Researchers: Adding Acetaminophen or An Opioid to Ibuprofen for Children Doesn’t Add Up

Samina Ali, MD, a researcher and clinician in the Department of Pediatrics, Faculty of Medicine & Dentistry at the University of Alberta, in Edmonton, and colleagues noted that as many as two-thirds of children report suboptimal pain reduction with ibuprofen alone. Assessment of the analgesic combinations was undertaken “given the need for more comprehensive analgesia for children with musculoskeletal injury, combined with the importance of responsible opioid use in children.”

Ali discussed the challenges in addressing children’s pain, particularly with gaps in the research on effective means, with Pain Medicine News. “It is very important that we treat children’s pain,” she explained. “Untreated pain in childhood can lead to chronic pain conditions in adulthood and a fear of medical care.

“Research with children is always a bit more complicated than with adults, as we treat families, not individuals, in pediatrics. This means that we have more explaining to do, and more perspectives to consider,” Ali observed. “And it is essential that we do this, as we should not be extrapolating adult science to children. Children are different and deserve to have health decisions tailored to their unique needs and based on evidence that is specific to them.”

Assessing Analgesic Combinations

Ali and colleagues conducted the two randomized controlled trials simultaneously, one of which had an opioid treatment arm. The participating children had presented with nonoperative acute limb injury at one of six Canadian tertiary pediatric emergency departments (members of Pediatric Emergency Research Canada) between April 2019 and March 2023. Using a verbal numerical rating scale (vNRS) ranging from 0 to 10, all participants reported pain scores of 5 or greater (mean 6.4±1.8).

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While families could opt out of participating in the trials, they could also indicate preference for participating in a trial with or without an opioid treatment arm. In the absence of preference, the child would be enrolled in the opioid trial, which had three rather than two medication treatment arms.

“A strength of the No OUCH studies was the preference-informed complementary trial design, which allowed families with strong opinions about opioid medications to still be involved with one of the trials,” the investigators noted.

With more families preferring the trial without an opioid treatment arm, 450 and 249 children were randomized to the nonopioid and opioid trial, respectively. All active medication and placebos were oral liquids. Hydromorphone was the chosen opioid as a potent, rapidly absorbed, and long-acting analgesic that, the investigators note, “has been suggested as an alternative to oral morphine, but evidence supporting its use in children is limited.”

The three treatment arms of the trial with an opioid were: 1) ibuprofen plus acetaminophen placebo plus hydromorphone (ibuprofen plus hydromorphone); 2) ibuprofen plus acetaminophen plus hydromorphone placebo (ibuprofen plus acetaminophen); and 3) ibuprofen plus acetaminophen placebo plus hydromorphone placebo (ibuprofen). The two arms of the nonopioid trial provided ibuprofen with acetaminophen or acetaminophen placebo.

Ibuprofen was dosed as 10 mg/kg (maximum 600 mg); acetaminophen as 15 mg/kg (max 1,000 mg); and hydromorphone as 0.05 mg/kg (max 5 mg), noted by the investigators as the upper limit of dosing of the most potent oral opioid available in liquid form. Nonpharmacologic interventions such as ice and splinting were documented in the pooled analysis.

The primary efficacy outcome was a self-reported vNRS pain score at 60 minutes post-medication administration, corresponding to the time of peak plasma concentration and analgesic efficacy for all three study drugs. The primary safety end point was the proportion of children with any adverse event related to study drug administration. There were several secondary efficacy outcomes, including pain scores at other time points up to 120 minutes post-medication, length of stay in the emergency department, and use of rescue analgesia during the 60 minutes.

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Ali and colleagues reported comparable mean vNRS scores 60 minutes post-administration of 4.8±2.6, 4.6±2.4, and 4.6±2.3 with ibuprofen plus hydromorphone, ibuprofen plus acetaminophen, and ibuprofen alone, respectively. Pain reduction of at least two points from baseline vNRS was reported by 44.9%, 47.0%, and 48.5% with ibuprofen plus hydromorphone, ibuprofen plus acetaminophen, and ibuprofen alone. There were also no significant differences between groups in secondary measures.

Although efficacy was comparable across groups, there was a 28.2% rate of adverse events with ibuprofen plus hydromorphone, compared with 6.1% with ibuprofen plus acetaminophen and 5.8% with ibuprofen alone. Central nervous system–related adverse effects (e.g., somnolence, fatigue, dizziness) and gastrointestinal (e.g., abdominal pain, nausea, vomiting) were most frequently reported.

Takeaway for Treating Children’s Pain

In the accompanying editorial, Jessica Calihan, MD, MSc, an adolescent and addiction medicine physician and health services researcher in the Division of Adolescent and Young Adult Medicine at Mass General Brigham Hospital for Children at Harvard Medical School, in Boston, and colleagues welcomed the study for providing “critical” new data.

“For clinicians, the study provides reassurance that avoiding opioids is not undertreatment for most youth, but likely best practice,” they remarked. “For families, the findings offer clarity: their child would likely not benefit from something stronger than ibuprofen to achieve adequate pain relief—and, in fact, their child might experience unnecessary central nervous system or gastrointestinal adverse effects from an opioid.”

While the No OUCH trial found no advantage to adding either hydromorphone or acetaminophen to ibuprofen for moderate to severe musculoskeletal injury–related pain in children, it also revealed that only about 20% of the children on ibuprofen alone obtained adequate analgesia (defined as a pain score of more than 3 out of 10). This suggests, the investigators indicate, the need for “further studies of adjuvant topical and nonpharmacological therapies, as well as novel drugs.”

It also suggests the need to approach each child with a range of options, Ali commented. “When I see a family in the ER and their child has a simple fracture, I might suggest that they use ibuprofen, ice packs, distraction, and a cast or splint.

“If this isn’t enough, and the child needs something in between doses of ibuprofen, they could try acetaminophen,” Ali advised. “Acetaminophen also works for fracture and sprain pain, with few side effects. It just doesn’t work as well as ibuprofen, so I suggest saving it for breakthrough pain.”

—Kenneth Bender

Ali serves as an unpaid scientific advisor to the National Pain Advocacy Center, in Washington, D.C., and reported no relevant financial disclosures.