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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:

  1. Did the study population include or focus on those in the emergency department? Yes
  2. Were the patients adequately randomized? Yes
  3. Was the randomization process concealed? Yes
  4. Were the patients analyzed in the groups to which they were randomized? Yes
  5. Were the patients recruited consecutively, minimizing selection bias? Unsure
  6. Were both groups similar with respect to prognostic factors? Yes
  7. Were all participants unaware of group allocation (blinded/masked)? Yes
  8. Were all groups treated equally except for the intervention? Yes
  9. Was follow-up complete, with at least 80% for both groups? Yes
  10. Were all patient-important outcomes considered? No
  11. Was the treatment effect large enough and precise enough to be clinically significant? No
  12. Who funded the trial? French Ministry of Health.
  13. 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. That makes the result frustratingly imprecise rather than convincingly negative. Noninferiority trials live and die by their confidence intervals; when the CI crosses the margin, the correct conclusion is that noninferiority has not been established, not that the treatments are necessarily different.  

2. mITT & PP Analyses Don’t Completely Remove Noninferiority Bias: The investigators appropriately reported both mITT and PP analyses, which is particularly important in noninferiority trials. However, this was not a pure ITT analysis: six randomized patients were excluded from mITT, while 393/430 remained in PP. In superiority trials, ITT generally protects the prognostic balance created by randomization. In noninferiority trials, nonadherence and crossover can instead bias results toward apparent similarity, which is why agreement between ITT and PP is desirable. Here, the results were reasonably consistent, which is reassuring, but the distinction still matters when the traumatic result misses the margin by one-hundredth of an NRS point. 

3. Nontraumatic Pain: This is not a diagnosis but a description. Pooling abdominal pain, headache, back pain, chest pain and other painful syndromes into a single bucket creates considerable clinical heterogeneity. Likewise, traumatic pain included several anatomical sites, although extremity injury dominated. Different pain mechanisms may respond differently to opioids and acetaminophen. Randomization protects the internal comparison on average, but it does not make renal colic, undifferentiated abdominal pain, migraine and back pain biologically interchangeable. This can dilute a benefit in one condition or manufacture an average that applies particularly well to none. The authors acknowledge this heterogeneity as a limitation. 

4. Thirty Minutes: The primary outcome was pain reduction at 30 minutes, and formal observation was primarily over 60 minutes. That makes sense for ED analgesia, but it captures only the front end of the patient’s experience. It tells us little about later pain, repeated opioid use, disposition, recurrent analgesic requirements or whether patients could walk, breathe deeply, undergo imaging or go home comfortably. The investigators themselves acknowledge that longer follow-up might have better characterized both analgesic effectiveness and harms. So, while 30 minutes is one patient-oriented outcome (POO), there are many others to consider.

5. Selected Population: Patients who had taken an analgesic within eight hours were excluded. There were also many more exclusions (see the PICOT statement). These restrictions create a relatively stable, analgesic-naïve population. They improve experimental control but reduce external validity. Many real ED patients with severe pain have already taken acetaminophen or an NSAID before arrival, are older or medically complex, use chronic analgesics, or have a condition requiring rapid procedures. The result therefore applies best to patients resembling those enrolled and not automatically to those coming to the ED with a chief complaint of pain.

Comment on the Authors’ Conclusion Compared to the SGEM Conclusion: We agree that morphine alone was not shown to be noninferior to morphine plus IV acetaminophen. Our friendly amendment is that this trial does not establish a clinically important benefit from adding acetaminophen; it simply leaves that possibility open.

The SGEM Bottom Line: Don’t toss the Tylenol. Adding acetaminophen to titrated morphine may provide some additional analgesia, and this trial could not establish that morphine alone was good enough.

Case Resolution: The patient receives weight-based IV morphine with reassessment and titration according to response. Given his severe acute abdominal pain, no contraindication to acetaminophen and the remaining uncertainty about a possible adjunctive benefit, you also give acetaminophen as part of a multimodal strategy. Thirty minutes later, his pain has decreased from 8/10 to 4/10. He is much more comfortable and can cooperate with the remainder of the examination and diagnostic work-up.

Clinical Application: I would not interpret this trial as evidence that every patient receiving IV morphine now needs IV acetaminophen. The trial failed to demonstrate that omitting acetaminophen was noninferior, but failure of noninferiority is not proof of superiority. For a patient who can safely receive acetaminophen, multimodal analgesia remains reasonable, particularly when reducing opioid exposure is desirable. What this trial changes for me are my level of confidence: I would be less comfortable claiming that acetaminophen adds nothing when morphine is being titrated.

 I would also separate the drug from the route. The study tested IV acetaminophen, not inexpensive oral acetaminophen. It does not demonstrate that the IV formulation is clinically superior to oral acetaminophen in patients capable of taking medication by mouth. That is an important distinction for cost-conscious ED practice and those places without IV acetaminophen.

What I Would Tell the Patient: I can see you’re in quite a bit of pain. We’re going to give you some Morphine. It is a strong pain medicine that usually works quickly. It can make you feel sick to your stomach or sleepy, and sometimes it can slow your breathing, so we’ll keep a close eye on you. We can also give you Tylenol along with the morphine. It may help with the pain in a different way. We may not be able to make the pain go away completely, but our goal is to get you feeling much more comfortable while we figure out what’s causing it.

Keener Kontest: Last episode’s winner was Ryker Kiel from Wyoming. He Googled and found that REMAP-CAP stands for A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia

Other SEGM Episodes on Pain:

  • SGEM#55: Drugs in My Pocket – Opioids in the Emergency Department — opioid prescribing and controlled-substance guidelines in the ED.  
  • SGEM#149: Shared Decision Making for Pain Control in Older ED Patients — involving older patients in analgesic selection.  
  • SGEM#173: Diazepam Won’t Get Back Pain Down — diazepam for acute low-back pain.  
  • SGEM#175: Dancing on the Ceiling with Ketorolac for Pain — the analgesic ceiling effect of IV ketorolac; 10 mg performed similarly to higher doses.  
  • SGEM#187: Pin Cushion – Acupuncture in the Emergency Department — acupuncture for ED pain, including back pain, ankle sprain, and migraine.  
  • SGEM#240: I Can’t Get No Satisfaction for My Chronic Non-Cancer Pain — opioids for chronic non-cancer pain, with an ED-focused clinical case.  
  • SGEM#304: Treating Acute Low Back Pain – It’s Tricky, Tricky, Tricky — acute low-back pain treatment.  
  • SGEM#342: Should We Get Physical, Therapy for Minor Musculoskeletal Disorders in the ED? — non-pharmacologic management with ED-based physiotherapy.  
  • SGEM#366: Relax, Don’t Do It – Skeletal Muscle Relaxants for Low Back Pain — muscle relaxants for acute low-back pain.  
  • SGEM#483: Electricity – TENS Units for Treating Back Pain — non-pharmacologic pain management with TENS.  

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. Cordell WH, Keene KK, Giles BK, Jones JB, Jones JH, Brizendine EJ. The high prevalence of pain in emergency medical care. Am J Emerg Med. 2002 May;20(3):165-9. doi: 10.1053/ajem.2002.32643. PMID: 11992334.
  2. Chang HY, Daubresse M, Kruszewski SP, Alexander GC. Prevalence and treatment of pain in EDs in the United States, 2000 to 2010. Am J Emerg Med. 2014 May;32(5):421-31. doi: 10.1016/j.ajem.2014.01.015. Epub 2014 Jan 21. PMID: 24560834.
  3. Mathieson S, Zadro JR, Narayan SW, McLachlan AJ, Ballantyne JC, Blyth FM, Day RO, Maher CG, McLachlan H, Lin CC, Kamper SJ, Abdel Shaheed C. Efficacy and Harms of Opioid Analgesics for Acute Pain: Overview of Systematic Reviews and Meta-analyses. Drugs. 2026 Apr;86(4):533-550. doi: 10.1007/s40265-026-02284-3. Epub 2026 Feb 25. PMID: 41739420; PMCID: PMC13005847.