Placebo may be inferior compared to acetaminophen when given with morphine for the management of acute pain in the emergency department

1. Morphine plus placebo is not noninferior to morphine plus acetaminophen in the management of acute pain in the emergency department (ED).

Evidence Rating Level: 1 (Excellent)

Study Rundown: Pain is a common reason for presentation to the ED, where opioids are commonly prescribed for moderate-to-severe acute pain. Multimodal analgesia has become more prevalent due to concerns about opioid-related adverse effects and potential misuse. However, prior trials comparing morphine to multimodal analgesia have been limited by inadequate power, heterogeneous pain etiologies, fixed dosing strategies, and variability in opioid regimens.

This prospective, double-blind, placebo-controlled noninferiority randomized clinical trial was conducted across 11 French EDs from December 2019 through December 2024. Participants included adults 18 years or older who had acute pain of less than 24 hours’ duration with a numeric rating scale (NRS) score of 5 or higher (0 = no pain; 10 = worst pain). Patients in the treatment group received acetaminophen 1 gram IV. Patients in the control group received 100 mL of normal saline. Both groups received an initial IV bolus of morphine at 0.10 mg/kg followed by subsequent boluses at 0.05 mg/kg until adequate pain relief was achieved (NRS ≤ 3) or the occurrence of a serious adverse event.

Overall, this study found that although both treatments led to pain relief, morphine plus placebo did not meet the criterion for noninferiority compared with morphine plus acetaminophen. The overall incidence of adverse effects was low, and there was no significant difference in incidence between the two groups.

Click here to read this study in JAMA Network Open

Relevant reading: Intravenous acetaminophen does not have an opioid sparing effect in Emergency Department patients with painful conditions

In-Depth [randomized clinical trial]:

Acute pain is a common presenting complaint to the ED. Previous studies have failed to show a clinically meaningful improvement in pain scores with the addition of acetaminophen to opioid therapy. This randomized clinical trial investigated whether morphine plus placebo provides noninferior initial pain relief compared with morphine plus acetaminophen. The primary outcome was the mean change in NRS pain score from baseline to 30 minutes. The noninferiority margin was 1 point.

424 patients were randomized in a 1:1 ratio to receive morphine plus placebo (n = 211; median [IQR] age, 40 [29-55] years; 54% female) or morphine plus acetaminophen (n = 213; median [IQR] age, 43 [30-58] years; 46% female). In patients with traumatic acute pain, per-protocol (PP) analysis showed between-group differences in NRS reduction of 0.32 points (95% CI, −0.29 to 0.94 points). In patients with nontraumatic acute pain, PP analysis showed between-group differences of 0.80 points (95% CI, 0.19-1.41 points). In modified intention-to-treat analyses, the differences were 0.36 points (95% CI, −0.28 to 1.01 points) and 0.76 points (95% CI, 0.11-1.41 points). Nausea was the most common adverse event (adjusted mean difference, 1.7 percentage points; 95% CI, −0.1 to 0.1 percentage points). Vomiting, respiratory depression, hypotension, and dizziness were rare and did not occur at significantly different rates between the two groups.

Image: PD

©2026 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.