SGEM#520: It takes my pain away – Morphine, but do I need to add acetaminophen?

Date: Sept 13, 2026 Caitlin Jones PhD Guest Skeptic: Dr. Caitlin Jones is a Postdoctoral Research Associate at Sydney University’s Institute for Musculoskeletal Health. Her research evaluates the benefits and harms of treatments for musculoskeletal conditions with a particular interest in high-risk treatment options such as opioid medicines and spinal cord stimulators for pain. She aims to improve patient outcomes and reduce harm from inappropriate treatments. Reference: Cattin et al. Morphine Plus Placebo vs Morphine Plus Acetaminophen for Acute Pain in the Emergency Department: A Randomized Clinical Trial. JAMA Netw Open. 2026 Feb Case: A 42-year-old otherwise healthy man presents to your emergency department (ED) with eight hours of severe abdominal pain. He rates it as 8/10. His vital signs are normal, Glasgow Coma Scale (GCS) score is 15 and he weighs 82 kg. He has not taken any analgesics in the previous eight hours and does not use chronic opioids. There is no evidence of acute coronary syndrome, respiratory failure or another immediately unstable condition. His initial work-up is underway, but he remains visibly uncomfortable. You decide that intravenous (IV) opioid analgesia is appropriate and start titrated morphine. Your resident asks whether adding IV acetaminophen will meaningfully improve his pain control. Background: Pain is one of the most common reasons patients show up in the ED. Depending on how you measure it, pain is the chief complaint in roughly half of ED visits and is documented somewhere in the chart in about 60% [1]. A large US data set found pain was the primary symptom in approximately 45% of ED visits [2]. So, treating pain is not exactly a niche part of emergency medicine; it is pretty much our bread and butter. Unfortunately, sometimes there is more bread (pain) than butter (pain control). We have several tools in the analgesic toolbox. Pharmacologic options include acetaminophen, NSAIDs, opioids, ketamine, local anesthetics and condition-specific medications. We can combine treatments as part of a multimodal approach rather than simply increasing the dose of one drug. There are also non-pharmacologic approaches such as ice, heat, elevation, splinting, positioning, distraction and, in selected patients, physical therapy or other supportive strategies. Current guidance generally encourages using non-opioid and non-pharmacologic approaches when appropriate, while reserving opioids for patients in whom the expected benefits outweigh the harms. The problem is that there is no magic bullet for pain control. We have covered this repeatedly on the SGEM. The practical target is usually to reduce suffering and restore sufficient function to examine, investigate, treat, and safely discharge the patient. The goal should not be to achieve the mythical 0/10 before anyone is allowed to leave the building. As said in The Princess Bride, “Life is pain, Highness. Anyone who says differently is selling something.” Opioids remain very effective analgesics for some conditions, including severe abdominal pain, and can have an important role in severe acute pain [3]. They also come with baggage. Immediate adverse effects include nausea, vomiting, sedation, dizziness, hypotension and respiratory depression. Longer exposure brings concerns about tolerance, dependence, misuse and overdose, which is why opioid stewardship matters both inside the ED and at discharge. This is not an argument for undertreating pain; it is an argument for treating it thoughtfully. We are looking for the Goldilocks zone of pain management, not too much but also not too little. The pendulum has swung back and forth over the years between the two extremes. Clinical Question: In adult ED patients with acute severe traumatic or nontraumatic pain receiving titrated IV morphine, is morphine without acetaminophen noninferior to morphine plus 1 g IV acetaminophen for reducing pain during the first 30 minutes of treatment? Reference: Cattin et al. Morphine Plus Placebo vs Morphine Plus Acetaminophen for Acute Pain in the Emergency Department: A Randomized Clinical Trial. JAMA Netw Open. 2026 Feb Population: Adults aged 18 years or older presenting to one of 11 French EDs with acute pain lasting less than 24 hours, either traumatic or nontraumatic, with an NRS pain score ≥5/10. Exclusions: Patients with unstable vital signs, GCS <15, pregnancy, weight <50 kg, immediate need for fracture treatment or joint reduction, acute cardiopulmonary emergencies such as pulmonary edema, respiratory failure or ACS, acute intoxication, analgesic use within the previous eight hours, inability to obtain IV access, hypersensitivity to the study drugs, kidney or hepatic insufficiency, chronic pain treatment, and use of buprenorphine, nalbuphine or pentazocine. Intervention: Titrated IV morphine plus placebo. Patients received an initial morphine dose of 0.10 mg/kg IV (maximum 10 mg), followed by 0.05 mg/kg IV every 10 minutes as needed (maximum 5 mg per bolus and 20 mg total in the first 30 minutes), together with 100 mL of 0.9% sodium chloride placebo. Comparison: Titrated IV morphine plus 1 g IV acetaminophen. The morphine regimen was identical to the intervention group, with patients also receiving 1 g acetaminophen in a 100-mL IV bag. Outcomes: Primary Outcome: The mean change in 0–10 numeric rating scale (NRS) pain score from baseline to 30 minutes after study drug administration. The prespecified noninferiority margin was 1 NRS point. Secondary Outcomes: These included change in pain score at 10, 20, 45 and 60 minutes; cumulative morphine dose at 30 minutes; successful analgesia at 30 minutes, defined as NRS ≤3; need for rescue analgesia; changes in vital signs; and adverse events including nausea, vomiting, oxygen saturation <94%, hypotension, dizziness, reduced GCS, rash and pruritus. Type of Study: A prospective, multicentre, double-blind, placebo-controlled, randomized noninferiority clinical trial. The Authors’ Conclusions: “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.” Quality Checklist for Randomized Clinical Trials: Did the study population include or focus on those in the emergency department? Yes Were the patients adequately randomized? Yes Was the randomization process concealed? Yes Were the patients analyzed in the groups to which they were randomized? Yes Were the patients recruited consecutively, minimizing selection bias? Unsure Were both groups similar with respect to prognostic factors? Yes Were all participants unaware of group allocation (blinded/masked)? Yes Were all groups treated equally except for the intervention? Yes Was follow-up complete, with at least 80% for both groups? Yes Were all patient-important outcomes considered? No Was the treatment effect large enough and precise enough to be clinically significant? No Who funded the trial? French Ministry of Health. Did the authors declare any conflicts of interest? Christelle Volteau reported grants from the Direction Générale de l’Offre de Soins during the conduct of the study. No other disclosures were reported. Results: 430 patients were randomized; 424 entered the mITT population. Median age was 42 years (IQR 29–57), approximately half were men, median estimated Body Mass Index (BMI) was 24.5, and median initial pain was 8/10. Of the mITT cohort, 243/424 (57%) had nontraumatic pain and 181/424 (43%) had traumatic pain. Key Results: Morphine plus placebo did not demonstrate noninferiority to morphine plus IV acetaminophen for 30-minute pain relief in either traumatic or nontraumatic acute pain; the estimates generally favoured acetaminophen, but the trial does not establish that acetaminophen was superior. Primary Outcome: For traumatic pain, the Per-Protocol (PP) mean reductions were -4.5 for Morphine + placebo vs -4.83 for Morphine + Acetaminophen Between-group difference: 0.32 points (95% CI −0.29 to 0.94) For nontraumatic pain, the PP difference was 0.80 points (95% CI 0.19 to 1.41) and the mITT difference was 0.76 (95% CI 0.11 to 1.41). Both crossed the 1-point noninferiority margin. Interestingly, both confidence intervals were entirely on the side favouring acetaminophen, but formal superiority/inferiority testing had not been prespecified. Secondary Outcomes: By 60 minutes, the differences had narrowed. For nontraumatic pain, both PP and mITT analyses met the 1-point noninferiority criterion at 60 minutes; traumatic pain met it by PP but narrowly missed it in mITT. Morphine consumption was essentially similar Successful analgesia NRS ≤3 at 30 minutes, was also similar: 69% vs 62% for nontraumatic pain and 67% vs 66% for traumatic pain. The notable secondary finding was the need for rescue analgesia in nontraumatic pain: 2% with acetaminophen vs 13% with placebo, P=.01. There was no meaningful difference in trauma. Adverse effects were generally similar, and no serious adverse event requiring study withdrawal or intervention occurred 1. Missed the Target: The original sample-size calculation called for 572 patients at 90% power. Recruitment was severely disrupted by COVID-19, and in 2022 the investigators reduced the target power to 80%, producing a revised target of 428. More importantly, the planned enrolment within the traumatic stratum was not achieved: only 181 traumatic patients entered mITT. The traumatic mITT CI ended at 1.01, essentially sitting on top of the 1-point margin....