admission (58/73 ibuprofen). The authors confirmed that bleeding of the upper gastrointestinal tract is a rare event; nevertheless, in one-third of the cases, it could be attributed to exposure to NSAIDs administered at analgesic or antipyretic doses [
34].
The risk of ibuprofen-induced gastrointestinal bleeding is higher in patients who take more than one type of NSAID simultaneously (because of a synergistic effect) and/or platelet antiaggregants/anticoagulants [
35]. Other predisposing factors are a positive history of peptic ulcer or gastrointestinal bleeding,
Helicobacter pylori infection, diverticulosis or chronic inflammatory bowel disease. With regard to these conditions at risk, Usta et al. [
36] evaluated the respective roles of NSAIDs and
H. pylori infection in the aetiology of upper gastrointestinal bleeding in 188 children (82 females and 106 males; mean age 8.43 ± 5.24 years) admitted to a paediatric gastroenterology unit. Endoscopic examination revealed oesophageal, gastric and duodenal mucosa damage in 37, 58 and 24.5% of the patients, respectively. The exact site of the bleeding remained unknown in 14.4% of the cases. In 21.3% of the cases, the patients had taken drugs prior to their admission to the hospital; in particular, 47.5% had taken ibuprofen, 35% acetylsalicylic acid and 17.5% other NSAIDs.
H. pylori infection was found in 20.7% of the children. The authors concluded that there is a positive correlation between ibuprofen or acetylsalicylic acid intake and upper gastrointestinal bleeding, whereas there was no significant connection with
H. pylori, although this bacterium is a well-known cause of gastritis [
36]. Table
2 summarises the literature regarding ibuprofen-induced gastrointestinal adverse events over the last 15 years.
Table 2
Gastrointestinal tolerability of ibuprofen in children
2000 | | 18 | 0–7 days | Bronchopulmonary dysplasia | Ibuprofen Initial: 10 mg/kg/day Maintenance: 5 mg/kg/day every 12 h | Gastrointestinal bleeding and necrotising enterocolitis | Resolved |
2003 | | 80 | 14–58 y | Tonsillectomy | Ibuprofen (42 patients): 800 mg Nimesulide (38 patients): 100 mg | Abdominal pain and other adverse events | Resolved |
2004 | | 1 | n/a | Overdose | Ibuprofen 14 g | Duodenal perforation | Resolved |
2004 | | 1 | 15 y | Cystic fibrosis | Ibuprofen: 1000 mg 2/day | Upper gastrointestinal tract bleeding | Resolved |
2005 | | 25 | 4 mo–22 y (median 10 y) | Various disorders | Various therapeutic regimens | Gastrointestinal, respiratory, rash, other | Resolved |
2007 | | 4 | 23.5 ± 9 mo | Fever, cough and rhinitis | Ibuprofen 1 dose (3 children) 2 doses (1 child) | Gastric antrum ulcer and gastrointestinal bleeding | Resolved |
2010 | | 177 | 2 mo–16 y | Pain and fever | Ibuprofen (58 cases): 18.4 ± 11 mg/kg/day | Upper gastrointestinal tract bleeding | – |
2012 | | – | n/a | Pain and fever | Ibuprofen per os: 5–10 mg/kg/dose every 6–8 h | Low risk of gastrointestinal complications | – |
2013 | | 2416 | 41 mo (15–71 mo) | Fever, pain, headache and other | Ibuprofen (40 cases) Ibuprofen + paracetamol (16 cases) Doses not defined | Gastroduodenal lesions, haematemesis or melena | – |
2013 | | 1 | 3 y | Viral infection with fever and sore throat | Ibuprofen per os: 10 mg/kg 3 doses per day for 4 days | Haematemesis, bleeding gastritis and antral ulcer | Resolved |
2013 | | 9 | 25 mo–5 y | Fever | Ibuprofen: 2 or 3 doses | Upper gastrointestinal tract bleeding | Resolved |
2015 | | 188 | 8.43 ± 5.24 y | Pain and fever | Ibuprofen (19 cases) | Upper gastrointestinal tract bleeding | – |
Although ibuprofen is one of the NSAIDs associated with a lower risk of serious gastrointestinal adverse events, its therapeutic use in children and adults must be accompanied by awareness of its possible adverse effects, which can present throughout the entire gastrointestinal tract. The most frequent gastrointestinal adverse event is bleeding, which can be minimised or avoided by limiting the use of ibuprofen to strict therapeutic indications and co-administering appropriate gastroprotection.
In particular, it is indicated to administer ranitidine or a proton pump inhibitor (PPI), with a superiority of the PPI, accordingly with several recent studies [
37]. Considering the paediatric age, it is recommended the use of histamine-2 receptor antagonists (H2RAs) or selected PPIs, accordingly to the European Society for Paediatric Gastroenterology Hepatology and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN NASPGHAN) guidelines [
38,
39].
It is also essential to consider the patient’s past history, evaluating possible contraindications to the use of NSAIDs, such as chronic inflammatory bowel disease or treatment with antiplatelet agents/anticoagulants. Although data from children are limited, it has been demonstrated that NSAIDs can cause gastrointestinal damage even when taken for a short period; signs and symptoms of possible effects on the small bowel and colon should not be overlooked.
All parts of the gastrointestinal tract can, potentially, be affected |
Damage to the upper gastrointestinal tract is usually mild and reversible |
Damage may occur even with short courses of treatment |
It is important to consider possible contraindications to the use of NSAIDs, such as chronic inflammatory bowel disease |
Ibuprofen should not be taken on an empty stomach |
2.2 Renal Tolerability
Over the years, nephrologists and paediatricians have expressed concern regarding the risks of serious renal adverse effects related to the use of NSAIDs in children [
10], because of the capacity of these drugs to reduce the renal synthesis of prostaglandins. In euvolaemic states, prostaglandins have a negligible effect on renal haemodynamics, but in cases of hypovolaemia, up-regulation of the renin-angiotensin system, as well as of the catecholaminergic system, causes systemic and renal vasoconstriction, which leads to production of renal prostaglandins with the aim of maintaining renal perfusion and glomerular filtration. This protective effect is inhibited by ibuprofen.
Febrile children are at an increased risk of dehydration because of greater insensible fluid loss (for example, sweating) and the commonly present difficulty in consuming liquids. The milder forms of dehydration can be difficult to detect in children and may go unnoticed. The patient’s clinical conditions can evolve with worsening dehydration because of the onset of diarrhoea and vomiting. Various authors have recommended not using ibuprofen in the treatment of pronounced fever or for mild-to-moderate pain in infants and children who are dehydrated or could become so during the course of the disease, because of an increased risk of acute renal failure [
40‐
42].
In detail, Ulinski et al. reported on 6 patients (including 1 kidney transplant recipient), aged between 4 and 15 years, who developed acute renal failure following therapeutic doses of ibuprofen. Renal impairment developed 1–3 days after treatment with ibuprofen, but the levels of creatinine returned to normal within 3–9 days following rehydration and withdrawal of the NSAID [
40]. Wong et al. also advised against the use of ibuprofen in preschool infants with fever/pain and dehydration [
41]. Leroy et al. reported an increased risk of acute renal failure in patients with hypovolaemia following treatment with ibuprofen [
42]. Balestracci et al. studied 105 children with acute gastroenteritis, 46 of whom developed acute kidney injury: 54% (34/63) of the patients treated with ibuprofen and 26% (12/46) of those not treated with the NSAID, demonstrating that ibuprofen treatment is a risk factor for the development of acute renal injury independently of the degree of hydration (OR 2.47 [95% CI 1.78–3.42]). The children who developed acute renal injury tended to be younger (0.66 vs. 1.74 years;
p < 0.001) and had more frequently taken ibuprofen (74 vs. 49%,
p = 0.01). The authors emphasised that children under 6 months old have a higher risk of ibuprofen-related renal toxicity [
8].
Misurac et al. studied the relationship between acute renal injury and NSAID intake in children [
43]. They retrospectively analysed the clinical records of 1015 children with a diagnosis of acute kidney injury: in 27 (2.7%) (aged between 0.5 and 17.7 years) an association with NSAIDs was found, and in 18 of these cases the drug involved was ibuprofen. Of the 27 patients with acute kidney injury, 21 had clinical, laboratory, radiographic and/or pathological signs of acute tubular necrosis, while 6 had evidence of acute interstitial nephritis. Ibuprofen was taken alone (67%) or together with naproxen (7%) or ketorolac (7%). Children <5 years of age were more likely to require dialysis (
p < 0.001), be admitted to an intensive care unit (
p = 0.013) and stay longer in hospital (
p = 0.037). The authors concluded that NSAIDs, administered at normal doses, accounted for 2.7% of the cases of acute renal injury and that damage to the kidneys may be more severe in younger children [
43].
Another side effect of ibuprofen that has been described is interstitial nephritis. Gallego et al. [
44] and Dixit et al. [
45] reported two cases of acute renal failure due to acute tubulo-interstitial nephritis that developed after administration of aspirin and ibuprofen in succession. Krause described the cases of seven children, aged between 13 and 17.5 years, who developed acute renal failure following treatment with NSAIDs, including ibuprofen; six of the seven patients had taken more than one type of NSAID and none reported previous kidney disease or concomitant treatment with other drugs [
46].
Table
3 summarises the literature regarding ibuprofen-associated renal adverse events in children over the last 15 years.
Table 3
Renal tolerability of ibuprofen in children
2000 | | 1 | Flu-like syndrome | Ibuprofen and aspirin | Tubulo-Interstitial-nephritis | Resolved |
2001 | | 1 | Febrile seizures | Ibuprofen and paracetamol | Acute renal failure | Resolved |
2001 | | 1 | Diarrhoea, vomiting and fever | Paracetamol as initial treatment Ibuprofen 5 mg/kg/dose 3/day | Acute renal failure | Resolved |
2004 | | 1 | Flu-like syndrome | Ibuprofen (50 mg, 6 doses) | Mild cortical necrosis | Resolved |
2004 | | 7 | Fever, diarrhoea and vomiting | Ibuprofen (n = 6): 11.5–32 mg/kg/day Ketoprofen (n = 1): 7.5 mg/kg | Acute renal failure | Resolved |
2005 | | 7 | Suicide attempt, fractures, headache | Ibuprofen (3 cases): 0.8–1.6 g | Acute renal failure | Resolved |
2007 | | – | Pain and fever | Ibuprofen: various doses | Acute renal failure | – |
2008 | | 1 | Fever | Ibuprofen and aspirin | Acute renal failure | Resolved |
2013 | | 1015 | – | Ibuprofen: 18 cases Ibuprofen + naproxen: 2 cases Ibuprofen + Ketorolac: 2 cases | Acute kidney injury | – |
2014 | | 47,803 | – | Ibuprofen + paracetamol | Increased risk of acute renal failure | – |
2015 | | 105 | Acute gastroenteritis | Ibuprofen | Acute kidney injury | – |
In conclusion, ibuprofen-induced acute kidney injury is a rare but severe occurrence in children and is (fortunately) usually reversible following suspension of treatment with the NSAID. Care must be taken when giving ibuprofen to children at risk of dehydration (i.e. those with fever, vomiting and/or diarrhoea), children with pre-existing renal disorders and to those taking potentially nephrotoxic drugs. Under these circumstances, NSAIDs should only be used if there are no alternatives and at the minimum effective dose. Careful use of NSAIDs is particularly important in children who were born prematurely or with a low birthweight, because these children have a reduced number of nephrons and are therefore at higher risk of renal impairment throughout their life. Chronic use of NSAIDs in such individuals is a strong risk factor, increasing the already high numbers developing chronic kidney disease [
47].
Ibuprofen inhibits the protective effects on prostaglandins on renal perfusion and glomerular filtration in cases of dehydration |
The reduction in glomerular filtration is usually asymptomatic and reversible once ibuprofen has been suspended; the renal impairment rarely requires medical intervention or admission to hospital |
The use of ibuprofen is contraindicated in children at risk of dehydration (i.e. those with fever, vomiting and/or diarrhoea) |
Care must be taken with ibuprofen when treating children born prematurely or with a low birthweight because of their reduced nephron mass and therefore at higher risk of kidney damage |
2.3 Pulmonary Tolerability
Various studies have shown that treatment with ibuprofen may be responsible for the worsening of some respiratory bacterial infections and the development of severe lung infections and complications, possibly as a result of reduced pulmonary blood flow and decreased production of inflammatory cytokines [
48,
49].
In order to investigate a possible causality between the intake of NSAIDs and the development of severe bacterial infections in childhood, Leroy et al. prospectively analysed 5182 children admitted to hospital: of these, 32 had severe bacterial infections following treatment with NSAIDs in the 15 days prior to the admission. Bacteriological studies identified the presence of
Staphylococcus aureus, group A streptococci (GAS) and
Streptococcus pneumoniae. Ibuprofen, prescribed mainly for the treatment of fever, was the most frequently used NSAID (94%) [
50].
François et al. studied 767 children admitted to hospital because of pneumonia: 90/767 had complications such as empyema and/or lung abscesses. Multivariate analysis of the data revealed that ibuprofen was the only pre-admission treatment independently correlated with suppurative complications. The authors did, however, recommend caution in interpreting this information because it was not certain whether administration of the NSAID had preceded the development of the complication in all cases [
9]. Elemraid et al. also investigated possible risk factors for the development of pleural complications in 160 children with community-acquired pneumonia and concluded that pre-admission administration of ibuprofen was associated with a higher risk of developing pleural empyema [
51].
Table
4 summarises the data on adverse pulmonary events in children taking ibuprofen.
Table 4
Pulmonary tolerability of ibuprofen in children
2000 | | 1 | Accidental overdose | Ibuprofen 7.2 g (600 mg/kg) | Lethargy and apnoea | Resolved |
2002 | | 85 | Respiratory disorders in cystic fibrosis | Ibuprofen and other drugs | Slows progression of respiratory disease | – |
2005 | | 1 | Chest pain | Ibuprofen: 600 mg qid for 3 days | Massive pulmonary embolism | Resolved |
2005 | | 1 | Allergic rhinitis, juvenile rheumatoid arthritis, fever and oral ulcers | Ibuprofen (3 doses) and paracetamol (1 dose) | Allergic reaction | Resolved |
2010 | | 767 | Complicated and uncomplicated pneumonia | Ibuprofen (100 cases) | Increase of suppurative complications | – |
2010 | | 32 | Pain and fever | Ibuprofen | Severe bacterial infections | – |
2015 | | 160 | Pneumonia | Ibuprofen | Empyema | – |
The published data on the use of ibuprofen in children with cystic fibrosis [
52] are more reassuring in that it seems that the NSAID slows disease progression notably, without causing serious adverse events.
2.3.1 Asthma
Hypersensitivity cross-reactions to ibuprofen in children sensitive to aspirin have been reported [
10]. The intake of ibuprofen can trigger bronchospasm and exacerbate the asthmatic symptoms of children with aspirin-induced asthma [
53].
Valkhoff et al. [
54] analysed various European databases (Germany, UK, The Netherlands and Italy) containing information on the demographics, diagnosis and pharmacological prescriptions of 7.7 million children and adolescents, of whom 17.3% had taken one of 45 NSAIDs for at least 1 day. The aim of the study was to evaluate the use of NSAIDs and related adverse events in the paediatric population. The authors found misuse of prescriptions for NSAIDs in all four countries; however, only for ibuprofen (the most widely prescribed NSAID) was it possible to identify an association (RR = 2) between consumption of the drug and exacerbation of asthma [
54]. Sordillo et al. [
55] investigated the potential correlation between antipyretic use during pregnancy or infancy and an increased risk of asthma in 1490 mother-child pairs. The multivariate analysis, including type of drug, its dose and period of intake, and presence of infection, showed an increased risk of asthma, particularly in infancy, in those individuals who had been exposed to ibuprofen (OR 1.35; 95% CI 1.19–1.52). However, adjusting for the presence of respiratory tract infection, this association appeared strongly attenuated (OR 1.19; 95% CI 1.05–1.36) [
55].
In another randomised controlled, double-blind trial in 100 schoolchildren with mild-to-moderate asthma, only 2% of the cases had ibuprofen-induced bronchospasm leading the authors to conclude that the prevalence of ibuprofen-associated asthma is low. Nevertheless, taking into account the prevalence of asthma among children, it is important to consider the possibility of ibuprofen-induced bronchospasm, especially in those children treated with ibuprofen during acute viral infections that can exacerbate asthma [
56]. The hypothesis that short-term use of ibuprofen increases the risk of asthma attacks was investigated in a double-blind, randomised controlled trial by Lesko et al, who concluded that there was no proof that ibuprofen is less safe in asthmatics than in control children [
57].
Two literature reviews conducted by Kader et al. [
58] and Body et al. [
59] showed that ibuprofen can be safely prescribed to febrile asthmatic children. Likewise, Kauffman et al. [
60] found little evidence that the use of ibuprofen increases morbidity in asthmatic children and concluded that, although cross-reactions with aspirin and NSAID-induced asthma are possible, the use of ibuprofen is substantially safe in asthmatic children [
60]. Another large review of the literature (472 articles) demonstrated that not only is there a low risk of ibuprofen-induced asthma in children, but that the drug might have protective and therapeutic effects [
61]. Interestingly, it was recently suggested that ibuprofen reduces the late response to specific bronchoprovocation with allergens and could, therefore, have a protective effect in allergen-induced asthma [
62], but further evidence is required.
Table
5 summarises the data on ibuprofen use and asthma in children.
Table 5
Ibuprofen and asthma
2001 | | 1 | Fever | Ibuprofen and paracetamol | Asthma attack | Resolved |
2002 | | 1879 | Fever | Ibuprofen 5 mg/kg (636 cases), 10 mg/kg (611 cases) and paracetamol (632 cases). | Low risk of asthma attacks | – |
2004 | | – | Fever | Ibuprofen | Low risk of asthma attacks | – |
2004 | | 150 | Fever | Ibuprofen and paracetamol | Low risk of asthma attacks | – |
2004 | | Literature analysis | Asthma | Ibuprofen (and aspirin) | Acute bronchospasm | – |
2005 | Debley JS [ 56] (crossover) | 100 | Asthma (mild and moderate) | Ibuprofen: 1 dose of 10 mg/kg or placebo | Bronchospasm | – |
2005 | | 1 | Post-operative pain | Ibuprofen per os 400 mg (~10 mg/kg) | Asthma attacks | Resolved |
2007 | | – | Fever | Ibuprofen vs. paracetamol | Low risk of asthma | – |
2007 | | 1 | Inappropriate use of the drug in an allergic subject | Ibuprofen | Asthma attacks | Death |
2013 | Nezvalová-Henriksen K [ 94] | 90,417 mother–child pairs | Various: migraine, inflammation musculoskeletal and rheumatic diseases | Ibuprofen | Asthma | – |
2013 | | 1,339,472 | SOS Project (Safety Of non-Steroidal drugs) | Ibuprofen (and other NSAIDs) | Asthma attacks | – |
2015 | | 1490 mother–child pairs | Fever | Ibuprofen vs. paracetamol | Increased risk of asthma | – |