Morphine Plus Placebo vs Morphine Plus Acetaminophen for Acute Pain in the Emergency Department: A Randomized Clinical Trial.

Importance: Intravenous (IV) acetaminophen is widely used in multimodal analgesia with opioids for the initial management of acute pain in emergency departments (EDs), but its additive benefit when combined with titrated morphine is uncertain. Objective: To determine whether titrated IV morphine plus placebo is noninferior to titrated IV morphine plus acetaminophen for pain relief in the first hour in adults seen in the ED with acute traumatic or nontraumatic pain. Design, Setting, and Participants: This multicenter, double-blind, randomized, placebo-controlled noninferiority clinical trial was conducted in 11 French EDs from December 3, 2019, to December 31, 2024, with 60 minutes of follow-up. Adults (aged ≥18 years) with severe acute pain (numeric rating scale [NRS] score ≥5 on a scale from 0 [no pain] to 10 [worst pain]) of traumatic or nontraumatic origin were eligible. Prespecified analyses were planned for traumatic and nontraumatic pain. Interventions: All patients received weight-based titrated IV morphine. In the control group, patients also received 1 g IV acetaminophen; in the intervention group, patients received matching placebo. Main Outcomes and Measures: The primary outcome was the mean change in NRS pain score from baseline to 30 minutes. The noninferiority margin was 1 point. Analyses were conducted in modified intention-to-treat (mITT) and per-protocol (PP) populations. Results: Among 430 randomized patients (median age, 42 years [IQR, 29-57 years]; 220 men [51.2%]), 424 were included in the mITT analysis (213 in the morphine plus placebo and 211 in the morphine plus acetaminophen group; 181 [42.7%] had traumatic pain and 243 [57.3%] had nontraumatic pain) and 393 were included in the PP analysis (197 morphine plus placebo and 196 morphine plus acetaminophen; 169 [43.0%] had traumatic pain and 224 [57.0%] had nontraumatic pain). In the PP analysis, the between-group difference in mean pain score reduction was 0.32 points (95% CI, -0.29 to 0.94 points) for traumatic pain and 0.80 points (95% CI, 0.19-1.41 points) for nontraumatic pain. In the mITT analysis, the corresponding differences were 0.36 points (95% CI, -0.28 to 1.01 points) and 0.76 points (95% CI, 0.11-1.41 points). In both strata, pain reduction favored the acetaminophen group, but the differences did not meet the prespecified noninferiority margin of 1 point. Conclusions and Relevance: In this randomized clinical trial of adults seen in the ED with acute pain, morphine plus placebo did not meet the criterion for noninferiority compared with morphine plus acetaminophen for pain relief during the initial management. The findings suggest acetaminophen may have potential benefit as an adjunct to morphine in individualized treatment approaches for acute pain in the ED. Trial Registration: ClinicalTrials.gov Identifier: NCT04148495.