TOPLINE:

Intravenous (IV) morphine plus placebo was not noninferior to IV morphine plus acetaminophen for initial pain relief in adults with acute pain, particularly nontraumatic pain, in the ED, according to a new trial.

METHODOLOGY:

• Researchers conducted a prospective, multicenter, double-blind, placebo-controlled noninferiority randomized clinical trial across 11 EDs in France from 2019 to 2024 and enrolled 430 adults (median age, 42 years; 51.2% men) with acute traumatic or nontraumatic pain and a numeric rating scale (NRS) score ≥ 5.
• Participants were randomly assigned to receive either titrated IV morphine plus acetaminophen (1 g) or titrated IV morphine plus placebo. The modified intention-to-treat (mITT) population included 424 patients (211 in the morphine-acetaminophen group and 213 in the morphine-placebo group), and the per-protocol (PP) population included 393 patients (196 in the morphine-acetaminophen group and 197 in the morphine-placebo group).
• All patients received an initial morphine bolus of 0.10 mg/kg, followed by titrated 0.05 mg/kg doses every 10 minutes until adequate analgesia (NRS score ≤ 3) was achieved, an adverse event occurred, or the maximum cumulative dose of 20 mg within 30 minutes was reached.
• The primary outcome was the mean change in NRS pain scores from baseline to 30 minutes, stratified by pain type, with a noninferiority margin of 1 point. Secondary outcomes included NRS score changes at 10, 20, 45, and 60 minutes, the cumulative morphine dose within 30 minutes, successful analgesia at 30 minutes (NRS score ≤ 3), rescue analgesia requirements, and adverse events.

TAKEAWAY:

• In the PP and mITT populations, the between-group difference in mean pain score reduction fell within the predefined noninferiority margin for traumatic pain and nontraumatic pain.
• In patients with nontraumatic pain, pain reduction favored the morphine plus acetaminophen group over the morphine alone group, with between-group differences exceeding the noninferiority threshold in both the PP and mITT populations.
• Pain intensity decreased over time in both groups. At 60 minutes, in the traumatic pain subgroup, mean reduction was 5.12 points with placebo vs 5.52 points with acetaminophen; in the nontraumatic pain subgroup, mean reduction was 5.84 points with placebo vs 6.07 points with acetaminophen.
• Among patients with traumatic pain, nausea was reported in 8.6% who received morphine plus placebo and 10.3% who received morphine plus acetaminophen. In patients with nontraumatic pain, nausea occurred in 28.0% with morphine plus placebo and 29.5% with morphine plus acetaminophen.
• Rescue analgesia at 30 minutes was more frequent with morphine plus placebo than with morphine plus acetaminophen in patients with nontraumatic pain, with no difference observed in those with traumatic pain. No increase in adverse events was observed after 30 minutes.

IN PRACTICE:

"In this randomized clinical trial of adults with acute traumatic or nontraumatic pain seen in the ED, morphine plus placebo did not meet the criterion for noninferiority compared with morphine plus acetaminophen for pain relief during the initial 60 minutes of management," the authors wrote.

"The findings suggest acetaminophen may have potential benefit as an adjunct to morphine in individualized treatment approaches for acute pain in the ED," they added.

SOURCE:

The study was led by Guillaume Cattin, MD, Service des Urgences, Nantes Université, Centre Hospitalier Universitaire Nantes, Nantes, France. It was published online on February 24, 2026, in JAMA Network Open.

LIMITATIONS:

The study was limited by prolonged COVID-related enrollment suspensions and delayed site reactivation, which may have introduced unmeasured confounding and reduced enrollment within pain strata — particularly traumatic pain — thereby lowering precision. Follow‑up duration was confined to 60 minutes; therefore, delayed effects, opioid use beyond the initial period, and subsequent adverse events were not captured. The analysis plan did not prespecify formal inferiority testing if noninferiority failed, complicating interpretation for nontraumatic pain. The trial also did not assess several patient‑centered outcomes such as time to meaningful relief, satisfaction, function, or ED length of stay, and heterogeneity within pain strata and unmeasured chronic pain history may have affected analgesic responsiveness.

DISCLOSURES:

The trial was funded by the French Ministry of Health. The sponsor of the study was Nantes University Hospital (Centre Hospitalier Universitaire de Nantes), Nantes, France. One author disclosed receiving grants from Direction Générale de l'Offre de Soins during the conduct of the study.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.