Adding acetaminophen to morphine boosts ER pain relief, study finds

Adding acetaminophen to morphine provides small incremental early pain relief for patients in the emergency room with either traumatic or nontraumatic acute pain, according to study results published Feb. 24, 2026, in JAMA Network Open.

Pain is a common reason patients go to the emergency room. Acetaminophen is often added to opioids both in the emergency room and after procedures as a way to limit the use of opioids. This practice is common in the United States and in European countries such as France, where this study was conducted.

Researchers wanted to determine whether adding IV acetaminophen to IV morphine improves pain relief in the emergency department. The study was led by Guillaume Cattin, M.D., at the Nantes Université, Centre Hospitalier Universitaire Nantes, in Nantes, France.

In the trial, 424 adults with severe traumatic or nontraumatic pain were randomized to receive IV morphine plus either acetaminophen or placebo. The study was conducted across 11 emergency departments from Dec. 3, 2019, to Dec. 31, 2024. The control group received the morphine-acetaminophen combination, and this was compared with patients who only received morphine.

Patients included in the study were 18 years of age and older with severe acute pain, which was assessed using a numeric rating scale (NRS) score of 0 to 10. The primary outcome was the mean change in verbal NRS pain scores from baseline to 30 minutes after study drug administration. Patients were observed for 60 minutes.

Secondary outcomes included mean NRS change at 10, 20, 45, and 60 minutes; cumulative morphine dose within 30 minutes; successful analgesia at 30 minutes, which was measured as NRS ≤3; and rescue analgesia at 30 minutes. Patients were also followed up for 24 hours after the last morphine dose to capture delayed adverse events.

Researchers had hypothesized that morphine alone would not be inferior to morphine plus acetaminophen. But they found that morphine alone did not meet the criteria to be considered noninferior to the combination regimen.

In fact, researchers found that at 30 minutes, pain reduction slightly favored the morphine‑acetaminophen combination. Additionally, they found that IV morphine plus placebo may be inferior to combination therapy in a subgroup of patients with nontraumatic pain, specifically pain resulting from nerve injury and nociplastic pain, that is, pain that comes from changes in how the nervous system detects stimuli. These types of pain are often less responsive to treatment with opioids, researchers said in the paper.

“In such cases, multimodal analgesia strategies that incorporate IV acetaminophen may improve pain control while potentially reducing overall opioid requirements,” they wrote. “The findings suggest acetaminophen may have potential benefit as an adjunct to morphine in individualized treatment approaches for acute pain in the ED.”

One of the limitations was that the follow-up was limited to 60 minutes. Researchers were not able to collect data on delayed effects, opioid use beyond the initial period or later adverse events. Longer follow-up with repeated dosing, they said, could better assess longer-term outcomes.

Researchers also did not assess other patient-centered outcomes, such as time to meaningful pain relief, satisfaction, function or ED length of stay.