Should acetaminophen or an opioid be added to ibuprofen for pediatric musculoskeletal injury pain?

Ibuprofen is considered first-line therapy for acute musculoskeletal pain, but two-thirds of children experience inadequate pain relief with ibuprofen alone. The efficacy of adding other medications to ibuprofen to treat moderate to severe acute musculoskeletal pain in children is unclear.1To examine this issue, Canadian researchers (members of the KidsCAN PERC Innovative Pediatric Clinical Trials No OUCH Study Team) investigated whether adding an opioid (hydromorphone) or acetaminophen to ibuprofen treatment decreased pain scores in children with moderate to severe acute musculoskeletal pain, compared with ibuprofen alone.1The researchers conducted two randomized, double-masked, placebo-controlled trials from April 2019 to March 2023 in six university-affiliated, tertiary care Canadian pediatric emergency departments. Children six to 17 years of age who presented with a nonoperative acute limb injury (< 24 hours) and a verbal numerical rating scale (vNRS) pain score of five or more out of 10 were enrolled.1 The opioid trial randomized participants to a single oral dose of ibuprofen plus hydromorphone, ibuprofen plus acetaminophen, or ibuprofen alone. The nonopioid trialrandomized participants to a single oral dose of ibuprofen plus acetaminophen or ibuprofen alone. Ibuprofen was dosed at 10 mg/kg (maximum, 600 mg), acetaminophen at 15 mg/kg (maximum, 1000 mg) and hydromorphone at 0.05 mg/kg (maximum, 5 mg). All study medications were administered as a single oral dose in liquid form.1The primary efficacy outcome was self-reported vNRS pain score at 60 minutes after medication administration (score range, 0 [no pain] to 10 [worst pain]; minimal clinically important difference, 1.5). The primary safety end point was the proportion of children with any adverse event related to study drug administration.1Key results:A total of 8,098 children were screened for eligibility; 699 were randomized and 653 were included in the efficacy analyses (mean age 11.5 years; 47.4% female).The opioid trial included 249 children: 110 randomized to ibuprofen plus hydromorphone, 70 to ibuprofen plus acetaminophen, and 69 to ibuprofen alone.The nonopioid trial included 450 children: 225 randomized to a single oral dose of ibuprofen plus acetaminophen and 225 to ibuprofen alone.The mean (SD) vNRS score at recruitment was 6.4 (1.8).In pooled analyses, mean (standard deviation) vNRS scores 60 minutes after drug administration were 4.8 (2.6) in the ibuprofen plus hydromorphone group, 4.6 (2.4) in the ibuprofen plus acetaminophen group, and 4.6 (2.3) in the ibuprofen alone group (p = 0.78).The proportion of children who achieved mild pain (i.e., vNRS score < 3) was 23.4% in the ibuprofen plus hydromorphone group, 19.9% in the ibuprofen plus acetaminophen group, and 19.3% in the ibuprofen group (p = 0.95).Any adverse event occurred at higher rates in the ibuprofen plus hydromorphone group (28.2%) compared with the ibuprofen plus acetaminophen (6.1%) or ibuprofen alone groups (5.8%).Central nervous system–related adverse events (somnolence, fatigue, dizziness) and gastrointestinal-related adverse events (abdominal pain, nausea, vomiting) were most common. No serious adverse events occurred.1The authors conclude that for children with moderate to severe pain due to acute nonoperative musculoskeletal injury, pain scores at 60 minutes after drug administration did not improve when acetaminophen or hydromorphone was added to ibuprofen, compared with ibuprofen alone. Furthermore, adverse events were four times more common when hydromorphone was added to ibuprofen. As ibuprofen alone (and the ibuprofen/hydromorphone or ibuprofen/acetaminophen combinations) adequately relieved pain in only about 20% of children, the authors contend that studies of adjuvant topical and nonpharmacologic therapies, as well as novel drugs, are still needed.1An accompanying editorial points out that these results provide clinicians with reassurance that avoiding opioids for acute musculoskeletal pain is not undertreatment for most youth, but likely best practice. In addition, families can be informed that their child will likely not benefit from adding acetaminophen or an opioid to ibuprofen to achieve adequate pain relief. In fact, their child might experience unnecessary central nervous system or gastrointestinal adverse effects from adding an opioid.2 The editorial highlights the fact that these were single-dose trials with repeated pain assessments up to two hours after medication administration. Future research should examine the effects of repeated analgesic dosing, the need for further analgesics after emergency department discharge, and how quickly youth with acute musculoskeletal injuries are able to return to school, sleep normally and resume physical activity. The editorial also emphasizes that these two trials focused on acute, nonoperative musculoskeletal injuries; the results should not be extrapolated to other types of pain or taken to mean that opioids should be avoided in youth in all pain situations.2References:Ali S, Klassen TP, Candelaria P, et al; KidsCAN PERC Innovative Pediatric Clinical Trials No OUCH Study Team. Acetaminophen (paracetamol) or opioid analgesia added to ibuprofen for children’s musculoskeletal injury: two randomized clinical trials. JAMA 2026;10.1001/jama.2025.25033. Published online January 8, 2026. (accessed January 12, 2026).Calihan JB, Sutherland TN, Hadland SE. Safe and sufficient—ibuprofen for pediatric musculoskeletal injuries (editorial). JAMA 2026; published online January 8, 2026. (accessed January 12, 2026).

Should acetaminophen or an opioid be added to ibuprofen for pediatric musculoskeletal injury pain?

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