Pharmacologic Treatment of Acute Migraine in the Pediatric Emergency Department: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Pharmacologic Treatment of Acute Migraine in the Pediatric Emergency Department: A Systematic Review and Meta-analysis of Randomized Controlled Trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Pharmacologic Treatment of Acute Migraine in the Pediatric Emergency Department: A Systematic Review and Meta-analysis of Randomized Controlled Trials Mohammed Alsabri, Toka Elboraay, Mohamed Amr Elkarargy, Sara M. Darawish, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8885764/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Acute migraine is a frequent cause of pediatric emergency department (ED) visits, yet comparative evidence for pharmacologic management in this setting remains limited and heterogeneous. We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of ED-based pharmacologic treatments for acute pediatric migraine. Methods We searched MEDLINE, Embase, CENTRAL, PubMed, Scopus, and Web of Science from inception to 2025 for RCTs evaluating acute pharmacologic therapies for migraine in patients < 18 years presenting to the ED. The primary outcome was pain response at 2 hours. Secondary outcomes included need for rescue therapy, ED length of stay, return visits, adverse events, and treatment satisfaction. Random-effects pairwise meta-analyses and a frequentist network meta-analysis were performed. Risk of bias was assessed using RoB 2, and certainty of evidence using GRADE. Results Nine RCTs involving 476 participants were included. Active ED migraine treatments were associated with a modest reduction in pain compared with control or standard care (mean difference of 5.96 points on a 0–100 scale; 95% CI 0.42 to 11.51), with low heterogeneity. The effect size was small and close to the minimal clinically important difference. Sensitivity analyses restricted to studies at moderate risk of bias showed no statistically significant benefit. Reporting of secondary outcomes and adverse events was inconsistent, precluding quantitative synthesis. Dopamine antagonists, particularly prochlorperazine, appeared more effective than NSAIDs for short-term pain relief but were associated with more extrapyramidal adverse effects. Conclusions Current pharmacologic treatments for acute pediatric migraine in the ED provide only modest short-term pain relief, with low-certainty evidence and no clearly superior therapy. Future large, multicenter ED-based trials with standardized, patient-centered outcomes and longer follow-up are needed to inform evidence-based care. pediatric migraine emergency department acute migraine pharmacologic therapy dopamine antagonists nonsteroidal anti-inflammatory drugs prochlorperazine Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Migraine is a prevalent neurological disorder affecting approximately 12% of the global population, with a higher prevalence observed in females ( 1 ). This primary headache disorder is characterized by episodic attacks that may persist for hours to days, resulting in significant impairments in daily functioning and overall quality of life ( 2 ). The disorder exhibits considerable heterogeneity, with migraine without aura being the most prevalent subtype, accounting for approximately 75% of cases (( 3 ). Migraine is a common condition among children and adolescents, with an estimated prevalence ranging from 7% to 9.1%. This prevalence increases with age, starting at approximately 5% in children aged 5 to 10 years and rising to around 15% in teenagers ( 4 , 5 ). Migraine diagnosis is primarily clinical, relying on patient history and physical examination in accordance with the ICHD-3 criteria ( 6 ). For migraine without aura, a diagnosis requires at least five attacks lasting 4 to 72 hours (about 6 days), characterized by at least two of the following: unilateral location, pulsating quality, moderate to severe intensity, and exacerbation by physical activity, along with one associated symptom such as nausea, vomiting, photophobia, or phonophobia. In the case of migraine with aura, at least two attacks must occur with reversible aura symptoms, along with two of the following criteria: gradual symptom spread, successive symptoms, duration of 5 to 60 minutes, and unilateral or positive symptoms; the aura should precede or coincide with the headache within 60 minutes. Neuroimaging is warranted for cases presenting atypical features, abnormal neurological examinations, sudden severe onset (thunderclap headaches), or new headaches in individuals over 50 years or those with immunosuppression ( 7 ). Migraine management is categorized into acute (abortive) therapies, preventive strategies, and lifestyle modifications. Acute treatments, designed to halt an ongoing attack, include nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans ( 8 ), with alternatives such as CGRP receptor antagonists (gepants) and lasmiditan for patients with contraindications; these are often supplemented by antiemetics to alleviate nausea ( 9 ). Preventive therapies are intended for those experiencing frequent or severe attacks and encompass pharmacologic options such as beta-blockers, antidepressants, anticonvulsants, calcium channel blockers, CGRP monoclonal antibodies, and onabotulinumtoxinA for chronic migraine. Non-pharmacologic approaches involve behavioral therapies and relaxation techniques, alongside the identification and avoidance of individual triggers, such as stress and specific foods ( 10 ). Managing acute pediatric migraine in the emergency department poses distinct challenges compared to adult care. Nearly one-third of pediatric migraine patients may leave without treatment, which could be due to diagnostic uncertainty or a predominant focus on excluding secondary causes. Additionally, neuroimaging is often overutilized, with CT scan rates between 16.3% and 20.9% in pediatric migraine cases ( 11 ), despite large studies showing no serious intracranial pathology ( 12 ). Treatment approaches also differ significantly between pediatric-only and mixed emergency departments; children in pediatric emergency settings are more likely to receive dopamine receptor antagonists and are less likely to be prescribed opioids. Notably, treatment within a pediatric emergency department is associated with a higher likelihood of achieving complete headache resolution ( 12 , 13 ). Pediatric emergency department (ED) visits for migraine are frequent, but comparative randomized controlled trial (RCT) evidence is limited and varied. Existing studies suggest IV prochlorperazine is effective, while combinations like metoclopramide+ketorolac show no added benefit over metoclopramide alone. A recent review favored dopamine antagonists but highlighted the need for an ED-specific RCT synthesis. This systematic review and network meta-analysis aims to rigorously analyze ED-based pediatric migraine RCTs to compare treatment efficacy and safety, ultimately aiding clinical decision-making and improving care. The primary objective is to compare the efficacy of ED pharmacologic treatments for pediatric acute migraine based on pain response at 2 hours. Secondary objectives include evaluating the need for rescue therapy, ED length of stay, return ED visits, adverse events, and treatment satisfaction. Methods This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420251123315 ( 14 ). Our analysis was based on data from previously published studies and, therefore, did not involve patient recruitment or active participation, eliminating the need for institutional review board approval. 1.1. Search Strategy A thorough literature review was performed across multiple electronic bibliographic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), Embase (via Ovid and Embase.com), MEDLINE, PubMed, and Scopus. Further inquiries were conducted on the Web of Science. The search covered the period from each database’s inception to the predefined search date in 2025, with no restrictions on publication date. The search strategy employed a combination of controlled vocabulary and free-text terms. Relevant Medical Subject Headings (MeSH) and Emtree terms included, but were not limited to, “Migraine Disorders,” “Child,” “Adolescent,” “Emergency Service, Hospital,” “Non-Steroidal Anti-Inflammatory Agents,” “Antiemetics,” “Dopamine Antagonists,” “Hypnotics and Sedatives,” “Ketorolac,” “Metoclopramide,” “Prochlorperazine,” and “Propofol.” Free-text keywords included “pediatric migraine,” “acute migraine,” “emergency department,” “ED,” “pharmacologic treatment,” “prochlorperazine,” “ketorolac,” “metoclopramide,” “propofol,” “pain response,” and “rescue therapy.” In addition, the reference lists of all included studies, as well as relevant prior systematic reviews and meta-analyses identified during the search, were manually examined to identify additional eligible studies. Backward citation tracking of key articles was undertaken. The search for unpublished studies was limited to trials indexed within the selected databases; dedicated gray literature sources and clinical trial registries were not independently searched. The detailed search strategy is presented in Supplementary Table 1 . 1.2. Criteria for Eligibility and Selection of Studies The evaluation included randomized controlled trials (RCTs) that assessed pharmacological interventions for the management of acute migraine in children and adolescents (< 18 years) presenting to the emergency department (ED). Eligible populations comprised patients diagnosed with an acute migraine episode based on International Classification of Headache Disorders (ICHD) criteria or a treating physician’s clinical assessment. Eligible interventions consisted of acute pharmacologic therapies administered in the ED, including dopamine antagonists (e.g., intravenous prochlorperazine, intravenous metoclopramide), nonsteroidal anti-inflammatory drugs (e.g., intravenous ketorolac), sedative-hypnotics (e.g., low-dose propofol), and antiemetic agents. Comparators include placebo, active pharmacologic controls, or standard/conventional therapy. Studies were excluded if they enrolled participants older than 18 years, evaluated non-migraine headache disorders, focused on preventive migraine therapies, or primarily involved treatment delivered outside the ED setting (e.g., inpatient wards or outpatient clinics). Non-randomized study designs were also excluded. 1.3. Selection of Studies Records identified through database searches were imported into reference management software for the systematic identification and removal of duplicate entries. The screening process was conducted in two stages: an initial assessment of titles and abstracts, followed by a full-text review of potentially eligible articles in accordance with the predefined inclusion and exclusion criteria. Each stage was performed independently by at least two reviewers, with disagreements resolved through discussion or, when consensus could not be reached, by consultation with a third reviewer. 1.4. Data Extraction Data extraction was conducted independently by at least two reviewers using a standardized, piloted data extraction form developed in Microsoft Excel. The form systematically captured key study characteristics (e.g., authors, year of publication, country, sample size, study design, and funding source), participant demographics (e.g., mean age, sex distribution, and diagnostic criteria such as ICHD or physician diagnosis), and detailed intervention and comparator information (e.g., drug name, dosage, route of administration, and co-interventions). The data extraction form was also used to collect information on all prespecified outcomes. This included primary outcome data on pain response at 2 hours (including outcome definitions and reported results) and secondary outcomes such as the need for rescue therapy, emergency department length of stay, repeat emergency department visits, specific adverse events (e.g., akathisia, dystonia, sedation), and measures of treatment satisfaction. To ensure accuracy and consistency, data extracted by the reviewers were compared, and discrepancies were resolved through discussion or, when necessary, by consultation with a third reviewer. Corresponding authors of the original studies were contacted to obtain missing or unclear information. 1.5. Analysis The analysis was performed using statistical software (e.g., R or Stata) with packages specifically designed for meta-analysis and network meta-analysis (NMA). Although a network meta-analysis was planned, it was not feasible because of the treatment network's disconnected nature and the limited number of included studies. The analysis was restricted to pairwise meta-analyses only where it was feasible. Random-effects models with Hartung–Knapp adjustment were applied for pairwise meta-analyses to account for anticipated clinical and methodological heterogeneity among included studies, providing more conservative and robust effect estimates. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes, such as pain response, while pooled mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs were calculated for continuous outcomes, including satisfaction scores. Statistical heterogeneity for each pairwise comparison was evaluated using the I² statistic, representing the proportion of variability attributable to between-study heterogeneity rather than chance. Between-study variance was quantified using the tau-squared (τ²) statistic. Forest plots were generated to display individual study estimates and pooled effects. Sensitivity analyses were performed to examine the robustness of the results, and the assumption of consistency between direct and indirect evidence in the network meta-analysis was assessed. 1.6. Quality Assessment The risk of bias of each included randomized controlled trial was assessed using the Cochrane Risk of Bias tool for randomized trials (RoB 2) ( 15 ). The assessment was performed independently by at least two reviewers, with disagreements resolved through discussion or, when necessary, by consultation with a third reviewer. 1.7. Certainty of evidence The certainty of evidence for all outcomes included in the meta-analysis was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework ( 16 ). Evidence derived from randomized controlled trials was initially rated as high certainty and was subsequently downgraded, when appropriate, based on predefined criteria including risk of bias, inconsistency, indirectness, imprecision, and publication bias. The overall certainty of evidence for each outcome was categorized as high, moderate, low, or very low, and the assessments were used to support transparent interpretation of the pooled findings. Results 2.1. Study selection and characteristics A total of 3,971 records were obtained on an initial search, of which 2,511 were screened following removal of duplicates. Of these, full texts of 122 records were retrieved for screening. Finally, 9 studies were included for qualitative and quantitative synthesis (( 17 – 25 )(Fig. 1 illustrates the systematic approach employed in identifying, screening, and including new studies for review. The process begins with the identification of records from various databases (Cochrane CENTRAL, PubMed, Web of Science, Scopus, and Embase) and progresses through screening stages, ultimately leading to the inclusion of nine new studies that meet the eligibility criteria. A total of nine randomized controlled trials with 476 patients were included, conducted between 1996 and 2023 across North America, predominantly in the United States and Canada. Most studies were single-country trials, with one multicenter study enrolling participants from both the USA and Canada. The mean age of participants across studies ranged from approximately 11.8 to 15 years, with comparable age distributions between intervention and control groups within individual trials. Pain outcomes were measured using heterogeneous assessment tools. Visual Analog Scales (VAS) were the most frequently used, with scores reported on either 0–100 or 0–10 scales; the latter converted to a 0–100 metric where applicable. Other studies employed the Verbal Numeric Rating Scale (VNRS) or face pain scales, with some scales not amenable to conversion. Baseline pain intensity, when reported and convertible, was generally high, ranging from approximately 62 to 87 on a 0–100 scale, indicating moderate to severe pain at presentation (Table 1 ). Table 1 Baseline Characteristics of included studies Study Country Intervention class Route N ("Comparator/Control) Mean age, years (Int / Con) Outcome timepoint (min) Pain scale used Baseline pain (0–100) Maki et al., 2022 Canada Anesthetic Intranasal 17 / 15 11.8 / 12.7 60 VAS (0–100) 62 Tsze et al., 2021 USA NSAID IV 27 / 29 15 / 14 60 VAS (0–10, converted) 87 Sheridan et al., 2018 USA & Canada Anesthetic (combination) IV 30 / 36 14.6 / 14.6 60 Not reported NA Richer et al., 2014 Canada IV fluid (saline bolus) IV 23 / 22 13.2 / 13.4 30 VAS (0–100) 63 Brousseau et al., 2004 USA Dopamine antagonist ± NSAID IV 33 / 29 13.8 / 13.7 60 Faces scale Not convertible Richer et al., 2022 Canada Dopamine antagonist + NSAID IV 26 / 27 12 / 13 120 VNRS (0–10, converted) 70 Boutin et al., 2023 Canada Opioid + NSAID Intranasal 31 / 31 NA 15 Faces scale Not convertible NCT00355394 USA Dopamine antagonist IV 10/10 12.9 / 10.8 120 VAS (0–100) 64 NCT02794441 USA Corticosteroid Oral 40 / 40 12.6 / 13.6 2880 VNRS (0–10, converted) 70 2.2. Quality assessment. Risk of bias was assessed using the Cochrane RoB 2 tool. Most published trials showed low risk of bias in the randomization process, with adequate sequence generation, allocation of concealment, and no important baseline imbalances. Deviations from intended interventions were uncommon, and analyses were generally conducted as assigned or using intention-to-treat approaches. Bias due to missing outcome data were judged as low to moderate, primarily reflecting small sample sizes or short follow-up rather than differential attrition. Outcome measurement was consistently rated as low risk, as pain outcomes were assessed using validated scales and did not differ systematically between groups. The main source of concern was selective reporting, particularly in earlier or pilot studies lacking prospective registration or prespecified analysis plans. Two studies (NCT00355394 and NCT02794441) were judged to be at high overall risk of bias due to incomplete outcome reporting and high likelihood of selective reporting ( 23 , 24 ) . Overall, three studies were classified as low risk of bias, four as moderate, and two as high. Sensitivity analyses restricted to studies at low or moderate risk of bias were limited by small numbers, reinforcing the exploratory nature of the findings. (Supplementary Figs. 1,2). 2.3. Outcomes 2.3.1. Analgesic efficacy Of the nine included studies, three provided extractable data on between-group differences in mean pain reduction suitable for pooling ( 17 , 21 , 25 ). An exploratory random-effects meta-analysis of studies reporting between group differences in mean pain reduction. Active ED migraine treatments were associated with a greater reduction in pain intensity compared with control or standard care. The pooled estimate showed an additional 5.96-point reduction on a 0–100 pain scale favoring intervention (MD 5.96; 95% CI 0.42 to 11.51; p = 0.035). (Fig. 2 ) which displays the mean differences (MD) and their corresponding 95% confidence intervals (CI) for each study included in the analysis. Each study is represented by a square, with the size indicating the weight of the study in the overall analysis. The diamond at the bottom represents the overall mean difference derived from the random effects model. The heterogeneity statistics (I 2 and Q ) indicate the variability among the study results. The remaining six studies could not be included in this meta-analysis due to heterogeneous outcome reporting, including the use of non-convertible pain scales (e.g., faces pain scales), reporting of median rather than mean values, assessment at timepoints differing from the 2-hour primary outcome, or absence of variance data necessary for pooling ( 17 – 20 , 23 , 24 ). The magnitude of effect indicates a small absolute benefit, with the lower confidence bound approaching thresholds commonly considered minimally clinically important. Between-study heterogeneity was low (I² = 0%), although precision around heterogeneity estimates was limited. Given the small evidence base and reliance on summary effect estimates rather than arm-level data, these findings should be interpreted as exploratory and hypothesis-generating. 2.3.2. Safety outcomes Safety data were reported in a subset of included studies and were heterogeneous in both definition and reporting. Adverse events were generally uncommon but varied across interventions. Adverse events were reported in six studies, with substantial variability in definitions and reporting practices. Shrestha et al. was excluded from the current analysis; among the remaining studies, Tsze et al. (2022) reported adverse events in 4 of 27 participants receiving IV NSAIDs ( 18 ). Richer et al. (2014) reported adverse events in 1 of 45 participants following IV fluid administration ( 25 ). Richer et al. (2022) reported adverse events in 4 of 26 participants receiving dopamine antagonist plus NSAID therapy ( 20 ). Higher adverse event counts were observed in Boutin et al. (2023), where 17 of 31 participants receiving intranasal opioid plus NSAID therapy experienced at least one adverse event, most commonly gastrointestinal symptoms ( 22 ). Serious adverse events were not systematically reported, and attribution to study intervention was often unclear. Due to inconsistent definitions and incomplete comparator-arm reporting, quantitative synthesis of safety outcomes was not feasible. 2.4. Secondary outcomes Binary secondary and safety outcomes, including pain-free response, headache recurrence, rescue medication use, and adverse events, were extracted where reported. However, reporting of comparator-arm event counts was inconsistent across studies, frequently precluding construction of valid 2×2 tables. Consequently, comparative meta-analysis was not feasible for most binary outcomes, and results are presented descriptively. 2.4.1. Pain-free response / responder outcomes Pain-free or responder outcomes were reported in four studies, with definitions and assessment timepoints varying across trials. Tsze et al. (2022) reported a responder outcome at 60 minutes in 2 of 27 participants receiving IV NSAIDs ( 18 ). Richer et al. (2022) reported pain freedom at 120 minutes in 5 of 26 participants receiving dopamine antagonist plus NSAID therapy, compared with 3 of 17 participants in the comparator arm ( 20 ). Boutin et al. (2023) reported pain freedom at 15 minutes in 2 of 31 participants receiving intranasal opioid plus NSAID therapy ( 22 ). Comparator-arm responder data were inconsistently reported, and outcome definitions differed across studies, including quantitative synthesis or formal comparative analysis. 2.4.2. Headache recurrence and return visits Headache recurrence or return visits were reported in three studies with heterogeneous follow-up durations. Richer et al. (2014) reported recurrence in 13 of 39 participants following IV fluid administration at follow-up, while Boutin et al. (2023) reported recurrence in 22 of 31 participants receiving intranasal opioid plus NSAID therapy ( 22 , 25 ). Tsze et al. (2022) reported recurrence in 4 of 27 participants following IV NSAID treatment ( 18 ). Follow-up intervals and outcome definitions varied across studies, and comparator-arm data were frequently unavailable, preventing quantitative synthesis. 2.5. Sensitivity analysis by risk of bias In a sensitivity analysis restricted to studies judged as having moderate risk of bias, the pooled estimate showed no statistically significant difference in pain reduction between intervention and control. The estimated mean difference favored intervention by 12.5 points on a 0–100 pain scale, but the confidence interval was wide and crossed the null (MD 12.5; 95% CI − 18.1 to 43.1; p = 0.42), indicating substantial imprecision. (Fig. 3 ). 2.6. Small-study effects and publication bias Visual inspection of the funnel plot for the primary outcome suggested some asymmetry , raising the possibility of small-study effects. Formal assessment using the Egger linear regression test did not provide statistical evidence of asymmetry (t = 2.32, df = 1, p = 0.26), although the estimated bias coefficient was 1.05 (SE = 0.45). Figure 4 . 2.7. Grade Assessment The certainty of evidence for the primary and sensitivity analyses was generally low, reflecting the small number of studies, limited sample sizes, reliance on summary effect estimates, and heterogeneity in reporting. The pooled mean pain reduction suggested a modest improvement with active ED migraine interventions compared with control, but the effect was small and of uncertain clinical significance (Table 2 ). Table 2 GRADE Summary of Findings Table. Outcome No. of studies (participants) Effect (95% CI) Certainty of Evidence Key comments Mean pain reduction (0–100 scale) 3 (summary-level comparisons) MD 5.96 (0.42 to 11.51) ⬤⬤○○ Low Exploratory continuous outcome; small absolute effect; few studies; imprecision; based on summary effect estimates rather than arm-level data Discussion This systematic review and meta-analysis of 9 randomized controlled trials of acute pharmacologic treatments for pediatric migraine in the emergency department found that current interventions provide only modest short-term pain reduction, with no single therapy consistently superior across outcomes. The pooled analysis demonstrated a small additional pain reduction of approximately 6 points on a 0–100 scale compared with control or standard care. This finding was not sensitive to sensitivity analysis. Upon restricting the analysis to studies with moderate bias risk, the effect ceased to be statistically significant (MD 12.5; 95% CI − 18.1 to 43.1), and the confidence interval expanded significantly, indicating high imprecision. This indicates that the statistical significance of the primary analysis may be influenced by the inclusion of studies with methodological flaws, which are recognized for exaggerating treatment effects. Therefore, the comprehensive pooled estimate must be regarded with significant care, and the low certainty level assigned by GRADE is substantiated by this lack of robustness. The point estimate of 6 points on a 100-point scale was statistically significant in the primary analysis; however, this effect size is near the minimal clinically significant difference and warrants careful interpretation. The bottom limit of the confidence interval (0.42) nears zero, further emphasizing the tenuousness of this result. Prior work has highlighted the limited number of randomized controlled trials for pediatric migraine in the emergency department, with most previous evidence derived from outpatient settings where medications are administered earlier in the attack course ( 26 , 27 ). Translating these findings to the ED context is challenging, given the greater symptom of severity and later presentation typical of emergency care. This highlighted the need for updated, ED specific evidence synthesis such as the present review.specific evidence synthesis such as the present review.-specific evidence synthesis such as the present review. Treatment effects varied across studies, reflecting differences in drug classes, routes of administration, outcome definitions, and the timing of pain assessment (Table 1 ). Placebo responses were also noticeable, and headache recurrence or repeat ED visits remained common despite initial symptom improvement. Clinically, this means that many children experience only transient relief in the ED and continue to have symptoms after discharge. These findings reflect the challenges of managing acute pediatric migraine in emergency settings and the limited strength of the current evidence base. Interpretation of Primary Findings and Clinical Relevance The modest magnitude of pain reduction observed across studies likely reflects both clinical and methodological influences rather than true absence of treatment effect. Pediatric migraine is a heterogeneous condition, with a wide variation in severity, duration, and response to treatment across age groups( 28 ). In the ED setting, children often arrive later during attack, when the nervous system may already be sensitized, which can reduce the effectiveness of a single dose of acute medication ( 29 ) . Interpretation is further complicated by important methodological differences across studies. Trials differed in drug selection, dosing, pain scales, and assessment of timepoints, limiting direct comparability. Although statistical heterogeneity was low, the small number of included studies and reliance on summary-level data reduced the precision of pooled estimates and limited the ability to detect clinically meaningful differences between interventions. A mean reduction of approximately 6 points on a 100 point pain scale represents a small absolute benefit near minimal clinically important difference, with wide confidence intervals reflecting limited precision. Sensitivity analyses restricted to studies with moderate risk of bias showed no longer statistically significant benefit. These findings suggest that the observed statistical significance should be interpreted cautiously and may not translate into meaningful clinical improvement for most children treated in the emergency department. Point pain scale represents a small absolute benefit near minimal clinically important difference, with wide confidence intervals reflecting limited precision. Sensitivity analyses restricted to studies with moderate risk of bias showed no longer statistically significant benefit. These findings suggest that the observed statistical significance should be interpreted cautiously and may not translate into meaningful clinical improvement for most children treated in the emergency department.-point pain scale represents a small absolute benefit near minimal clinically important difference, with wide confidence intervals reflecting limited precision. Sensitivity analyses restricted to studies with moderate risk of bias showed no longer statistically significant benefit. These findings suggest that the observed statistical significance should be interpreted cautiously and may not translate into meaningful clinical improvement for most children treated in the emergency department. Safety and Secondary Outcomes Safety data were inconsistently reported across studies and could not be pooled quantitatively. Overall, adverse events were relatively uncommon, but their frequency varied by intervention type. Higher numbers of adverse events were observed in studies evaluating combination therapies and opioid-containing regimens( 17 , 30 ). No serious adverse events were reported, but incomplete reporting, variable definitions, and missing comparator-arm data limited meaningful safety comparisons. While no clear safety concerns emerged, these findings highlight the need for standardized adverse event reporting in future pediatric migraine trials. Containing regimens. (-containing regimens.( Secondary outcomes, including pain freedom, need for rescue medication, and headache recurrence, were also reported inconsistently, with substantial variation in outcome definitions and assessment timing. As a result, firm conclusions regarding these clinically important endpoints could not be drawn. Future ED-based pediatric migraine trials should prioritize standardized, patient-centered outcome measures to better inform clinical decision-making and comparative effectiveness. Rebound and Recurrence of Headache Across multiple studies, headache recurrence within 24–72 hours were common, even among patients who initially improved. In contrast, return visits to the ED were relatively infrequent, suggesting that recurrence may be underestimated when ED-based outcomes are used alone. Discharge decisions are likely influenced by factors beyond symptom resolution, including caregiver expectations and system-level constraints. Some interventions, such as low-dose propofol, were associated with lower recurrence rates despite similar short-term pain relief ( 22 ). This raises the possibility that certain agents may influence underlying migraine mechanisms rather than providing analgesia alone. However, the need for sedation protocols and intensive monitoring limits the feasibility of such approaches in routine pediatric ED practice. Placebo response and expectation effects A notable placebo response was observed across several included trials, particularly in studies involving more invasive interventions such as intravenous fluids or intranasal therapies. In trials assessing IV fluids alone, pain reduction often did not reach clinically meaningful levels, despite many patients reporting feeling better. This suggests that contextual factors including treatment expectations, clinical setting, and route of administration may play a meaningful role in perceived symptom relief in pediatric migraine. High placebo responsiveness complicates interpretation of treatment effects and may partly explain the lack of clear superiority between active treatment arms in several studies. These findings highlight important challenges for trial design in pediatric migraine and suggest that future studies may benefit from approaches that better account for expectancy effects, including standardized baseline assessments, improved outcome selection, or trial designs that enhance discrimination between pharmacologic and non-specific treatment effects. Clinical implications Across included trials, early pain improvement within the first hour was generally moderate, and complete pain freedom was achieved in only a minority of patients. Several comparisons failed to show meaningful differences between therapeutic approaches, including combination regimens versus monotherapy and alternative routes of administration for the same agent. This suggests that escalation of treatment intensity does not necessarily translate into improved short-term analgesic benefit in the pediatric ED setting. Prior to our study, the only systematic review exploring migraine ED treatment in children was conducted in 2024 by Ghirigato et al. However, their review included only six RCT studies, and with no meta-analysis highlighting the limited scope of prior research in this area ( 28 ). Dopamine antagonists, particularly prochlorperazine, were associated with higher treatment success rates and greater reductions in pain scores compared with nonsteroidal anti-inflammatory drugs (NSAIDs) such as ketorolac. This observation is consistent with prior pediatric and adult literature and may reflect the central antiemetic and antidopaminergic mechanisms of these agents. However, their apparent efficacy must be balanced against a less favorable adverse effect profile, as akathisia and dystonic reactions were more frequently reported than with NSAIDs. Overall, the modest magnitude of benefit observed across interventions, together with substantial heterogeneity and incomplete outcome reporting, limits the strength of comparative effectiveness of conclusions. These findings emphasize the need for standardized outcome measures, consistent follow-up, and adequately powered trials to better inform evidence-based management of pediatric migraine in emergency care settings. Strengths and Limitations This review’s strengths lie in its exclusive focus on RCTs within the ED setting, ensuring high internal validity and clinical relevance. Adherence to rigorous PRISMA methods and the GRADE framework provides a transparent assessment of evidence of certainty However, the findings have been limited by small sample numbers and considerable clinical heterogeneity in both interventions and outcomes. The inconsistency in reporting and dependence on summary-level data significantly constrained the viability of meta-analysis for secondary outcomes.Several significant constraints. The proposed network meta-analysis proved unfeasible due to the fragmented structure of the treatment network and the insufficient number of included studies, limiting thorough comparative efficacy evaluations. The principal meta-analysis relied on merely three research, and the results were fragile when subjected to sensitivity analysis limited to moderate-risk studies. The analysis depended on summary-level intergroup differences instead of individual patient data, which is less reliable. Fourth, variable reporting among studies impeded the quantitative synthesis of secondary outcomes and safety data. The limited quantity of studies constrains precision and generalizability. Ultimately, publication bias could not be adequately evaluated due to the limited number of studies in meta-analysis. Conclusion Currently, no single ED therapy guarantees sustained pain freedom for pediatric migraines. While dopamine antagonists may outperform NSAIDs for short-term relief, their safety profile and the substantial influence of placebo effects warrant caution. Future research should prioritize large-scale, multicenter trials with standardized outcomes and longer follow-up. Emphasis must shift toward evaluating sustained pain relief and integrating ED care with post-discharge management to reduce the high rate of recurrence. Declarations Ethics approval and consent to participate Not applicable. This study is a systematic review and meta-analysis of previously published data and did not involve human participants or animal subjects. Consent for publication Not applicable. Availability of data and materials All data generated or analyzed during this study are included in the published article and its supplementary materials. Additional details are available from the corresponding author upon a reasonable request. Competing interests The authors declare that they have no competing interests. Funding This research received no external funding. Clinical trial registration Not applicable. Authors’ contributions Mohammed Alsabri, MD, FAAP (first) conceived and designed the study, developed the protocol, coordinated all stages of manuscript development, drafted substantial portions of the manuscript, supervised the research team, and managed all communications with co-authors. Mohamed Amr Elkarargy led the analysis, results of synthesis, and manuscript drafting. Toka Elboraay drafted the discussion section and assisted with quality assessment. Sara M. Darawish (corresponding author) registered the study in PROSPERO and wrote the introduction and methods sections. Summayya Anwar conducted data extraction, performed quality assessment, and contributed to manuscript writing. Eslam Abady performed data extraction and quality assessment. Shree Rath conducted study validation and critically reviewed and recapitulated the manuscript. Bara M. Hammadeh assisted in the analytical process and interpretation of findings. Manar Adel supported literature screening and study selection. Ameer Hassoun, MD provided critical revision of the manuscript for important intellectual content. All authors reviewed and approved the final manuscript. Acknowledgments The authors thank all collaborators and contributors who supported data collection, screening, and manuscript development. References Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: Data from the American Migraine Study II. Headache. 2001;41(7). Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5). Burch R, Rizzoli P, Loder E. The Prevalence and Impact of Migraine and Severe Headache in the United States: Figures and Trends From Government Health Studies. Headache. 2018;58(4). Abu-Arafeh I, Razak S, Sivaraman B, Graham C. Prevalence of headache and migraine in children and adolescents: A systematic review of population-based studies. Vol. 52, Developmental Medicine and Child Neurology. 2010. Onofri A, Pensato U, Rosignoli C, Wells-Gatnik W, Stanyer E, Ornello R, et al. Primary headache epidemiology in children and adolescents: a systematic review and meta-analysis. Vol. 24, Journal of Headache and Pain. 2023. Olesen J. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Vol. 38, Cephalalgia. 2018. Evans RW. Diagnostic Testing for Migraine and Other Primary Headaches. Vol. 37, Neurologic Clinics. 2019. Hsu YC, Lin KC, Wang SJ, Wang PJ, Wang YF, Lee LH, et al. Medical treatment guidelines for acute migraine attacks. Acta Neurol Taiwan. 2017;26(2). Curto M, Capi M, Cipolla F, Cisale GY, Martelletti P, Lionetto L. Ubrogepant for the treatment of migraine. Expert Opin Pharmacother. 2020;21(7). Migraine Headache - StatPearls - NCBI Bookshelf [Internet]. [cited 2026 Feb 14]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560787/ Richer LP, Laycock K, Millar K, Fitzpatrick E, Khangura S, Bhatt M, et al. Treatment of children with migraine in emergency departments: National practice variation study. Pediatrics. 2010;126(1). Gelfand AA, Goadsby PJ. Treatment of pediatric migraine in the emergency room. Vol. 47, Pediatric Neurology. 2012. Richer L, Graham L, Klassen T, Rowe B. Emergency department management of acute migraine in children in Canada: A practice variation study - CME. Headache. 2007;47(5). Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ [Internet]. 2021 Mar 29 [cited 2026 Feb 14];372. Available from: https://www.bmj.com/content/372/bmj.n71 Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ [Internet]. 2019 Aug 28 [cited 2026 Feb 14];366. Available from: https://www.bmj.com/content/366/bmj.l4898 Brozek JL, Canelo-Aybar C, Akl EA, Bowen JM, Bucher J, Chiu WA, et al. GRADE Guidelines 30: the GRADE approach to assessing the certainty of modeled evidence—An overview in the context of health decision-making. J Clin Epidemiol. 2021;129. Sheridan DC, Hansen ML, Lin AL, Fu R, Meckler GD. Low-Dose Propofol for Pediatric Migraine: A Prospective, Randomized Controlled Trial. Journal of Emergency Medicine. 2018;54(5). Tsze DS, Lubell TR, Carter RC, Chernick LS, DePeter KC, McLaren SH, et al. Intranasal ketorolac versus intravenous ketorolac for treatment of migraine headaches in children: A randomized clinical trial. Academic Emergency Medicine. 2022;29(4). Brousseau DC, Duffy SJ, Anderson AC, Linakis JG. Treatment of Pediatric Migraine Headaches: A Randomized, Double-Blind Trial of Prochlorperazine Versus Ketorolac. Ann Emerg Med [Internet]. 2004 [cited 2026 Feb 15];43(2):256–62. Available from: https://pubmed.ncbi.nlm.nih.gov/14747817/ Richer LP, Ali S, Johnson DW, Rosychuk RJ, Newton AS, Rowe BH. A randomized trial of ketorolac and metoclopramide for migraine in the emergency department. Headache [Internet]. 2022 Jun 1 [cited 2026 Feb 15];62(6):681–9. Available from: /doi/pdf/10.1111/head.14307 Maki K, Doan Q, Sih K, Stillwell K, Chun A, Meckler G. A randomized controlled pilot study of intranasal lidocaine in acute management of paediatric migraine and migraine-like headache. Paediatr Child Health [Internet]. 2022 Oct 3 [cited 2026 Feb 15];27(6):340–5. Available from: https://dx.doi.org/10.1093/pch/pxac054 Boutin A, Gouin S, Bailey B, Lebel D, Gravel J. Additive Value of Intranasal Fentanyl on Ibuprofen for Pain Management of Children With Moderate to Severe Headaches: A Randomized Controlled Trial. Journal of Emergency Medicine [Internet]. 2023 Aug 1 [cited 2026 Feb 15];65(2):e119–31. Available from: https://www.jem-journal.com/action/showFullText?pii=S0736467923002913 Study Details | NCT00355394 | Treatment of Acute Migraine Headache in Children | ClinicalTrials.gov [Internet]. [cited 2026 Feb 15]. Available from: https://clinicaltrials.gov/study/NCT00355394 Study Details | NCT02358681 | Intranasal Ketorolac Versus Intravenous Ketorolac for Treatment of Migraine Headaches in Children | ClinicalTrials.gov [Internet]. [cited 2026 Feb 15]. Available from: https://clinicaltrials.gov/study/NCT02358681 Richer L, Craig W, Rowe B. Randomized controlled trial of treatment expectation and intravenous fluid in pediatric migraine. Headache [Internet]. 2014 Oct 1 [cited 2026 Feb 15];54(9):1496–505. Available from: /doi/pdf/10.1111/head.12443 Study Details | NCT02794441 | Oral Dexamethasone for the Treatment of Acute Migraine Recurrence in the Pediatric Emergency Department | ClinicalTrials.gov [Internet]. [cited 2026 Feb 15]. Available from: https://clinicaltrials.gov/study/NCT02794441 Patniyot IR, Gelfand AA. Acute Treatment Therapies for Pediatric Migraine: A Qualitative Systematic Review. Vol. 56, Headache. 2016. Ghirigato E, Zupin L, Celsi F, Capaci V, Amaddeo A, Cozzi G. What is the best approach to treat acute migraine in children in the emergency department? Vol. 13, Frontiers in Pediatrics. 2025. Sun Q, Xie H, Hao L, Ding J, Hong J, Lin X, et al. Global Epidemiology and Burden of Migraine in Children and Adolescents from 1990 to 2021: Insights from the Global Burden of Disease Study 2021. J Pain Res. 2025;18. Suzuki K, Suzuki S, Shiina T, Kobayashi S, Hirata K. Central Sensitization in Migraine: A Narrative Review. Vol. 15, Journal of Pain Research. 2022. Additional Declarations No competing interests reported. Supplementary Files Supplementary.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8885764","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":593232556,"identity":"20a7d7b8-e0df-4260-84e0-03cc5cf2db65","order_by":0,"name":"Mohammed Alsabri","email":"","orcid":"","institution":"St. Christopher's Hospital for Children","correspondingAuthor":false,"prefix":"","firstName":"Mohammed","middleName":"","lastName":"Alsabri","suffix":""},{"id":593232557,"identity":"5eccfd19-4484-47e7-9b2b-49b4487b02f8","order_by":1,"name":"Toka Elboraay","email":"","orcid":"","institution":"Zagazig University","correspondingAuthor":false,"prefix":"","firstName":"Toka","middleName":"","lastName":"Elboraay","suffix":""},{"id":593232559,"identity":"2fb5aa5c-36bc-44b0-8d60-f2b97bb343da","order_by":2,"name":"Mohamed Amr Elkarargy","email":"","orcid":"","institution":"University College Cork","correspondingAuthor":false,"prefix":"","firstName":"Mohamed","middleName":"Amr","lastName":"Elkarargy","suffix":""},{"id":593232561,"identity":"9bb707f0-275a-45bc-a625-b713b4a4ba36","order_by":3,"name":"Sara M. Darawish","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYDCCAwiS8QGQ4OEjQQszswFICxspWtgkQEyCWvhuH34mzfPnjj3/7PPHKr/m2MmwMTA/fHQDjxbJc2lm0rxtzxJnnEtmuy27LRnoMDZj4xw8WgzOMJjd5m04nMBwhpnttuQ2ZqAWHjZp/FrYv93m+XPYXh6opVhyWz0xWnjMbvOwHWbcANTC+HHbYcJaJM/wlP+c23Y4ceMZZmNpxm3HediYCfiF7wz7ZoM3QIfJnWF8+PHntmp7fvbmh4/xaQEBJh4ogxnMYCagHAQYf6AzRsEoGAWjYBQgAwC26UhWU57k7gAAAABJRU5ErkJggg==","orcid":"","institution":"Al-Quds University","correspondingAuthor":true,"prefix":"","firstName":"Sara","middleName":"M.","lastName":"Darawish","suffix":""},{"id":593232562,"identity":"3a8c69c0-28a5-4761-a578-1d0a62330ca8","order_by":4,"name":"Summayya Anwar","email":"","orcid":"","institution":"COMSATS University Islamabad","correspondingAuthor":false,"prefix":"","firstName":"Summayya","middleName":"","lastName":"Anwar","suffix":""},{"id":593232563,"identity":"35eb5ba5-5536-4082-80b2-3c63fc951314","order_by":5,"name":"Eslam Abady","email":"","orcid":"","institution":"Tanta University","correspondingAuthor":false,"prefix":"","firstName":"Eslam","middleName":"","lastName":"Abady","suffix":""},{"id":593232564,"identity":"d623262f-620f-469e-95dc-d903db7aef1f","order_by":6,"name":"Shree Rath","email":"","orcid":"","institution":"All India Institute of Medical Sciences Bhubaneswar","correspondingAuthor":false,"prefix":"","firstName":"Shree","middleName":"","lastName":"Rath","suffix":""},{"id":593232565,"identity":"ada6d79d-e3a4-4f2f-a927-106df361271a","order_by":7,"name":"Manar Adel","email":"","orcid":"","institution":"Tanta University","correspondingAuthor":false,"prefix":"","firstName":"Manar","middleName":"","lastName":"Adel","suffix":""},{"id":593232566,"identity":"3375f03a-236c-4e58-9728-7b06aa5d2cdd","order_by":8,"name":"Bara M. Hammadeh","email":"","orcid":"","institution":"Al-Balqa Applied University","correspondingAuthor":false,"prefix":"","firstName":"Bara","middleName":"M.","lastName":"Hammadeh","suffix":""},{"id":593232567,"identity":"25355294-df00-470c-82bf-d32be109ca10","order_by":9,"name":"Ameer Hassoun","email":"","orcid":"","institution":"NewYork–Presbyterian Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ameer","middleName":"","lastName":"Hassoun","suffix":""}],"badges":[],"createdAt":"2026-02-15 11:54:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8885764/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8885764/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103505856,"identity":"83199735-7ae5-47b2-b7fe-d6213e98ab21","added_by":"auto","created_at":"2026-02-26 13:33:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":168158,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA\u003cem\u003e flowchart for screening and study inclusion.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLegend\u003c/strong\u003e: This figure illustrates the systematic approach employed in identifying, screening, and including new studies for review. The process begins with the identification of records from various databases (Cochrane CENTRAL, PubMed, Web of Science, Scopus, and Embase) and progresses through screening stages, ultimately leading to the inclusion of nine new studies that meet the eligibility criteria.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8885764/v1/2dd5c1e5c354311edf5eac76.png"},{"id":103504708,"identity":"73359cc8-b246-4130-bd2a-89222e64bb67","added_by":"auto","created_at":"2026-02-26 13:21:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":135151,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of mean pain reduction difference.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLegend:\u003c/strong\u003e This forest plot displays the mean differences (MD) and their corresponding 95% confidence intervals (CI) for each study included in the analysis. Each study is represented by a square, with the size indicating the weight of the study in the overall analysis. The diamond at the bottom represents the overall mean difference derived from the random effects model. The heterogeneity statistics (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e \u003c/em\u003eand \u003cem\u003eQ\u003c/em\u003e) indicate the variability among the study results. Indicate the variability among the study results.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8885764/v1/bebf5d1056ec71c1ac53eaf4.png"},{"id":103199521,"identity":"f3e046ef-6d58-4fff-8d26-379e19757e1a","added_by":"auto","created_at":"2026-02-23 05:37:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":86766,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity Forest plot of only Moderate Risk studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLegend\u003c/strong\u003e: This figure presents a forest plot illustrating the mean differences (MD) and corresponding to 95% confidence intervals (CIs) for various studies related to the specified outcome. Each horizontal line represents the confidence interval for a study's mean difference, while the square indicates the estimated mean difference and its associated weight in the overall analysis. The diamond at the bottom reflects the combined mean difference based on the random effects model, with an overall mean difference of 12.50 (95% CI: [−18.03, 43.08]).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8885764/v1/2157702d311a7d2800c461ab.png"},{"id":103199519,"identity":"fc630b5f-e1c0-4d3f-b366-5e51e56f021c","added_by":"auto","created_at":"2026-02-23 05:37:21","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":43742,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel Plot of Mean Differences vs. Standard Error\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLegend\u003c/strong\u003e: This funnel plot illustrates the relationship between the mean differences and their corresponding standard errors for the studies included in the analysis. Each point represents an individual study, with the horizontal axis displaying the mean difference and the vertical axis showing the standard error. The triangular shape indicates the expected distribution of studies, with smaller studies appearing at the top and larger studies at the bottom. The symmetry of the plot can provide insights into publication bias; however, the observed asymmetry in this plot may suggest potential biases in study publication or reporting.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8885764/v1/44cb8100f9a34d7073bc53e4.png"},{"id":107716554,"identity":"37f96321-9773-4dee-a03a-b6c8f03b5091","added_by":"auto","created_at":"2026-04-24 10:06:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":659596,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8885764/v1/979fb623-b633-4b45-92e8-6e0d96c1fda4.pdf"},{"id":103199522,"identity":"6a5b834f-f224-4af5-813c-6ce3da8d5a13","added_by":"auto","created_at":"2026-02-23 05:37:21","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":141765,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-8885764/v1/8108adf07faf9c91ad0afad3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pharmacologic Treatment of Acute Migraine in the Pediatric Emergency Department: A Systematic Review and Meta-analysis of Randomized Controlled Trials","fulltext":[{"header":"Background","content":"\u003cp\u003eMigraine is a prevalent neurological disorder affecting approximately 12% of the global population, with a higher prevalence observed in females (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). This primary headache disorder is characterized by episodic attacks that may persist for hours to days, resulting in significant impairments in daily functioning and overall quality of life (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The disorder exhibits considerable heterogeneity, with migraine without aura being the most prevalent subtype, accounting for approximately 75% of cases ((\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Migraine is a common condition among children and adolescents, with an estimated prevalence ranging from 7% to 9.1%. This prevalence increases with age, starting at approximately 5% in children aged 5 to 10 years and rising to around 15% in teenagers (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMigraine diagnosis is primarily clinical, relying on patient history and physical examination in accordance with the ICHD-3 criteria (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). For migraine without aura, a diagnosis requires at least five attacks lasting 4 to 72 hours (about 6 days), characterized by at least two of the following: unilateral location, pulsating quality, moderate to severe intensity, and exacerbation by physical activity, along with one associated symptom such as nausea, vomiting, photophobia, or phonophobia. In the case of migraine with aura, at least two attacks must occur with reversible aura symptoms, along with two of the following criteria: gradual symptom spread, successive symptoms, duration of 5 to 60 minutes, and unilateral or positive symptoms; the aura should precede or coincide with the headache within 60 minutes. Neuroimaging is warranted for cases presenting atypical features, abnormal neurological examinations, sudden severe onset (thunderclap headaches), or new headaches in individuals over 50 years or those with immunosuppression (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMigraine management is categorized into acute (abortive) therapies, preventive strategies, and lifestyle modifications. Acute treatments, designed to halt an ongoing attack, include nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), with alternatives such as CGRP receptor antagonists (gepants) and lasmiditan for patients with contraindications; these are often supplemented by antiemetics to alleviate nausea (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Preventive therapies are intended for those experiencing frequent or severe attacks and encompass pharmacologic options such as beta-blockers, antidepressants, anticonvulsants, calcium channel blockers, CGRP monoclonal antibodies, and onabotulinumtoxinA for chronic migraine. Non-pharmacologic approaches involve behavioral therapies and relaxation techniques, alongside the identification and avoidance of individual triggers, such as stress and specific foods (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eManaging acute pediatric migraine in the emergency department poses distinct challenges compared to adult care. Nearly one-third of pediatric migraine patients may leave without treatment, which could be due to diagnostic uncertainty or a predominant focus on excluding secondary causes. Additionally, neuroimaging is often overutilized, with CT scan rates between 16.3% and 20.9% in pediatric migraine cases (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), despite large studies showing no serious intracranial pathology (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Treatment approaches also differ significantly between pediatric-only and mixed emergency departments; children in pediatric emergency settings are more likely to receive dopamine receptor antagonists and are less likely to be prescribed opioids. Notably, treatment within a pediatric emergency department is associated with a higher likelihood of achieving complete headache resolution (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePediatric emergency department (ED) visits for migraine are frequent, but comparative randomized controlled trial (RCT) evidence is limited and varied. Existing studies suggest IV prochlorperazine is effective, while combinations like metoclopramide+ketorolac show no added benefit over metoclopramide alone. A recent review favored dopamine antagonists but highlighted the need for an ED-specific RCT synthesis. This systematic review and network meta-analysis aims to rigorously analyze ED-based pediatric migraine RCTs to compare treatment efficacy and safety, ultimately aiding clinical decision-making and improving care. The primary objective is to compare the efficacy of ED pharmacologic treatments for pediatric acute migraine based on pain response at 2 hours. Secondary objectives include evaluating the need for rescue therapy, ED length of stay, return ED visits, adverse events, and treatment satisfaction.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420251123315 (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Our analysis was based on data from previously published studies and, therefore, did not involve patient recruitment or active participation, eliminating the need for institutional review board approval.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e1.1. Search Strategy\u003c/h2\u003e \u003cp\u003e A thorough literature review was performed across multiple electronic bibliographic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), Embase (via Ovid and Embase.com), MEDLINE, PubMed, and Scopus. Further inquiries were conducted on the Web of Science. The search covered the period from each database\u0026rsquo;s inception to the predefined search date in 2025, with no restrictions on publication date.\u003c/p\u003e \u003cp\u003eThe search strategy employed a combination of controlled vocabulary and free-text terms. Relevant Medical Subject Headings (MeSH) and Emtree terms included, but were not limited to, \u0026ldquo;Migraine Disorders,\u0026rdquo; \u0026ldquo;Child,\u0026rdquo; \u0026ldquo;Adolescent,\u0026rdquo; \u0026ldquo;Emergency Service, Hospital,\u0026rdquo; \u0026ldquo;Non-Steroidal Anti-Inflammatory Agents,\u0026rdquo; \u0026ldquo;Antiemetics,\u0026rdquo; \u0026ldquo;Dopamine Antagonists,\u0026rdquo; \u0026ldquo;Hypnotics and Sedatives,\u0026rdquo; \u0026ldquo;Ketorolac,\u0026rdquo; \u0026ldquo;Metoclopramide,\u0026rdquo; \u0026ldquo;Prochlorperazine,\u0026rdquo; and \u0026ldquo;Propofol.\u0026rdquo; Free-text keywords included \u0026ldquo;pediatric migraine,\u0026rdquo; \u0026ldquo;acute migraine,\u0026rdquo; \u0026ldquo;emergency department,\u0026rdquo; \u0026ldquo;ED,\u0026rdquo; \u0026ldquo;pharmacologic treatment,\u0026rdquo; \u0026ldquo;prochlorperazine,\u0026rdquo; \u0026ldquo;ketorolac,\u0026rdquo; \u0026ldquo;metoclopramide,\u0026rdquo; \u0026ldquo;propofol,\u0026rdquo; \u0026ldquo;pain response,\u0026rdquo; and \u0026ldquo;rescue therapy.\u0026rdquo;\u003c/p\u003e \u003cp\u003eIn addition, the reference lists of all included studies, as well as relevant prior systematic reviews and meta-analyses identified during the search, were manually examined to identify additional eligible studies. Backward citation tracking of key articles was undertaken. The search for unpublished studies was limited to trials indexed within the selected databases; dedicated gray literature sources and clinical trial registries were not independently searched. The detailed search strategy is presented in \u003cb\u003eSupplementary Table\u0026nbsp;1\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e1.2. Criteria for Eligibility and Selection of Studies\u003c/h2\u003e \u003cp\u003eThe evaluation included randomized controlled trials (RCTs) that assessed pharmacological interventions for the management of acute migraine in children and adolescents (\u0026lt;\u0026thinsp;18 years) presenting to the emergency department (ED). Eligible populations comprised patients diagnosed with an acute migraine episode based on International Classification of Headache Disorders (ICHD) criteria or a treating physician\u0026rsquo;s clinical assessment.\u003c/p\u003e \u003cp\u003eEligible interventions consisted of acute pharmacologic therapies administered in the ED, including dopamine antagonists (e.g., intravenous prochlorperazine, intravenous metoclopramide), nonsteroidal anti-inflammatory drugs (e.g., intravenous ketorolac), sedative-hypnotics (e.g., low-dose propofol), and antiemetic agents. Comparators include placebo, active pharmacologic controls, or standard/conventional therapy.\u003c/p\u003e \u003cp\u003eStudies were excluded if they enrolled participants older than 18 years, evaluated non-migraine headache disorders, focused on preventive migraine therapies, or primarily involved treatment delivered outside the ED setting (e.g., inpatient wards or outpatient clinics). Non-randomized study designs were also excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e1.3. Selection of Studies\u003c/h2\u003e \u003cp\u003eRecords identified through database searches were imported into reference management software for the systematic identification and removal of duplicate entries. The screening process was conducted in two stages: an initial assessment of titles and abstracts, followed by a full-text review of potentially eligible articles in accordance with the predefined inclusion and exclusion criteria. Each stage was performed independently by at least two reviewers, with disagreements resolved through discussion or, when consensus could not be reached, by consultation with a third reviewer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e1.4. Data Extraction\u003c/h2\u003e \u003cp\u003eData extraction was conducted independently by at least two reviewers using a standardized, piloted data extraction form developed in Microsoft Excel. The form systematically captured key study characteristics (e.g., authors, year of publication, country, sample size, study design, and funding source), participant demographics (e.g., mean age, sex distribution, and diagnostic criteria such as ICHD or physician diagnosis), and detailed intervention and comparator information (e.g., drug name, dosage, route of administration, and co-interventions).\u003c/p\u003e \u003cp\u003eThe data extraction form was also used to collect information on all prespecified outcomes. This included primary outcome data on pain response at 2 hours (including outcome definitions and reported results) and secondary outcomes such as the need for rescue therapy, emergency department length of stay, repeat emergency department visits, specific adverse events (e.g., akathisia, dystonia, sedation), and measures of treatment satisfaction.\u003c/p\u003e \u003cp\u003eTo ensure accuracy and consistency, data extracted by the reviewers were compared, and discrepancies were resolved through discussion or, when necessary, by consultation with a third reviewer. Corresponding authors of the original studies were contacted to obtain missing or unclear information.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e1.5. Analysis\u003c/h2\u003e \u003cp\u003eThe analysis was performed using statistical software (e.g., R or Stata) with packages specifically designed for meta-analysis and network meta-analysis (NMA). Although a network meta-analysis was planned, it was not feasible because of the treatment network's disconnected nature and the limited number of included studies. The analysis was restricted to pairwise meta-analyses only where it was feasible.\u003c/p\u003e \u003cp\u003eRandom-effects models with Hartung\u0026ndash;Knapp adjustment were applied for pairwise meta-analyses to account for anticipated clinical and methodological heterogeneity among included studies, providing more conservative and robust effect estimates. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes, such as pain response, while pooled mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs were calculated for continuous outcomes, including satisfaction scores.\u003c/p\u003e \u003cp\u003eStatistical heterogeneity for each pairwise comparison was evaluated using the I\u0026sup2; statistic, representing the proportion of variability attributable to between-study heterogeneity rather than chance. Between-study variance was quantified using the tau-squared (τ\u0026sup2;) statistic. Forest plots were generated to display individual study estimates and pooled effects. Sensitivity analyses were performed to examine the robustness of the results, and the assumption of consistency between direct and indirect evidence in the network meta-analysis was assessed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e1.6. Quality Assessment\u003c/h2\u003e \u003cp\u003eThe risk of bias of each included randomized controlled trial was assessed using the Cochrane Risk of Bias tool for randomized trials (RoB 2) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The assessment was performed independently by at least two reviewers, with disagreements resolved through discussion or, when necessary, by consultation with a third reviewer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e1.7. Certainty of evidence\u003c/h2\u003e \u003cp\u003eThe certainty of evidence for all outcomes included in the meta-analysis was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Evidence derived from randomized controlled trials was initially rated as high certainty and was subsequently downgraded, when appropriate, based on predefined criteria including risk of bias, inconsistency, indirectness, imprecision, and publication bias. The overall certainty of evidence for each outcome was categorized as high, moderate, low, or very low, and the assessments were used to support transparent interpretation of the pooled findings.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study selection and characteristics\u003c/h2\u003e \u003cp\u003eA total of 3,971 records were obtained on an initial search, of which 2,511 were screened following removal of duplicates. Of these, full texts of 122 records were retrieved for screening. Finally, 9 studies were included for qualitative and quantitative synthesis ((\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the systematic approach employed in identifying, screening, and including new studies for review. The process begins with the identification of records from various databases (Cochrane CENTRAL, PubMed, Web of Science, Scopus, and Embase) and progresses through screening stages, ultimately leading to the inclusion of nine new studies that meet the eligibility criteria.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA total of nine randomized controlled trials with 476 patients were included, conducted between 1996 and 2023 across North America, predominantly in the United States and Canada. Most studies were single-country trials, with one multicenter study enrolling participants from both the USA and Canada.\u003c/p\u003e \u003cp\u003eThe mean age of participants across studies ranged from approximately 11.8 to 15 years, with comparable age distributions between intervention and control groups within individual trials. Pain outcomes were measured using heterogeneous assessment tools. Visual Analog Scales (VAS) were the most frequently used, with scores reported on either 0\u0026ndash;100 or 0\u0026ndash;10 scales; the latter converted to a 0\u0026ndash;100 metric where applicable. Other studies employed the Verbal Numeric Rating Scale (VNRS) or face pain scales, with some scales not amenable to conversion. Baseline pain intensity, when reported and convertible, was generally high, ranging from approximately 62 to 87 on a 0\u0026ndash;100 scale, indicating moderate to severe pain at presentation (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIntervention class\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRoute\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN (\"Comparator/Control)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMean age, years (Int / Con)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOutcome timepoint (min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePain scale used\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBaseline pain (0\u0026ndash;100)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaki et al., 2022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnesthetic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntranasal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17 / 15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11.8 / 12.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVAS (0\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTsze et al., 2021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNSAID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27 / 29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15 / 14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVAS (0\u0026ndash;10, converted)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSheridan et al., 2018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA \u0026amp; Canada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnesthetic (combination)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30 / 36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14.6 / 14.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNot reported\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRicher et al., 2014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIV fluid (saline bolus)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 / 22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.2 / 13.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVAS (0\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBrousseau et al., 2004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDopamine antagonist\u0026thinsp;\u0026plusmn;\u0026thinsp;NSAID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33 / 29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.8 / 13.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFaces scale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNot convertible\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRicher et al., 2022\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDopamine antagonist\u0026thinsp;+\u0026thinsp;NSAID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26 / 27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12 / 13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVNRS (0\u0026ndash;10, converted)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBoutin et al., 2023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOpioid\u0026thinsp;+\u0026thinsp;NSAID\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntranasal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31 / 31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFaces scale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNot convertible\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNCT00355394\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDopamine antagonist\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10/10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.9 / 10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVAS (0\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNCT02794441\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCorticosteroid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e40 / 40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.6 / 13.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2880\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVNRS (0\u0026ndash;10, converted)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Quality assessment.\u003c/h2\u003e \u003cp\u003eRisk of bias was assessed using the Cochrane RoB 2 tool. Most published trials showed low risk of bias in the randomization process, with adequate sequence generation, allocation of concealment, and no important baseline imbalances. Deviations from intended interventions were uncommon, and analyses were generally conducted as assigned or using intention-to-treat approaches.\u003c/p\u003e \u003cp\u003eBias due to missing outcome data were judged as low to moderate, primarily reflecting small sample sizes or short follow-up rather than differential attrition. Outcome measurement was consistently rated as low risk, as pain outcomes were assessed using validated scales and did not differ systematically between groups. The main source of concern was selective reporting, particularly in earlier or pilot studies lacking prospective registration or prespecified analysis plans. Two studies (NCT00355394 and NCT02794441) were judged to be at high overall risk of bias due to incomplete outcome reporting and high likelihood of selective reporting (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eOverall, three studies were classified as low risk of bias, four as moderate, and two as high. Sensitivity analyses restricted to studies at low or moderate risk of bias were limited by small numbers, reinforcing the exploratory nature of the findings. (Supplementary Figs.\u0026nbsp;1,2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Outcomes\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1. Analgesic efficacy\u003c/h2\u003e \u003cp\u003eOf the nine included studies, three provided extractable data on between-group differences in mean pain reduction suitable for pooling (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). An exploratory random-effects meta-analysis of studies reporting between group differences in mean pain reduction. Active ED migraine treatments were associated with a greater reduction in pain intensity compared with control or standard care. The pooled estimate showed an additional 5.96-point reduction on a 0\u0026ndash;100 pain scale favoring intervention (MD 5.96; 95% CI 0.42 to 11.51; p\u0026thinsp;=\u0026thinsp;0.035). (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) which displays the mean differences (MD) and their corresponding 95% confidence intervals (CI) for each study included in the analysis. Each study is represented by a square, with the size indicating the weight of the study in the overall analysis. The diamond at the bottom represents the overall mean difference derived from the random effects model. The heterogeneity statistics \u003cem\u003e(I\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e and \u003cem\u003eQ\u003c/em\u003e) indicate the variability among the study results.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe remaining six studies could not be included in this meta-analysis due to heterogeneous outcome reporting, including the use of non-convertible pain scales (e.g., faces pain scales), reporting of median rather than mean values, assessment at timepoints differing from the 2-hour primary outcome, or absence of variance data necessary for pooling (\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe magnitude of effect indicates a small absolute benefit, with the lower confidence bound approaching thresholds commonly considered minimally clinically important. Between-study heterogeneity was low (I\u0026sup2; = 0%), although precision around heterogeneity estimates was limited. Given the small evidence base and reliance on summary effect estimates rather than arm-level data, these findings should be interpreted as exploratory and hypothesis-generating.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e2.3.2. Safety outcomes\u003c/h2\u003e \u003cp\u003eSafety data were reported in a subset of included studies and were heterogeneous in both definition and reporting. Adverse events were generally uncommon but varied across interventions. Adverse events were reported in six studies, with substantial variability in definitions and reporting practices. Shrestha et al. was excluded from the current analysis; among the remaining studies, Tsze et al. (2022) reported adverse events in 4 of 27 participants receiving IV NSAIDs (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Richer et al. (2014) reported adverse events in 1 of 45 participants following IV fluid administration (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Richer et al. (2022) reported adverse events in 4 of 26 participants receiving dopamine antagonist plus NSAID therapy (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHigher adverse event counts were observed in Boutin et al. (2023), where 17 of 31 participants receiving intranasal opioid plus NSAID therapy experienced at least one adverse event, most commonly gastrointestinal symptoms (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Serious adverse events were not systematically reported, and attribution to study intervention was often unclear. Due to inconsistent definitions and incomplete comparator-arm reporting, quantitative synthesis of safety outcomes was not feasible.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Secondary outcomes\u003c/h2\u003e \u003cp\u003eBinary secondary and safety outcomes, including pain-free response, headache recurrence, rescue medication use, and adverse events, were extracted where reported. However, reporting of comparator-arm event counts was inconsistent across studies, frequently precluding construction of valid 2\u0026times;2 tables. Consequently, comparative meta-analysis was not feasible for most binary outcomes, and results are presented descriptively.\u003c/p\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e2.4.1. Pain-free response / responder outcomes\u003c/h2\u003e \u003cp\u003ePain-free or responder outcomes were reported in four studies, with definitions and assessment timepoints varying across trials. Tsze et al. (2022) reported a responder outcome at 60 minutes in 2 of 27 participants receiving IV NSAIDs (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Richer et al. (2022) reported pain freedom at 120 minutes in 5 of 26 participants receiving dopamine antagonist plus NSAID therapy, compared with 3 of 17 participants in the comparator arm (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Boutin et al. (2023) reported pain freedom at 15 minutes in 2 of 31 participants receiving intranasal opioid plus NSAID therapy (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eComparator-arm responder data were inconsistently reported, and outcome definitions differed across studies, including quantitative synthesis or formal comparative analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e2.4.2. Headache recurrence and return visits\u003c/h2\u003e \u003cp\u003eHeadache recurrence or return visits were reported in three studies with heterogeneous follow-up durations. Richer et al. (2014) reported recurrence in 13 of 39 participants following IV fluid administration at follow-up, while Boutin et al. (2023) reported recurrence in 22 of 31 participants receiving intranasal opioid plus NSAID therapy (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Tsze et al. (2022) reported recurrence in 4 of 27 participants following IV NSAID treatment (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFollow-up intervals and outcome definitions varied across studies, and comparator-arm data were frequently unavailable, preventing quantitative synthesis.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Sensitivity analysis by risk of bias\u003c/h2\u003e \u003cp\u003eIn a sensitivity analysis restricted to studies judged as having moderate risk of bias, the pooled estimate showed no statistically significant difference in pain reduction between intervention and control. The estimated mean difference favored intervention by 12.5 points on a 0\u0026ndash;100 pain scale, but the confidence interval was wide and crossed the null (MD 12.5; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;18.1 to 43.1; p\u0026thinsp;=\u0026thinsp;0.42), indicating substantial imprecision. (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e2.6. Small-study effects and publication bias\u003c/h2\u003e \u003cp\u003eVisual inspection of the funnel plot for the primary outcome suggested \u003cb\u003esome asymmetry\u003c/b\u003e, raising the possibility of small-study effects. Formal assessment using the Egger linear regression test did not provide statistical evidence of asymmetry (t\u0026thinsp;=\u0026thinsp;2.32, df\u0026thinsp;=\u0026thinsp;1, p\u0026thinsp;=\u0026thinsp;0.26), although the estimated bias coefficient was 1.05 (SE\u0026thinsp;=\u0026thinsp;0.45). Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e2.7. Grade Assessment\u003c/h2\u003e \u003cp\u003eThe certainty of evidence for the primary and sensitivity analyses was generally low, reflecting the small number of studies, limited sample sizes, reliance on summary effect estimates, and heterogeneity in reporting. The pooled mean pain reduction suggested a modest improvement with active ED migraine interventions compared with control, but the effect was small and of uncertain clinical significance (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGRADE Summary of Findings Table.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of studies (participants)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEffect (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCertainty of Evidence\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eKey comments\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean pain reduction (0\u0026ndash;100 scale)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (summary-level comparisons)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMD 5.96 (0.42 to 11.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e⬤⬤○○ Low\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExploratory continuous outcome; small absolute effect; few studies; imprecision; based on summary effect estimates rather than arm-level data\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review and meta-analysis of 9 randomized controlled trials of acute pharmacologic treatments for pediatric migraine in the emergency department found that current interventions provide only modest short-term pain reduction, with no single therapy consistently superior across outcomes. The pooled analysis demonstrated a small additional pain reduction of approximately 6 points on a 0\u0026ndash;100 scale compared with control or standard care. This finding was not sensitive to sensitivity analysis. Upon restricting the analysis to studies with moderate bias risk, the effect ceased to be statistically significant (MD 12.5; 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;18.1 to 43.1), and the confidence interval expanded significantly, indicating high imprecision. This indicates that the statistical significance of the primary analysis may be influenced by the inclusion of studies with methodological flaws, which are recognized for exaggerating treatment effects. Therefore, the comprehensive pooled estimate must be regarded with significant care, and the low certainty level assigned by GRADE is substantiated by this lack of robustness.\u003c/p\u003e \u003cp\u003eThe point estimate of 6 points on a 100-point scale was statistically significant in the primary analysis; however, this effect size is near the minimal clinically significant difference and warrants careful interpretation. The bottom limit of the confidence interval (0.42) nears zero, further emphasizing the tenuousness of this result.\u003c/p\u003e \u003cp\u003ePrior work has highlighted the limited number of randomized controlled trials for pediatric migraine in the emergency department, with most previous evidence derived from outpatient settings where medications are administered earlier in the attack course (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Translating these findings to the ED context is challenging, given the greater symptom of severity and later presentation typical of emergency care. This highlighted the need for updated, ED specific evidence synthesis such as the present review.specific evidence synthesis such as the present review.-specific evidence synthesis such as the present review.\u003c/p\u003e \u003cp\u003eTreatment effects varied across studies, reflecting differences in drug classes, routes of administration, outcome definitions, and the timing of pain assessment (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Placebo responses were also noticeable, and headache recurrence or repeat ED visits remained common despite initial symptom improvement. Clinically, this means that many children experience only transient relief in the ED and continue to have symptoms after discharge. These findings reflect the challenges of managing acute pediatric migraine in emergency settings and the limited strength of the current evidence base.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInterpretation of Primary Findings and Clinical Relevance\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe modest magnitude of pain reduction observed across studies likely reflects both clinical and methodological influences rather than true absence of treatment effect. Pediatric migraine is a heterogeneous condition, with a wide variation in severity, duration, and response to treatment across age groups(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). In the ED setting, children often arrive later during attack, when the nervous system may already be sensitized, which can reduce the effectiveness of a single dose of acute medication (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) .\u003c/p\u003e \u003cp\u003eInterpretation is further complicated by important methodological differences across studies. Trials differed in drug selection, dosing, pain scales, and assessment of timepoints, limiting direct comparability. Although statistical heterogeneity was low, the small number of included studies and reliance on summary-level data reduced the precision of pooled estimates and limited the ability to detect clinically meaningful differences between interventions.\u003c/p\u003e \u003cp\u003eA mean reduction of approximately 6 points on a 100 point pain scale represents a small absolute benefit near minimal clinically important difference, with wide confidence intervals reflecting limited precision. Sensitivity analyses restricted to studies with moderate risk of bias showed no longer statistically significant benefit. These findings suggest that the observed statistical significance should be interpreted cautiously and may not translate into meaningful clinical improvement for most children treated in the emergency department. Point pain scale represents a small absolute benefit near minimal clinically important difference, with wide confidence intervals reflecting limited precision. Sensitivity analyses restricted to studies with moderate risk of bias showed no longer statistically significant benefit. These findings suggest that the observed statistical significance should be interpreted cautiously and may not translate into meaningful clinical improvement for most children treated in the emergency department.-point pain scale represents a small absolute benefit near minimal clinically important difference, with wide confidence intervals reflecting limited precision. Sensitivity analyses restricted to studies with moderate risk of bias showed no longer statistically significant benefit. These findings suggest that the observed statistical significance should be interpreted cautiously and may not translate into meaningful clinical improvement for most children treated in the emergency department.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSafety and Secondary Outcomes\u003c/b\u003e \u003c/p\u003e \u003cp\u003eSafety data were inconsistently reported across studies and could not be pooled quantitatively. Overall, adverse events were relatively uncommon, but their frequency varied by intervention type. Higher numbers of adverse events were observed in studies evaluating combination therapies and opioid-containing regimens(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). No serious adverse events were reported, but incomplete reporting, variable definitions, and missing comparator-arm data limited meaningful safety comparisons. While no clear safety concerns emerged, these findings highlight the need for standardized adverse event reporting in future pediatric migraine trials. Containing regimens. (-containing regimens.(\u003c/p\u003e \u003cp\u003eSecondary outcomes, including pain freedom, need for rescue medication, and headache recurrence, were also reported inconsistently, with substantial variation in outcome definitions and assessment timing. As a result, firm conclusions regarding these clinically important endpoints could not be drawn. Future ED-based pediatric migraine trials should prioritize standardized, patient-centered outcome measures to better inform clinical decision-making and comparative effectiveness.\u003c/p\u003e \u003cp\u003e \u003cb\u003eRebound and Recurrence of Headache\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAcross multiple studies, headache recurrence within 24\u0026ndash;72 hours were common, even among patients who initially improved. In contrast, return visits to the ED were relatively infrequent, suggesting that recurrence may be underestimated when ED-based outcomes are used alone. Discharge decisions are likely influenced by factors beyond symptom resolution, including caregiver expectations and system-level constraints.\u003c/p\u003e \u003cp\u003eSome interventions, such as low-dose propofol, were associated with lower recurrence rates despite similar short-term pain relief (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). This raises the possibility that certain agents may influence underlying migraine mechanisms rather than providing analgesia alone. However, the need for sedation protocols and intensive monitoring limits the feasibility of such approaches in routine pediatric ED practice.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePlacebo response and expectation effects\u003c/b\u003e \u003c/p\u003e \u003cp\u003eA notable placebo response was observed across several included trials, particularly in studies involving more invasive interventions such as intravenous fluids or intranasal therapies. In trials assessing IV fluids alone, pain reduction often did not reach clinically meaningful levels, despite many patients reporting feeling better. This suggests that contextual factors including treatment expectations, clinical setting, and route of administration may play a meaningful role in perceived symptom relief in pediatric migraine.\u003c/p\u003e \u003cp\u003eHigh placebo responsiveness complicates interpretation of treatment effects and may partly explain the lack of clear superiority between active treatment arms in several studies. These findings highlight important challenges for trial design in pediatric migraine and suggest that future studies may benefit from approaches that better account for expectancy effects, including standardized baseline assessments, improved outcome selection, or trial designs that enhance discrimination between pharmacologic and non-specific treatment effects.\u003c/p\u003e \u003cp\u003e \u003cb\u003eClinical implications\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAcross included trials, early pain improvement within the first hour was generally moderate, and complete pain freedom was achieved in only a minority of patients. Several comparisons failed to show meaningful differences between therapeutic approaches, including combination regimens versus monotherapy and alternative routes of administration for the same agent. This suggests that escalation of treatment intensity does not necessarily translate into improved short-term analgesic benefit in the pediatric ED setting.\u003c/p\u003e \u003cp\u003ePrior to our study, the only systematic review exploring migraine ED treatment in children was conducted in 2024 by Ghirigato et al. However, their review included only six RCT studies, and with no meta-analysis highlighting the limited scope of prior research in this area (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDopamine antagonists, particularly prochlorperazine, were associated with higher treatment success rates and greater reductions in pain scores compared with nonsteroidal anti-inflammatory drugs (NSAIDs) such as ketorolac. This observation is consistent with prior pediatric and adult literature and may reflect the central antiemetic and antidopaminergic mechanisms of these agents. However, their apparent efficacy must be balanced against a less favorable adverse effect profile, as akathisia and dystonic reactions were more frequently reported than with NSAIDs.\u003c/p\u003e \u003cp\u003eOverall, the modest magnitude of benefit observed across interventions, together with substantial heterogeneity and incomplete outcome reporting, limits the strength of comparative effectiveness of conclusions. These findings emphasize the need for standardized outcome measures, consistent follow-up, and adequately powered trials to better inform evidence-based management of pediatric migraine in emergency care settings.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStrengths and Limitations\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis review\u0026rsquo;s strengths lie in its exclusive focus on RCTs within the ED setting, ensuring high internal validity and clinical relevance. Adherence to rigorous PRISMA methods and the GRADE framework provides a transparent assessment of evidence of certainty\u003c/p\u003e \u003cp\u003eHowever, the findings have been limited by small sample numbers and considerable clinical heterogeneity in both interventions and outcomes. The inconsistency in reporting and dependence on summary-level data significantly constrained the viability of meta-analysis for secondary outcomes.Several significant constraints. The proposed network meta-analysis proved unfeasible due to the fragmented structure of the treatment network and the insufficient number of included studies, limiting thorough comparative efficacy evaluations. The principal meta-analysis relied on merely three research, and the results were fragile when subjected to sensitivity analysis limited to moderate-risk studies. The analysis depended on summary-level intergroup differences instead of individual patient data, which is less reliable. Fourth, variable reporting among studies impeded the quantitative synthesis of secondary outcomes and safety data. The limited quantity of studies constrains precision and generalizability. Ultimately, publication bias could not be adequately evaluated due to the limited number of studies in meta-analysis.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCurrently, no single ED therapy guarantees sustained pain freedom for pediatric migraines. While dopamine antagonists may outperform NSAIDs for short-term relief, their safety profile and the substantial influence of placebo effects warrant caution. Future research should prioritize large-scale, multicenter trials with standardized outcomes and longer follow-up. Emphasis must shift toward evaluating sustained pain relief and integrating ED care with post-discharge management to reduce the high rate of recurrence.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This study is a systematic review and meta-analysis of previously published data and did not involve human participants or animal subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in the published article and its supplementary materials. Additional details are available from the corresponding author upon a reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMohammed Alsabri, MD, FAAP (first) conceived and designed the study, developed the protocol, coordinated all stages of manuscript development, drafted substantial portions of the manuscript, supervised the research team, and managed all communications with co-authors.\u003c/p\u003e\n\u003cp\u003eMohamed Amr Elkarargy led the analysis, results of synthesis, and manuscript drafting.\u003c/p\u003e\n\u003cp\u003eToka Elboraay drafted the discussion section and assisted with quality assessment.\u003c/p\u003e\n\u003cp\u003eSara M. Darawish (corresponding author) registered the study in PROSPERO and wrote the introduction and methods sections.\u003c/p\u003e\n\u003cp\u003eSummayya Anwar conducted data extraction, performed quality assessment, and contributed to manuscript writing.\u003c/p\u003e\n\u003cp\u003eEslam Abady performed data extraction and quality assessment.\u003c/p\u003e\n\u003cp\u003eShree Rath conducted study validation and critically reviewed and recapitulated the manuscript.\u003c/p\u003e\n\u003cp\u003eBara M. Hammadeh assisted in the analytical process and interpretation of findings.\u003c/p\u003e\n\u003cp\u003eManar Adel supported literature screening and study selection.\u003c/p\u003e\n\u003cp\u003eAmeer Hassoun, MD provided critical revision of the manuscript for important intellectual content.\u003c/p\u003e\n\u003cp\u003eAll authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all collaborators and contributors who supported data collection, screening, and manuscript development.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: Data from the American Migraine Study II. Headache. 2001;41(7). \u003c/li\u003e\n\u003cli\u003eLipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. 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Available from: https://www.bmj.com/content/366/bmj.l4898\u003c/li\u003e\n\u003cli\u003eBrozek JL, Canelo-Aybar C, Akl EA, Bowen JM, Bucher J, Chiu WA, et al. GRADE Guidelines 30: the GRADE approach to assessing the certainty of modeled evidence\u0026mdash;An overview in the context of health decision-making. J Clin Epidemiol. 2021;129. \u003c/li\u003e\n\u003cli\u003eSheridan DC, Hansen ML, Lin AL, Fu R, Meckler GD. Low-Dose Propofol for Pediatric Migraine: A Prospective, Randomized Controlled Trial. Journal of Emergency Medicine. 2018;54(5). \u003c/li\u003e\n\u003cli\u003eTsze DS, Lubell TR, Carter RC, Chernick LS, DePeter KC, McLaren SH, et al. Intranasal ketorolac versus intravenous ketorolac for treatment of migraine headaches in children: A randomized clinical trial. Academic Emergency Medicine. 2022;29(4). \u003c/li\u003e\n\u003cli\u003eBrousseau DC, Duffy SJ, Anderson AC, Linakis JG. Treatment of Pediatric Migraine Headaches: A Randomized, Double-Blind Trial of Prochlorperazine Versus Ketorolac. Ann Emerg Med [Internet]. 2004 [cited 2026 Feb 15];43(2):256\u0026ndash;62. Available from: https://pubmed.ncbi.nlm.nih.gov/14747817/\u003c/li\u003e\n\u003cli\u003eRicher LP, Ali S, Johnson DW, Rosychuk RJ, Newton AS, Rowe BH. A randomized trial of ketorolac and metoclopramide for migraine in the emergency department. Headache [Internet]. 2022 Jun 1 [cited 2026 Feb 15];62(6):681\u0026ndash;9. Available from: /doi/pdf/10.1111/head.14307\u003c/li\u003e\n\u003cli\u003eMaki K, Doan Q, Sih K, Stillwell K, Chun A, Meckler G. A randomized controlled pilot study of intranasal lidocaine in acute management of paediatric migraine and migraine-like headache. Paediatr Child Health [Internet]. 2022 Oct 3 [cited 2026 Feb 15];27(6):340\u0026ndash;5. Available from: https://dx.doi.org/10.1093/pch/pxac054\u003c/li\u003e\n\u003cli\u003eBoutin A, Gouin S, Bailey B, Lebel D, Gravel J. Additive Value of Intranasal Fentanyl on Ibuprofen for Pain Management of Children With Moderate to Severe Headaches: A Randomized Controlled Trial. Journal of Emergency Medicine [Internet]. 2023 Aug 1 [cited 2026 Feb 15];65(2):e119\u0026ndash;31. Available from: https://www.jem-journal.com/action/showFullText?pii=S0736467923002913\u003c/li\u003e\n\u003cli\u003eStudy Details | NCT00355394 | Treatment of Acute Migraine Headache in Children | ClinicalTrials.gov [Internet]. [cited 2026 Feb 15]. Available from: https://clinicaltrials.gov/study/NCT00355394\u003c/li\u003e\n\u003cli\u003eStudy Details | NCT02358681 | Intranasal Ketorolac Versus Intravenous Ketorolac for Treatment of Migraine Headaches in Children | ClinicalTrials.gov [Internet]. [cited 2026 Feb 15]. Available from: https://clinicaltrials.gov/study/NCT02358681\u003c/li\u003e\n\u003cli\u003eRicher L, Craig W, Rowe B. Randomized controlled trial of treatment expectation and intravenous fluid in pediatric migraine. Headache [Internet]. 2014 Oct 1 [cited 2026 Feb 15];54(9):1496\u0026ndash;505. Available from: /doi/pdf/10.1111/head.12443\u003c/li\u003e\n\u003cli\u003eStudy Details | NCT02794441 | Oral Dexamethasone for the Treatment of Acute Migraine Recurrence in the Pediatric Emergency Department | ClinicalTrials.gov [Internet]. [cited 2026 Feb 15]. Available from: https://clinicaltrials.gov/study/NCT02794441\u003c/li\u003e\n\u003cli\u003ePatniyot IR, Gelfand AA. Acute Treatment Therapies for Pediatric Migraine: A Qualitative Systematic Review. Vol. 56, Headache. 2016. \u003c/li\u003e\n\u003cli\u003eGhirigato E, Zupin L, Celsi F, Capaci V, Amaddeo A, Cozzi G. What is the best approach to treat acute migraine in children in the emergency department? Vol. 13, Frontiers in Pediatrics. 2025. \u003c/li\u003e\n\u003cli\u003eSun Q, Xie H, Hao L, Ding J, Hong J, Lin X, et al. Global Epidemiology and Burden of Migraine in Children and Adolescents from 1990 to 2021: Insights from the Global Burden of Disease Study 2021. J Pain Res. 2025;18. \u003c/li\u003e\n\u003cli\u003eSuzuki K, Suzuki S, Shiina T, Kobayashi S, Hirata K. Central Sensitization in Migraine: A Narrative Review. Vol. 15, Journal of Pain Research. 2022. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"pediatric migraine, emergency department, acute migraine, pharmacologic therapy, dopamine antagonists, nonsteroidal anti-inflammatory drugs, prochlorperazine","lastPublishedDoi":"10.21203/rs.3.rs-8885764/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8885764/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAcute migraine is a frequent cause of pediatric emergency department (ED) visits, yet comparative evidence for pharmacologic management in this setting remains limited and heterogeneous. We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of ED-based pharmacologic treatments for acute pediatric migraine.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe searched MEDLINE, Embase, CENTRAL, PubMed, Scopus, and Web of Science from inception to 2025 for RCTs evaluating acute pharmacologic therapies for migraine in patients\u0026thinsp;\u0026lt;\u0026thinsp;18 years presenting to the ED. The primary outcome was pain response at 2 hours. Secondary outcomes included need for rescue therapy, ED length of stay, return visits, adverse events, and treatment satisfaction. Random-effects pairwise meta-analyses and a frequentist network meta-analysis were performed. Risk of bias was assessed using RoB 2, and certainty of evidence using GRADE.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNine RCTs involving 476 participants were included. Active ED migraine treatments were associated with a modest reduction in pain compared with control or standard care (mean difference of 5.96 points on a 0\u0026ndash;100 scale; 95% CI 0.42 to 11.51), with low heterogeneity. The effect size was small and close to the minimal clinically important difference. Sensitivity analyses restricted to studies at moderate risk of bias showed no statistically significant benefit. Reporting of secondary outcomes and adverse events was inconsistent, precluding quantitative synthesis. Dopamine antagonists, particularly prochlorperazine, appeared more effective than NSAIDs for short-term pain relief but were associated with more extrapyramidal adverse effects.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCurrent pharmacologic treatments for acute pediatric migraine in the ED provide only modest short-term pain relief, with low-certainty evidence and no clearly superior therapy. Future large, multicenter ED-based trials with standardized, patient-centered outcomes and longer follow-up are needed to inform evidence-based care.\u003c/p\u003e","manuscriptTitle":"Pharmacologic Treatment of Acute Migraine in the Pediatric Emergency Department: A Systematic Review and Meta-analysis of Randomized Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-23 05:37:17","doi":"10.21203/rs.3.rs-8885764/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"79bffa83-071c-413e-a5de-49a3af336b41","owner":[],"postedDate":"February 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-24T10:06:15+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-23 05:37:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8885764","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8885764","identity":"rs-8885764","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}