The Skeptics Guide to Emergency Medicine Global

Date: October 3, 2025 Reference: Doheim et al. Meta-Analysis of Randomized Controlled Trials on IV Thrombolysis in Patients With Minor Acute Ischemic Stroke. Neurology 2025 Guest Skeptic: Dr. Casey Parker is a Rural Generalist, Evidence-based medicine enthusiast and Ultrasound Nerd. This episode was recorded live, in beautiful Broome, Australia, at the Spring Seminar on Emergency Medicine (SSEM 2025). You can get copies of the slides used in the presentation at this LINK. You can also watch the episode on YouTube. Case: Dani is a recently retired emergency department (ED) doc who has spent the last year travelling the world, playing banjo & sharing time with family and friends. This morning, whilst eating a breakfast of eggs and ham, Dani had a sudden onset of right-hand weakness and difficulty speaking. Dani’s family called 000 (911 in North America), and she was taken to the ED within one hour. On arrival at your medium-sized rural ED, Dani is assessed by the “Stroke Team aka, you” as having mild motor weakness in the right hand and mild dysarthria. Dani is given an NIHSS score of 4. A rapid CT and CTA is quickly reported as “no acute large vessel occlusion” and “No intracranial bleed and no established cortical infarction”. You know that many centers in the city are offering intravenous tPA for patients with acute ischemic stroke.  You wonder if Dani should get a dose?  Background: Minor ischemic strokes (MIS), often defined by NIHSS ≤5, are very common, with roughly half of all ischemic strokes presenting with mild deficits. Despite the mild presentation, these strokes are not always benign. About 30% of patients with initially minor stroke symptoms end up significantly disabled (unable to walk independently) at 90 days [1].  In short, a small stroke can still have a big impact on a patient’s life if it isn’t effectively treated or if it progresses. Dr. Daniel Fatovich There have been gallons of ink spilled in the discussion of the stroke literature, with much debate on previous SGEM episodes about the relative risks and benefits of IV thrombolytic therapy for acute strokes. Drs. Ken Milne and Danny Fatovich have earned themselves the title of “non-expert EM contrarians” when discussing the literature around acute ischemic stroke management with Neurologists all over the world. IV thrombolysis (tissue plasminogen activator [tPA], or newer Tenecteplase [TNK]) is a well-established therapy for acute ischemic stroke based on some questionable evidence [2-6]. However, its role in mild strokes has been hotly debated. On one hand, treating early might prevent a minor stroke from evolving or causing hidden disability. On the other hand, tPA carries a risk of intracerebral hemorrhage, and many minor stroke patients recover well without aggressive intervention. Guidelines have wrestled with this nuance: current recommendations endorse tPA for mild strokes that have clearly disabling deficits, but advise against tPA for mild non-disabling strokes [7]. The core controversy is whether the potential functional benefit in MIS is worth the bleeding risk if the patient is already doing okay. Things changed 10 years ago after Mr. CLEAN was published. It showed that endovascular interventions (EVT) for acute large vessel occlusions (LVOs) could have impressive results (NNT of 7). However, the role of IV thrombolytics for minor stroke syndromes remains unclear and controversial.  Legendary (now-retired) ED Dr. Joe Lex once stated, “If I can kick the syringe outta’ your hand – then don’t give me the tPA!”  Was Joe right? Before 2019, practice varied widely. Some neurologists treated almost any stroke within the window, reasoning that “time is brain” even for mild deficits, while others were more conservative. Observational studies yielded mixed signals. Several studies suggested that thrombolysis in mild strokes improves the chance of an excellent outcome at discharge or 90 days, while others showed minimal benefit. The PRISMS trial (2018) was a key randomized study in this area. It compared alteplase vs. aspirin in patients with minor non-disabling strokes (NIHSS ≤5). PRISMS found no difference in 90-day functional outcomes (mRS score 0-1) between the tPA and aspirin groups, but did find an increase in symptomatic intracerebral hemorrhage with tPA [8]. However, that trial was stopped early after only ~1/3 of the planned enrolment (313/948). This was reported due to a lack of funding. There are issues with stopping trials early, which we have discussed on previous SGEM episodes. Stopping PRISMS early meant it lacked the power to definitively settle the question of lysis minor, non-disabling strokes. Consequently, equipoise remained, and actual practice often followed guideline nuance, treating “minor-but-disabling” strokes (for example, isolated aphasia or hemiparesis that significantly limits function) while generally avoiding tPA in trivial or rapidly improving strokes. Viele et al JAMA 2016, Guyatt et al BMJ 2012, Tyson et al Trials 2016 Clinical Question: In adults with minor acute ischemic stroke (generally NIHSS ≤5), does IV thrombolysis (IVT) improve functional outcomes compared with non‑thrombolytic standard care? Reference: Doheim et al. Meta-Analysis of Randomized Controlled Trials on IV Thrombolysis in Patients With Minor Acute Ischemic Stroke. Neurology 2025 Population: Adults (≥18 y) with minor ischemic stroke (NIHSS <6) eligible to receive IVT within 12 hours of onset from RCTs. Excluded: Nonrandomized studies or those without a control arm. Trials included patients with nondisabling and, in some RCTs, mildly disabling symptoms. Intervention: A variety of IV thrombolytic drugs (Alteplase, Tenecteplase, pro-urokinase) given within varying time windows, but most within 3 to 4.5 hours, followed by standard care. Comparison: Non-thrombolytic standard care (NT‑SC), which could include dual or single antiplatelet therapy, anticoagulants, statins, antihypertensives, glucose control, and other risk‑factor–directed treatments. Outcome: Primary Outcome: Excellent functional outcome at ~90 days, defined as mRS 0-1. (For IST‑3 subgroup data, OHS was converted to mRS; where only 6-month data existed, it was used.) Secondary Outcomes: Favourable outcome mRS 0-2, 90-day mortality, recurrent ischemic or hemorrhagic stroke and safety (symptomatic ICH [sICH]and any ICH). Type of Study: Systematic review and meta-analysis or RCTs  Authors’ Conclusions: “IVT does not confer improved functional outcomes among patients with minor strokes and can be associated with higher odds of sICH and mortality.”      Quality Checklist for Therapeutic Systematic Reviews: (yes/no/unsure) Was the clinical question sensible and answerable? Yes Was the search detailed and exhaustive? Yes Were primary studies of high methodological quality? Yes Were the assessments of studies reproducible? Yes Were the outcomes clinically relevant? Yes Was there low statistical heterogeneity for the primary outcomes? Unsure Was the treatment effect large and precise enough to be clinically significant? No  Who funded the review? No targeted funding reported. Conflicts of interest declared? Authors report no relevant disclosures. (though not true for the primary trials - most had conflicts/funding by drug companies) Results: A total of 3,364 patients from four RCTs were included in the primary analysis. The age ranged from ~56 to 80 years across trials. Most had non-disabling deficits. Some RCTs included a minority with disabling symptoms. Trials varied in time windows (≤3 h, ≤4.5 h, ≤12 h) and imaging criteria (TEMPO‑2 required evidence of intracranial occlusion). The typical baseline NIHSS medians ~2 to 4 in the RCT. Key Results: Compared with non-thrombolytic standard care, IV thrombolysis did not improve excellent 90‑day functional outcome (mRS 0-1) and was associated with higher odds of symptomatic ICH and mortality in patients with minor stroke. Primary Outcome: mRS 0-1 at ~90 days: OR 85 (95% CI 0.70–1.03). No significant benefit of IVT vs NT‑SC. Similar null results across Alteplase, Tenecteplase, and prourokinase subgroups. Null also across disabling and nondisabling presentations.  Secondary Outcomes: mRS 0–2 at ~90 days: OR 71 (95% CI 0.55–0.91). Lower odds of independence with IVT. It became non-significant when post hoc IST‑3 data were added (OR 0.85, 95% CI 0.58–1.24).  Symptomatic ICH: OR 10 (95% CI 2.01–12.96). Increased with IVT.  Any ICH: OR 21 (95% CI 1.63–3.01). Increased with IVT.  90‑day Mortality: OR 84 (95% CI 1.18–2.89). Increased with IVT.  Recurrent Stroke: OR 01 (95% CI 0.79–1.29). No statistical difference. What Goes Into the Sausage Machine: This meta-analysis includes a range of trials with different inclusion, exclusion criteria, differing baselines, geographic/demographic and “standard care” comparators, so it is a bit of an evidentiary fruit salad. It can be hard to know how this data applies to the patient and the drugs/system of care that you are working with in your hospital. To make this decision, we may need to look back at individual cohorts and see if they represent our patients and system of care. Rural Stroke Application: In large tertiary hospitals where access to immediate imaging, stroke teams, and endovascular “clot retrieval” interventions has become the standard of care, all of the options are available. However, in rural or remote hospitals where we often do not have as much information or access to interventional neuro-radiology, we run the risk of delivering “second-class” care to our patients with acute ischemic strokes. This trial gives us some clarification around the role of tPA in our smaller community.  Is it best to transfer patients with large, disabling strokes to a bigger centre,

Date: October 26, 2023 Reference: Jones et al. Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial placebo-controlled trial. Lancet July 2023 Guest Skeptic: Dr. Sergey Motov is an Emergency Physician in the Department of Emergency Medicine, Maimonides Medical Center in New York City. He is also one of the world’s leading researchers on pain management in the emergency department, specifically the use of ketamine. His twitter handle is @PainFreeED. Case: A 37-year-old man without a significant past medical history presents to the emergency department (ED) with a chief complaint of lower back pain that started three days prior to the ED visit after unloading a truck with furniture. He states that pain is severe (7/10 in intensity), sharp, constant, non-radiating, and is exacerbated by any movement. The patient is unable to go to work due to pain and is experiencing severe limitations in his daily activities. He denies any weakness or numbness of the lower extremities or bowel or bladder dysfunction. You perform a physical examination and note prominent tenderness to palpation at bilateral lumbar paraspinal regions with normal neuro-vascular examination. You engage the patient in shared decision making about his most likely diagnosis (muscle strain) and treatment approach such as a short course of non-steroidal anti-inflammatory drugs (Ibuprofen) and gradual physical activity as tolerated. The patient, however, believes that ibuprofen will not touch his pain and insists on receiving an opioid-containing medication. Background: Low back pain and neck pain are extremely common conditions worldwide [1]. We have covered the issue of back pain several times on the SGEM including: SGEM#87:Let Your Back Bone Slide (Paracetamol for Low-Back Pain) SGEM#173: Diazepam Won’t Get Back Pain Down SGEM#240: I Can’t Get No Satisfaction for My Chronic Non-Cancer Pain SGEM#304: Treating Acute Low Back Pain – It’s Tricky, Tricky, Tricky SGEM#366: Relax, Don’t Do It – Skeletal Muscle Relaxants for Low Back Pain Back pain and neck pain are leading causes of disability on a global scale [2,3]. The substantial disability burden imposes enormous costs both directly on healthcare systems, and indirectly through productivity losses [4,5]. Not only are these conditions common and painful they are difficult to treat. Many pharmacologic treatments have been tried with limited efficacy. Acetaminophen (Williams et al Lancet 2014) Muscle relaxants (Friedman et al JAMA 2015) NSAIDs (Machado et al  Ann Rheum Dis 2017) Steroids (Balakrishnamoorthy et al Emerg Med J 2014) Benzodiazepines (Friedman et al Ann Emerg Med 2017) Many non-pharmacologic therapies have also been tried with limited efficacy. Cognitive Behavioral Therapy and mindfulness (Cherkin et al JAMA 2016) Chiropractic (Paige et al JAMA 2017) Physical therapy (Paolucci et al J Pain Research 2018) Acupuncture (Colquhoun and Novella Anesthesia and Analgesia 2013) One treatment modality, opioids, can be effective but comes with very real potential harms. The American College Physicians (ACP) has a 2017 policy on guidelines for treating non-radicular low back pain (Qaseem et al Annals of Int Med). Their third recommendations states: Clinicians should only consider opioids as an option in patients who have failed the aforementioned treatments and only if the potential benefits outweigh the risks for individual patients and after a discussion of known risks and realistic benefits with patients. (Grade: weak recommendation, moderate-quality evidence) The American College of Emergency Physicians (ACEP) has addressed the issue of opioid use in patients being discharged home after an acute episode of pain. They give a Level C Recommendations saying: Do not routinely prescribe, or knowingly cause to be co-prescribed, a simultaneous course of opioids and benzodiazepines (as well as other muscle relaxants/sedative-hypnotics) for treatment of an acute episode of pain in patients discharged from the emergency department (Consensus recommendation).  Despite guidelines and policy recommendations for prudent short-term opioid use only after other analgesics fail [6], opioid medications are frequently prescribed as the initial treatment for patients presenting with acute low back pain or neck pain. Estimates suggest up to two-thirds of these patients in Australia may receive opioids first-line [7]. Opioid prescription rates remain high in many countries including the USA. One study reported 43 prescriptions dispensed per 100 people in the US in 2020, though efforts have been made recently to curtail this use [8]. The prevalent use of opioids for acute back and neck pain is concerning given the lack of direct, high-quality evidence supporting efficacy [9]. Clinical Question: Is a short course of an opioid analgesic effective at reducing pain severity and improving function and quality of life in patients with acute non-specific low back pain or neck pain compared to placebo? Reference: Jones et al. Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial placebo-controlled trial. Lancet July 2023 Population: Adults aged 18 years or older with acute low back pain, neck pain, or both with or without radiation to the leg or arm of at least moderate severity that has been lasting for 12 weeks or less and preceded by at least a 1-month period free from back and neck pain. Participants were recruited via emergency department, primary care offices or through a social media campaign. Exclusions: Known or suspected serious spinal pathology; contraindications to opioid analgesics; taken a prescription opioid analgesic for the current episode of low back pain or neck pain at a dose higher than 15 mg of oral morphine equivalent per day for 5 or more consecutive days; spinal surgery in the preceding 6 months; scheduled or being considered for surgery or interventional procedures for low back pain or neck pain (or both) during the 6-week treatment period; younger than 18 years; insufficient English language skills or if interpretation was unavailable; and female participants who were planning conception, pregnant, or breastfeeding. Intervention: Oxycodone-naloxone modified release tablets (5mg oxycodone/2.5mg naloxone) given orally for up to 6 weeks twice daily with allowable titration up to a maximum of 10mg oxycodone/5mg naloxone twice daily based on pain severity, tolerability, and sedation scores. Down-titration and cessation occurred once adequate pain improvement was achieved (pain score 0-1 out of 10 for 3 consecutive days or for a maximum of 6 weeks) Comparison: Identical-appearing placebo tablets containing inactive ingredients that followed the same dosing regimen and schedule as the intervention group. Both groups also received guideline-recommended care for acute spinal pain in addition to the study medication/placebo. Outcome: Primary Outcome: Pain intensity measured on a 0–10 scale by the Brief Pain Inventory Pain Severity Subscale at 6 weeks after randomization. Secondary Outcomes: Global Perceived Effect Scale: Assessed at weeks 2, 4, 6, and 12. Physical Functioning (Generic): Measured by the Brief Pain Inventory Interference Subscale (BPI-IS) at weeks 2, 4, 6, and 12. Physical Functioning (Back): Measured by the Roland Morris Disability Questionnaire (RMDQ) at week 6. Physical Functioning (Neck): Measured by the Neck Disability Index (NDI) as a percentage at week 6. Quality of Life (Physical Score): Measured by the SF-12v2 at weeks 2, 4, 6, and 12. Quality of Life (Mental Score): Measured by the SF-12v2 at weeks 2, 4, 6, and 12. Pain severity at other timepoints (2, 4, 12, 26, 52 weeks) Time to recovery Healthcare utilization Work absenteeism Adverse events Risk of opioid misuse (Current Opioid Misuse Measure scale) Type of Study: A randomized, triple-blinded, placebo-controlled trial with parallel groups and intention-to-treat analysis. Authors’ Conclusions: “Opioids should not be recommended for acute non-specific low back pain or neck pain given that they found no significant difference in pain severity compared with placebo. This finding calls for a change in the frequent use of opioids for these conditions.” Quality Checklist for Randomized Clinical Trials: The study population included or focused on those in the emergency department. No The patients were adequately randomized. Yes The randomization process was concealed. Yes The patients were analyzed in the groups to which they were randomized. Yes The study patients were recruited consecutively (i.e. no selection bias). Unsure The patients in both groups were similar with respect to prognostic factors. Yes All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Unsure All groups were treated equally except for the intervention. Yes Follow-up was complete (i.e. at least 80% for both groups). No All patient-important outcomes were considered. Yes The treatment effect was large enough and precise enough to be clinically significant. No Financial conflicts of interest. The authors stated that the funders of the study had no role in the study design, data collection, analysis, interpretation, or reporting. The sources of funding included government agencies and academic institutions. No industry funding was reported. All authors declared no competing interests related to the submitted work. Two authors received research fellowships from the National Health and Medical Research Council of Australia. No other financial relationships or conflicts of interest were reported. Results: 347 participants were recruited to be randomized.