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Ibuprofen versus acetaminophen for acute mild-to-moderate pain management in pediatric populations: a systematic review and meta-analysis of their efficacy.

UNLABELLED: Ibuprofen and acetaminophen are the most widely used analgesics in pediatric practice for the management of acute mild-to-moderate pain. Despite their widespread use, the comparative analgesic efficacy of these two agents in children remains a subject of ongoing debate, with existing evidence largely derived from heterogeneous clinical settings and small individual trials. Therefore, this study aimed to systematically review and meta-analyze randomized controlled trials comparing the analgesic efficacy of ibuprofen versus acetaminophen in pediatric populations with acute mild-to-moderate pain. A systematic literature search was conducted up to May 2026 in PubMed, Scopus, and Web of Science. The review was conducted and reported in accordance with the PRISMA-Children and Adolescents (PRISMA-C) 2026 reporting guideline. Eligible studies were randomized controlled trials comparing ibuprofen with acetaminophen in children and adolescents (defined as individuals aged 0 to&#x2009;<&#x2009;18&#xa0;years) with acute pain, reporting at least one extractable efficacy outcome. Continuous outcomes were synthesized as standardized mean differences (Hedges' g) using random-effects models; dichotomous outcomes were pooled as risk ratios (RRs) with 95% confidence intervals. Risk of bias was assessed using the Cochrane RoB 2 tool and certainty of evidence was evaluated using the GRADE framework. Eight randomized controlled trials enrolling 1325 participants were included. Three pediatric trials contributed to the primary continuous pain outcome meta-analysis (n&#x2009;=&#x2009;196 analyzable participants), yielding a pooled SMD of&#x2009;-&#x2009;0.28 (95% CI&#x2009;-&#x2009;0.57 to 0.00; p&#x2009;=&#x2009;0.052; I2&#x2009;=&#x2009;0%), indicating a small effect favoring ibuprofen that did not reach conventional statistical significance. Given the small number of contributing studies (k&#x2009;=&#x2009;3), the I2 statistic should be interpreted with caution as it has limited power to detect heterogeneity in this context. For the dichotomous pain freedom outcome (2 trials, n&#x2009;=&#x2009;114), no significant difference was observed (pooled RR 1.03, 95% CI 0.53-1.99; p&#x2009;=&#x2009;0.93; I2&#x2009;=&#x2009;0%). A prespecified sensitivity analysis including an adult soft-tissue injury trial attenuated the pooled effect toward the null (SMD&#x2009;-&#x2009;0.15, 95% CI&#x2009;-&#x2009;0.38 to 0.09; p&#x2009;=&#x2009;0.23; I2&#x2009;=&#x2009;36.6%). Narrative synthesis of additional studies generally demonstrated comparable analgesic efficacy between the two agents across postoperative and outpatient pediatric settings. The overall certainty of evidence was rated as low for both primary outcomes, primarily due to imprecision and indirectness. CONCLUSION: Current evidence from randomized controlled trials does not demonstrate a superiority of ibuprofen over acetaminophen for acute mild-to-moderate pain management in children. Both agents appear to provide clinically meaningful analgesia across heterogeneous pediatric pain settings. The clinical choice between agents should be guided by individual patient factors, including contraindications to NSAIDs, the inflammatory nature of the pain etiology, and patient-specific characteristics. The low certainty of evidence underscores the need for adequately powered, methodologically rigorous trials to definitively establish the comparative efficacy of these two analgesics in the pediatric population. WHAT IS KNOWN: &#x2022; Ibuprofen and acetaminophen are the two most widely used non-opioid analgesics for acute mild-to-moderate pain in children, and both are recommended as first-line agents by major international guidelines. &#x2022; Prior meta-analyses in mixed pediatric-adult populations have suggested a modest analgesic advantage of ibuprofen over acetaminophen, but pediatric-specific evidence has remained limited and methodologically heterogeneous. WHAT IS NEW: &#x2022; This systematic review and meta-analysis, restricted to randomized controlled trials in pediatric populations, found that ibuprofen showed a small effect favoring pain reduction compared with acetaminophen (SMD&#x2009;-&#x2009;0.28, p&#x2009;=&#x2009;0.052), although this did not reach conventional statistical significance. &#x2022; The analgesic advantage of ibuprofen may be more pronounced in pain etiologies with a significant inflammatory component (e.g., fractures). At the same time, both agents appear broadly equivalent in most other acute pediatric pain settings, supporting individualized analgesic selection based on clinical context and patient-specific factors.

Humans

The aspirin-ibuprofen interaction in rheumatoid arthritis.

1 This was a double-blind crossover trial of ibuprofen and soluble aspirin against each drug alone and against placebo in patients with rheumatoid arthritis. Two dosage regimes were tested. 2 A weak clinical additive effect was demonstrated between soluble aspirin and ibuprofen in patients with rheumatoid arthritis using moderate (1600 mg ibuprofen and 3.6 g aspirin daily) but not low (800 mg ibuprofen and 2.4 g aspirin daily) dosages of both drugs. 3 A significant correlation between clinical efficacy and serum ibuprofen but not salicylate level was found in the single drug periods of the trial. 4 No consistent effect of ibuprofen administration on serum salicylate levels was found. 5 Concurrent salicylate administration produced significant lowering of serum ibuprofen levels without affecting elimination half-lives of the drug.

Adult

Beneficial effects of ibuprofen in acute myocardial ischemia.

Ibuprofen, a nonsteriodal anti-inflammatory agent, was studied in the early stages of myocardial ischemia in order to determine whether it helps preserve myocardial integrity. Ibuprofen was administered intravenously at a dose of 12.5 mg/kg at the time of coronary artery occlusion and again 2.5 h later. Ibuprofen significantly prevented the loss of myocardial creatine phosphokinase (CPK) release in ischemic cardiac tissue. In addition, this drug significantly returned S-T segment elevation toward normal values, and significantly prevented the myocardial loss of compounds having free amino nitrogen groups, an index of proteolysis. Although ibuprofen moderated the increased plasma CPK activity, plasma CPK values 5 h after coronary occlusion were above control values. Thus, ibuprofen significantly prevented alterations in three of the four indices used to assess myocardial ischemic damage. The protective mechanism of ibuprofen may be via stabilization of cellular membranes (i.e., lysosomal membranes) and to a lesser extent on reduction in myocardial oxygen demand.

Acute Disease

The effects of ibuprofen, indomethacin, aspirin, naproxen, and placebo on the gastric mucosa of normal volunteers: a gastroscopic and photographic study.

The effects of various nonsteroidal antiinflammatory drugs on the gastric mucosa were endoscopically evaluated in 40 normal volunteers. Eight groups, each containing five subjects were designed: aspirin (3600 mg/d); placebo; ibuprofen (1600 mg/d); ibuprofen (2400 mg/d); indomethacin (100 mg/d); indomethacin (150 mg/d); naproxen (500 mg/d); and naproxen (750 mg/d). All volunteers took medication for seven days and gastroscopy was carried out on day one and day eight. All findings were documented by photography. Severe gastric mucosal injury occurred with aspirin (P less than 0.05), both doses of indomethacin, and the higher dose of naproxen. Lesser changes were seen with the lower dose of naproxen, both doses of ibuprofen and placebo. The higher doses of ibuprofen, indomethacin, and naproxen caused a greater degree of gastric mucosal injury, but statistical significance was achieved only with naproxen (P less than 0.01). Subjective gastrointestinal complaints generally correlated with endoscopic pathology; however, nine volunteers had evidence of severe injury to the gastric mucosa with no symptomatology. This was confined to the patients on indomethacin, naproxen, and ibuprofen. Aspirin patients all had some degree of symptomatology but to a lesser degree than expected in view of the endoscopic findings.

Adult

Butacote and ibuprofen: a comparative assessment in rheumatic diseases in general practice.

A multicentre double-blind trial in general practice compared Butacote (enteric-coated phenylbutazone) 300 mg daily, ibuprofen 1200 mg daily, and a placebo in the treatment of rheumatic conditions. Each patient recieved two of the three treatments for one month each. Twenty-nine doctors admitted 193 patients. One hundred and sixty-eight patients (sixty-four with inflammatory polyarthritis, and sixty-three with osteoarthrosis) completed the study, which showed that Butacote was significantly better than both ibuprofen and placebo for the relief of pain and morning stiffness, and improvement of function. Butacote was significantly preferred to both ibuprofen and placebo by patients and doctors, to placebo by the patients. Ibuprofen was significantly better than placebo for relief of morning stiffness and for reducing the amount of supplementary analgesics. All three preparations were well tolerated and showed a similar incidence of gastric side-effects. It is concluded from this study that Butacote is more effective and as well tolerated as ibuprofen in the treatment of rheumatic conditions in general practice.

Arthritis, Rheumatoid

A double-blind cross-over evaluation of ketoprofen (Orudis) and ibuprofen in the management of rheumatoid arthritis.

In a multi-centre double-blind cross-over trial using the double-placebo technique, 55 patients with rheumatoid arthritis were treated for 10 days for each trial drug with ketoprofen (200 mg/day) and ibuprofen (1200 mg/day). Both drugs induced a clinically and statistically significant improvement of all the symptoms studied, except for pain at night during ibuprofen administration. Ketoprofen displayed a therapeutic efficacy significantly superior to ibuprofen in five of the eight symptoms studied. Side-effects were recorded in 10 patients receiving ketoprofen (one patient withdrew because of heartburn) and in nine patients receiving ibuprofen.

Arthritis, Rheumatoid

Ibuprofen in osteoarthritis.

In a double-blind, multiclinic study, 437 patients with osteoarthritis were treated sequentially with ibuprofen, 1,800 mg/day, and placebo, or with aspirin, 3,600 mg/day, and placebo. Each treatment was given for four weeks. Considering relief of pain, ability to function, and general well-being, the patients preferred drug to placebo, usually by a statistically significant margin. Combined results showed no significant differences between ibuprofen and aspirin. Patients' evaluations of exercise-related pain, ability to perform a selected activity, and total discomfort and disability, and physicians' evaluations of discomfort and disability, all favored drug over placebo, and the differences were significant for a number of endpoints. The results indicated ibuprofen, 1,800 mg/day, offers about the same antiarthritic benefit as aspirin, 3,600 mg/day. Both drugs are superior to placebo. The incidence of gastrointestinal complaints with ibuprofen was similar to that with placebo and significantly lower than that with aspirin.

Activities of Daily Living

A comparative trial of ketoprofen and ibuprofen in patients with rheumatic disease.

A comparative controlled study was carried out in 40 patients suffering from rheumatoid arthritis, osteoarthrosis or ankylosing spondylitis to assess the efficacy of ketoprofen and ibuprofen. Patients were allocated at random to receive either 100 mg ketoprofen twice daily or 400 mg ibuprofen 3-times daily over a period of 3 months. Subjective overall assessments of symptoms, based on rating scale scores for pain, duration of morning stiffness and inflammation, showed that there was a greater, more rapid and more sustained improvement in those patients treated with ketoprofen. Measurements of inflamed joint size and of grip strength also improved more with ketoprofen than with ibuprofen. Side-effects, notably nausea, epigastric discomfort and abdominal pain, were more frequent and severe with ketoprofen, leading to the withdrawal of 2 patients in the early stage of the trial, and were probably related to the high dosage used. Three patients receiving ibuprofen needed 7 injections of ACTH to control their symptoms.

Clinical Trials as Topic

A comparative study on ibuprofen (Brufen) and indomethacin in non-articular rheumatism.

Sixty hospital out-patients between 18 and 67 years of age entered this double-blind parallel study set up to compare ibuprofen 1200 mg daily with indomethacin 75 mg daily. Both groups of patients received one capsule three times daily. Ten patients withdrew from the trial because of side effects and a further 3 were excluded--one because of an incorrect diagnosis and 2 because of incomplete assessments--leaving the statistical analysis to be performed on 47 patients. Assessments made after one and two weeks showed significant improvement for the parameters of pain and tenderness at each examination in both treatment groups. Restriction of movement also showed improvement, though not reaching statistical significance. Although there was no statistically significant difference beteen the two drug groups the mean improvement in all three parameters was consistently better with ibuprofen than with indomethacin. The commonest side effects were related to the gastrointestinal tract. Altogether, 10 patients withdrew because of side effects--4 on ibuprofen and 6 on indomethacin. The gastric symptoms occurring with indomethacin appeared to be generally more severe and usually occurred early, within 3 or 4 days of commencing treatment, whereas patients on ibuprofen withdrew usually after 7 or 8 days.

Clinical Trials as Topic

A long-term double-blind comparative study on proquazone (Biarison) and ibuprofen in rheumatoid arthritis.

The efficacy and tolerance of proquazone, 900 mg, and ibuprofen, 1200 mg, were compared in a randomized, double-blind clinical trial of 6 months' duration, with 44 patients, 21 on proquazone and 23 on ibuprofen. Comparison of proquazone-treated patients with patients treated with iburofen showed a significantly better improvement , as is demonstrated by the significant differences in the Lansbury Index, in nocturnal pain, final assessment of therapeutic effect, and number of interruptions due to lack of efficacy. All differences were in favour of proquazone, proving its therapeutic superiority over ibuprofen. The side effects in the proquazone group were mainly gastrointestinal, and 2 patients broke off treatment prematurely due to diarrhoea (in one patient, lack of efficacy was a contributory cause). A third patient discontinued because of moderate nausea and dizziness. In the ibuprofen group, 4 patients discontinued because of side effects (skin eruptions, dizziness, epigastric discomfort, and one thrombocytopenia) in addition to lack of efficacy. Proquazone seems to be an effective and well tolerated anti-inflammatory analgesic.

Adult

Comparative analgesic potency of aspirin and ibuprofen.

The object of a study was to evaluate the analgesic efficacy of ibuprofen for dental pain. The subjects were outpatients who were undergoing surgical removal of impacted teeth. We compared aspirin, 325 mg; aspirin, 650 mg; ibuprofen, 200 mg; ibuprofen, 400 mg; and placebo. Each patient received a single dose of one of the test medications; there was a minimum of 37 patients in each treatment group. Patients recorded pain intensity before receiving medication; then hourly, for four hours after medication, they recorded pain intensity, amount of relief, and side effects. Time-effect and dose-response curves were generated from the relief and change in pain-intensity scores. First-hour scores, peak scores, and total scores were analyzed. All active medications were significantly better than placebo and the mean effect for ibuprofen was significantly more than for aspirin.

Analgesics

Relief of dysmenorrhea with the prostaglandin synthetase inhibitor ibuprofen: effect on prostaglandin levels in menstrual fluid.

The prostaglandin synthetase inhibitor ibuprofen was evaluated for relief of severe primary dysmenorrhea in a controlled, double-blind, cross-over study in seven patients for a total of 23 menstrual cycles. In eight untreated cycles, the amount of prostaglandin (PG) in the menstrual fluid was higher than in nondysmenorrheic subjects. There was good to excellent relief of dysmenorrhea in seven ibuprofen-treated cycles, which was associated with a threefold to fourfold reduction in menstrual PG released. When a placebo was given in five cycles, only poor or minimal relief of dysmenorrhea was obtained and the menstrual PG released was similar to that in control cycles. In individual patients, there was a remarkable correlation between the severity of menstrual pain as assessed daily by the patient and the level of menstrual PG released during the corresponding period. The effect of ibuprofen therapy on menstrual fluid volume was inconsistent. The study shows that in severe primary dysmenorrhea there is increased release of PG in the menstrual fluid; this can be effectively suppressed with ibuprofen, which provides excellent relief from the symptoms of dysmenorrhea.

Adult

The effect of ibuprofen on the intrauterine pressure and menstrual pain of dysmenorrheic patients.

In 12 dysmenorrheic patients we examined the therapeutic action of the Prostaglandin-synthesis inhibitor: Ibuprofen, a non-steroidal analgesic agent. Ibuprofen highly significantly reduced the resting pressure (P less than 0.001), active pressure (P less than 0.001) and frequency (P less than 0.05) of cyclic activity of the uterus, as well as menstrual pain (P less than 0.001). Since these effects occurred after a single oral dose of 800 mg Ibuprofen, without side effects or complications, extensive field trials are recommended with this and other PG-synthesis inhibitors, to assess their therapeutic benefits.

Administration, Oral

Evaluation of preoperative ibuprofen for postoperative pain after removal of third molars.

An evaluation of the analgesic effects of preoperatively administered ibuprofen on prospective pain after the surgical removal of impacted third molar was undertaken in 100 patients in a double-blind parallel treatment trial. The pretreatment with ibuprofen delayed the mean time of onset of postoperative pain more than 100 minutes, as compared to pretreatment with placebo. The severity of pain initially experienced postoperatively was less in the pretreated group. There was no detectable interaction between the pretreatment and the analgesics administered postoperatively. The results of this study suggest that it is possible to delay the onset and lessen the severity of postoperative pain by preoperative administration of a nonsteroidal, antiinflammatory analgesic, such as ibuprofen.

Adolescent

Effect of ibuprofen on menstrual blood prostaglandin levels in dysmenorrheic women.

In a randomized crossover study 15 dysmenorrheic women were treated during two consecutive menstrual period, once with the potent prostaglandin-synthesis inhibitor: ibuprofen and once with an identical looking placebo. Each patient was medicated for 12 hours during the first day of her menstrual flow and was subsequently fitted with a cervical cup for the collection of menstrual blood during three hours. In these samples the concentrations of prostaglandin (PG)F and PGE were measured by radioimmunoassay. The patients receiving placebo had high PGF levels 135 +/- 27 ng/ml (Mean +/- S.E.) which were significnatly reduced by Ibuprofen to 24 +/- 5 ng/ml (P less than 0.001). The PGE concentrations decreased from 5 +/- 1 ng/ml to 2 +/- 1 ng/ml (P less than 0.05). Ibuprofen also reduced the menstrual pain significantly (P less than 0.001). These results substantiate the earlier conclusion that a causal relationship exists between effective treatment with PG-synthesis inhibitors and decrease in menstrual blood PG levels, intrauterine pressure and dysmenorrheic pain.

Adult

Acute erosive gastritis induced by aspirin, ketoprofen, ibuprofen, and naproxen: its prevention by metiamide and cimetidine.

Aspirin, ketoprofen, ibuprofen, and naproxen all produced acute gastric erosions in rats. Aspirin produced significantly more erosions than ketoprofen, ibuprofen, or naproxen. There was no significant difference between the effects of ketoprofen, ibuprofen, and naproxen. Aspirin and naproxen produced a synergistic effect at higher dosage. Metiamide and cimetidine were effective in preventing this type of experimental acute erosive gastritis.

Acute Disease

Age-dependent changes in the response of the lamb ductus arteriosus to oxygen and ibuprofen.

Circular strips of ductus arteriosus from lambs of gestational age between 90 and 144 days (term 147 days) were studied in vitro at low (8--16 torr (1 torr = 133.322 Pa)) and high (426--622 torr) PO2. Potassium- and oxygen-induced contractions increased with the gestational age and attained a maximum at term. At low PO2, ibuprofen, a blocker of prostaglandin synthesis, produced a dose-dependent contraction of the ductus at all ages and enhanced the potassium-induced contraction of the immature ductus (90--124 days). Both effects were relatively greater in the 103- to 107-day gestational group. At that age, ibuprofen also potentiated the oxygen-induced contraction. These findings, while confirming that a prostaglandin is involved in ductus patency, indicate that the prostaglandin-relaxing mechanism becomes functional at an early stage of gestation and reaches maximal activity before term. The existence of an active, prostaglandin-mediated relaxation in the preterm ductus may account, in part, for the reduced responsiveness of the vessel to oxygen. It is confirmed that ibuprofen and other nonsteroidal antiinflammatory drugs are well suited for the management of the premature infant with patent ductus arteriosus.

Animals