Impact of Botulinum Toxin Versus CGRP Monoclonal Antibodies on Return Visits and Acute Medication Use in Chronic Migraine: First Real-World, Multicenter, Head-to-Head Analysis Using TriNetX

Impact of Botulinum Toxin Versus CGRP Monoclonal Antibodies on Return Visits and Acute Medication Use in Chronic Migraine: First Real-World, Multicenter, Head-to-Head Analysis Using TriNetX | 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 Article Impact of Botulinum Toxin Versus CGRP Monoclonal Antibodies on Return Visits and Acute Medication Use in Chronic Migraine: First Real-World, Multicenter, Head-to-Head Analysis Using TriNetX Chun-Fu Lin, Chen-Chih Chung, Jia-Hung Chen, Nai-Fang Chi, Chaur-Jong Hu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8506523/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: Botulinum toxin type A and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) are widely used preventive treatments for chronic migraine. However, real-world comparative evidence regarding their effects on health-care utilization and acute medication use remains lacking. Objectives: To directly compare the real-world effectiveness of botulinum toxin and CGRP mAbs in reducing migraine-related return visits and acute triptan medication prescription use among patients with chronic migraine across a large, multicenter cohort. Methods: A retrospective cohort analysis was conducted using data collected from the TriNetX global health-care database for the period from 2018 to 2024. Adults with a diagnosis of chronic migraine were assigned to botulinum toxin or CGRP mAb cohorts on the basis of prescription records. Propensity score matching was used to balance key demographic, clinical, and comorbidity variables between the cohorts. The primary outcomes were (1) migraine-related return visits and (2) acute triptan prescription risk within 1 year of treatment initiation. Sensitivity analyses were conducted by expanding diagnostic criteria to include broader headache codes ( International Classification of Diseases, Tenth Revision, Clinical Modification R51), and subgroup analyses were performed to examine outcome consistency across age, sex, and comorbidity strata. Results: After propensity score matching, each cohort comprised 10,140 patients. Botulinum toxin was associated with a significantly lower acute triptan prescription risk (hazard ratio: 0.513, 95% confidence interval: 0.481–0.546, p < 0.001), whereas migraine-related return visit rates were comparable between the cohorts. The increased triptan prescription risk observed in the CGRP mAb cohort persisted across sensitivity and subgroup analyses. In the expanded cohorts, higher migraine recurrence was observed among CGRP mAb users. Conclusions: This multicenter real-world study demonstrated that botulinum toxin was associated with a superior reduction in acute triptan prescription risk compared with CGRP mAbs in patients with chronic migraine. These findings were robust across diverse subgroups and sensitivity analyses, supporting phenotype-driven preventive therapy selection to optimize acute medication control and health-care resource utilization. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Neurology chronic migraine botulinum toxin calcitonin gene-related peptide monoclonal antibodies drug therapy triptan medication adherence medical visits real-world evidence propensity score matching Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction Chronic migraine is a prevalent and disabling neurological disorder that substantially impairs patients’ quality of life and imposes a substantial burden on health-care resources [1]. Preventive treatment strategies primarily include the administration of botulinum toxin type A and monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway [2]. Both therapies have demonstrated efficacy in reducing migraine frequency; however, their direct comparative effects on clinical outcomes, including headache recurrence, health-care utilization, and acute medication use, remain insufficiently clarified in large real-world populations. A systematic review and meta-analysis demonstrated that both botulinum toxin and CGRP mAbs substantially reduced headache days and exhibited favorable safety profiles [3]. Recent large-scale real-world observational studies, including the pan-European PEARL study examining fremanezumab, a CGRP monoclonal antibody, reported substantial reductions in monthly migraine days and acute medication use, along with good tolerability over 6 months of treatment [4]. However, variations in patient responses and differences in cost-effectiveness underscore the need for head-to-head comparisons between preventive therapies [5, 6]. Emerging real-world evidence also reveals potential benefits of combining botulinum toxin with CGRP antagonists, indicating the possibility of synergistic effects [7–9]. Patient-centered indicators such as the frequency of return visits and use of acute pain medications, particularly nonsteroidal anti-inflammatory drugs and triptans, are crucial indirect measures of preventive treatment effectiveness and health-care resource utilization. These indicators are emphasized in both Taiwanese headache society guidelines and international studies [10–12]. However, large-scale comparative data on these outcomes in botulinum toxin versus CGRP mAb users are lacking. To address the aforementioned gaps, the present study used the TriNetX US Collaborative Network—a subset of the global TriNetX health-care database comprising approximately 70 health-care organizations, which predominantly represent the United States (80%), with limited European and Asian representation [13, 14]—to conduct the first large-scale, multicenter, head-to-head comparison of real-world outcomes in propensity score–matched cohorts of chronic migraine patients receiving botulinum toxin versus CGRP mAbs. We conducted binary time-to-event analyses over a 1-year follow-up period to examine migraine-related return visits and acute triptan prescriptions in order to determine differences in health-care utilization patterns between these preventive therapies. Despite inherent limitations in the availability of detailed dosing and visit-level information, these real-world data address critical evidence gaps and inform phenotype-driven preventive treatment selection and health-care resource allocation in migraine management. Methods Study Design, Participants, and Data Collection This retrospective cohort study used deidentified patient data collected from the TriNetX global health-care research network, which aggregates electronic health records from several health-care organizations worldwide and supports large-scale population-based analyses. The study period was from January 1, 2018, to December 31, 2024. This study was approved by the Taipei Medical University Joint Institutional Review Board (TMU-JIRB No: N202512042). Eligible participants were adults aged ≥18 years with a diagnosis of chronic migraine ( International Classification of Diseases, Tenth Revision, Clinical Modification [ ICD-10-CM ] codes G43, G43.7, G43.70, and G43.709). The study cohorts comprised patients who received botulinum toxin type A or CGRP mAbs (erenumab, fremanezumab, galcanezumab, or eptinezumab) and initiated treatment within 1 month after their initial migraine diagnosis. Patients who received both therapies within 1 month before or after the index date were excluded to prevent overlapping exposures. All data were fully anonymized, and the study adhered to applicable ethical and privacy regulations governing secondary use of deidentified data. This study used the TriNetX research network, which aggregates real-time electronic health records from participating health-care organizations. To ensure data authenticity and transparency, particularly for laboratory parameters such as body mass index and immunoglobulin E, the platform applies no imputation or deletion procedures; missing values are retained in their original state for analysis. TriNetX does not implement a formal definition of loss to follow-up; instead, when no subsequent health-care encounters are recorded, the patient’s last documented visit is used as the endpoint of follow-up. All data undergo strict deidentification in accordance with the Health Insurance Portability and Accountability Act and the General Data Protection Regulation. To protect patient privacy, cell counts representing fewer than 10 individuals are masked in the reported results. Exposure and Outcome Definitions Exposure cohorts were defined using prescription records. The botulinum toxin cohort was identified using RxNorm code 1712, and the CGRP mAb cohort was identified using the corresponding RxNorm codes. The primary outcomes were defined as binary events occurring during the follow-up period: (1) migraine recurrence (return visit), identified by the presence of a subsequent diagnostic record for migraine ( ICD-10-CM code G43) in the electronic health records, including outpatient, emergency department, or inpatient encounters; and (2) acute medication use, defined as the prescription of any triptan-class medication (identified using RxNorm codes; e.g., sumatriptan or rizatriptan). Because of the inherent limitations of the TriNetX platform in capturing the precise dosage, days of supply, or cumulative prescription counts, acute medication use was analyzed as a time-to-event outcome, defined as the time to the first recorded triptan prescription, rather than as a quantitative measure of total medication consumption. We conducted sensitivity analyses by expanding the diagnostic definition to include all headache-related codes ( ICD-10-CM code R51) and examining the robustness of the findings across key subgroups stratified by age, sex, and comorbidities. Covariates We adjusted for covariates such as demographic variables (age, sex, and race), lifestyle characteristics (nicotine dependence, tobacco use, and alcohol-related disorders), comorbidities (including, but not limited to, hypertension, diabetes, sleep disorders, depression, and anxiety), health-care utilization measures (outpatient visits, emergency department visits, and inpatient admissions), concurrent medication use (opioids, psychoanaleptics, and glucocorticoids), and laboratory values (C-reactive protein, hemoglobin, and estimated glomerular filtration rate). Statistical Analysis Propensity score matching was conducted using a 1:1 nearest-neighbor algorithm without replacement to balance covariates across cohorts. Covariate balance was examined using standardized mean differences, with values <0.1 indicating acceptable balance. Kaplan–Meier survival analyses were performed to estimate the cumulative incidence of the outcomes. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) between the treatment groups. A two-sided p value of <0.05 was considered statistically significant. Sensitivity and Subgroup Analyses We conducted sensitivity analyses by expanding the diagnostic definition of migraine to include headache symptoms ( ICD-10-CM code R51) and evaluating the robustness of the findings. Subgroup analyses were conducted to investigate treatment effects across groups stratified by age, sex, and key comorbidities. Ethical Considerations This study was approved by the Taipei Medical University Joint Institutional Review Board (TMU-JIRB No: N202512042), and all data used were fully deidentified and aggregated. Results Cohort Characteristics A total of 29,938 patients with chronic migraine were identified in the TriNetX database after the application of the eligibility criteria (Figure 1). After propensity score matching to balance baseline characteristics, each treatment cohort (botulinum toxin or CGRP mAb cohort) comprised 10,140 patients. Table 1 presents a summary of the baseline demographic, clinical, and comorbidity characteristics of the matched cohorts. Both cohorts were well balanced in terms of age, sex, race, comorbidities, and key clinical parameters, with standardized mean differences of <0.1 for all covariates. Primary Outcomes Acute Triptan Prescription Risk The risk of receiving an acute triptan prescription within 1 year after the index treatment was significantly higher in the CGRP mAb cohort than in the botulinum toxin cohort. In the primary time-to-event analysis, the risk of receiving an acute triptan prescription was significantly lower in the botulinum toxin cohort than in the CGRP mAb cohort (HR: 0.513, 95% CI: 0.481–0.546; Figure 2). This finding was consistent across complementary analytical approaches, including Kaplan–Meier survival analyses and cumulative incidence estimates, which confirmed clear between-group differences (Figure 3). Figure 3 displays the cumulative incidence of acute triptan prescriptions over a 3-year follow-up period among patients initiating CGRP mAbs or botulinum toxin. The CGRP mAb cohort had a consistently higher cumulative incidence, with the survival curves diverging early after the index date and remaining separated over time. By contrast, the botulinum toxin cohort exhibited a lower and more gradual increase in cumulative incidence. The log-rank test confirmed that these differences were statistically significant (p < 0.001), indicating that the CGRP mAb cohort required acute triptans more frequently than did the botulinum toxin cohort. Risk of Migraine-Related Health-Care Visits In the primary analysis, no statistically significant difference in the risk of migraine-related return visits was observed between the botulinum toxin and CGRP mAb cohorts (HR: 1.008, 95% CI: 0.977–1.039; p > 0.05). Kaplan–Meier curves revealed similar trajectories for both groups, characterized by a sharp increase in cumulative incidence during the initial months, followed by gradual plateauing with minimal divergence throughout the 1-year follow-up period (Figure 4). The CI closely centered around unity, indicating comparable rates of migraine-related health-care encounters between the two preventive treatments. Sensitivity Analysis To evaluate the robustness of our primary findings, we conducted a sensitivity analysis by expanding the migraine cohort to include patients with broader headache diagnoses defined by ICD-10-CM code R51. This enabled us to examine whether the inclusion of headache symptoms beyond strict chronic migraine criteria affected the observed outcomes. The results revealed that in the expanded cohort, patients treated with botulinum toxin continued to exhibit a significantly lower risk of receiving an acute triptan prescription than did those treated with CGRP mAbs (HR: 0.437, 95% CI: 0.409–0.467; p < 0.01). Additionally, the risk of migraine-related return visits was significantly lower among patients treated with botulinum toxin than those treated with CGRP mAbs, suggesting a higher recurrence or breakthrough headache burden in the CGRP mAb cohort (HR: 0.741, 95% CI: 0.717–0.766; p < 0.01; Figure 5). Kaplan–Meier survival curves for time to first acute triptan prescription under the expanded diagnostic criteria were also consistent with the findings of our primary analyses, supporting the observation that patients treated with CGRP mAbs more frequently required acute medication despite receiving preventive therapy (Figure 6). In contrast to the primary cohort, in which migraine-related return visits were comparable between the treatment cohorts, the Kaplan–Meier curves in the expanded cohort revealed a significant increase in migraine-related return visits among patients treated with CGRP mAbs compared with those treated with botulinum toxin. This increase may reflect the inclusion of less strictly defined headache cases in the expanded cohort and highlight potential differences in real-world effectiveness across a broader patient population (Figure 7). Subgroup Analyses of Preventive Treatment: Botulinum Toxin Versus CGRP mAbs We performed subgroup analyses (Figure 8) to examine acute triptan prescription risk across demographic, clinical, and lifestyle strata in patients treated with botulinum toxin or CGRP mAbs. In the propensity score–matched cohort, the risk of receiving an acute triptan prescription was lower in the botulinum toxin cohort than in the CGRP mAb cohort (HR: 0.513, 95% CI: 0.481–0.546; p < 0.001). This difference was consistent across the male (HR: 0.491, 95% CI: 0.417–0.579; p < 0.001) and female (HR: 0.517, 95% CI: 0.483–0.555; p < 0.001) subgroups and across the age subgroups. Specifically, this risk was lower in individuals aged 20–64 years (HR: 0.530, 95% CI: 0.495–0.566; p < 0.001), with a more pronounced reduction observed in those aged ≥65 years (HR: 0.392, 95% CI: 0.315–0.488; p < 0.001). In the racial subgroup analyses, botulinum toxin treatment was associated with a significantly lower triptan prescription risk in the White subgroup (HR: 0.484, 95% CI: 0.450–0.520; p < 0.001), with similar directional trends observed in the Black/African American and Asian subgroups; however, CIs were wider in these groups due to smaller sample sizes. Comorbidity subgroup analyses also demonstrated that botulinum toxin treatment was associated with a significantly reduced risk of acute triptan prescription in patients with hypertension (HR: 0.543, 95% CI: 0.455–0.648; p < 0.001) and diabetes mellitus (HR: 0.579, 95% CI: 0.403–0.781; p < 0.001). Similarly, lifestyle subgroup analysis results revealed that botulinum toxin treatment was associated with reduced triptan prescription risk among smokers (HR: 0.657, 95% CI: 0.478–0.905; p < 0.05); however, results for alcohol-related disorders were limited and inconclusive. Subgroup Analyses of Migraine-Related Return Visits We conducted prespecified subgroup analyses to evaluate whether the comparative effectiveness of botulinum toxin type A versus CGRP mAbs regarding migraine-related return visits varied by demographic and clinical factors (Figure 9). Overall, the 1-year risk of migraine-related return visits remained comparable between CGRP mAb and botulinum toxin users (HR: 1.008, 95% CI: 0.977–1.039). Sex did not modify this effect, with similar HRs observed in men (HR: 1.012, 95% CI: 0.942–1.086) and women (HR: 1.014, 95% CI: 0.980–1.048). Age significantly moderated the outcomes. CGRP mAb therapy was associated with a higher risk of migraine-related return visits in adults aged 20–64 years (HR: 1.048, 95% CI: 1.013–1.083) but a lower risk in those aged ≥65 years (HR: 0.893, 95% CI: 0.825–0.966), indicating age-specific benefits. Racial subgroups displayed no significant differences favoring either treatment. Among lifestyle factors, smoking yielded a nonsignificant HR (0.911, 95% CI: 0.793–1.048), whereas alcohol-related disorders exhibited a trend toward lower return visit risk with CGRP mAbs (HR: 0.761, 95% CI: 0.523–1.107). However, this finding was constrained by limited sample size. Comorbidity subgroup analyses revealed notable heterogeneity across conditions. Hypertension was associated with reduced migraine-related return visit risk among CGRP mAb users (HR: 0.862, 95% CI: 0.801–0.927), whereas no significant difference was observed in patients with diabetes mellitus (HR: 0.918, 95% CI: 0.817–1.031), suggesting a superior response of CGRP mAbs in cardiovascular phenotypes. Collectively, these results demonstrate equivalent overall effects but highlight improved outcomes with CGRP mAbs in older patients and those with hypertension, whereas younger adults may benefit more from botulinum toxin, emphasizing phenotype-driven therapy personalization. Summary of Findings Botulinum toxin was associated with a significantly lower risk of receiving an acute triptan prescription (HR: 0.513, 95% CI: 0.481–0.546) compared with CGRP mAbs across matched chronic migraine cohorts, although migraine-related return visit rates were equivalent between the cohorts (HR: 1.008, 95% CI: 0.977–1.039). This difference in triptan prescription risk persisted in sensitivity analyses incorporating broader headache diagnoses and across subgroup analyses stratified by age, sex, and comorbidities. Together, these findings reveal mechanistic differences that support phenotype-driven preventive therapy selection to optimize acute medication control. Discussion Clinical Implications and Comparison With the Literature Patients treated with CGRP mAbs exhibited significantly higher acute triptan requirements after the initiation of preventive therapy, despite having migraine-related return visit risks comparable to those of patients treated with botulinum toxin. The present study also confirmed that CGRP mAbs were associated with a higher risk of acute triptan use. This finding is consistent with those of the RAMO study [15], which reported reductions in Headache Impact and Allodynia scores with both CGRP mAbs and botulinum toxin, thereby addressing a gap in real-world head-to-head evidence. Previous clinical trials and real-world studies have primarily evaluated preventive efficacy by using reductions in headache days or patient-reported disability measures, yielding inconsistent signals of superiority across treatments [3, 5, 6]. However, few studies have examined acute triptan utilization as a definitive outcome, despite its direct relevance to acute migraine management and health-care resource planning. Moreover, previous meta-analyses have primarily focused on reductions in headache days or indirect treatment comparisons and have lacked direct real-world evidence on acute medication use and health-care utilization [3, 5, 20]. By contrast, the present TriNetX-based study directly evaluated acute triptan prescription risk and migraine-related return visits and applied propensity score matching to enhance comparability between the treatment cohorts, thereby addressing a crucial gap in the literature. Novel Contribution: Direct Comparison of Return Visits and Acute Medication Use In addition to our primary analysis, we conducted sensitivity analyses by broadening the diagnostic definition of migraine to include headache symptoms ( ICD-10-CM code R51). The results of this approach confirm a higher risk of acute triptan use in the CGRP mAb cohort and additionally identified an increased risk of migraine recurrence ( ICD-10-CM G43). To our knowledge, this is the first real-world study to directly compare return visit rates and acute triptan prescriptions as dual endpoints in a head-to-head study. These outcomes have been infrequently examined in previous research, which has predominantly focused on reductions in headache days. Our findings provide more actionable endpoints that reflect both patient burden and health-care system impact. Mechanisms and Clinical Applications The higher acute triptan use observed among patients treated with CGRP mAbs likely reflects incomplete preventive efficacy or the occurrence of breakthrough attacks caused by non-CGRP triggers. CGRP mAbs target a single pathway by blocking the CGRP ligand or receptor, which reduces migraine frequency but may result in a persistent need for residual acute treatment [5, 15–18]. By contrast, botulinum toxin type A inhibits acetylcholine and multiple neuropeptides (CGRP, substance P, and glutamate), providing broader control of peripheral and central sensitization and reducing severe breakthrough attacks [3, 19, 20]. CGRP mAbs block peripheral CGRP signaling, whereas botulinum toxin inhibits multiple neuropeptides at the trigeminal ganglia [3, 15, 19, 21]. We observed that both therapies equivalently reduced the risk of migraine-related return visits (HR: 1.008), whereas botulinum toxin was associated with a lower risk of acute triptan prescription (HR: 0.513) across most subgroups (Figure 2). The age- and comorbidity-related heterogeneity observed in return visit risk (Figure 9) supports a phenotype-driven approach to therapy selection. Comorbidity-Specific Insights In the hypertension and diabetes subgroups, botulinum toxin reduced the risk of acute triptan prescription, likely due to its multitarget inhibition of neuropeptides (CGRP, substance P, and glutamate), mitigating sensitization and vascular or inflammatory effects in patients with comorbidities [22-24]. However, when compared with botulinum toxin, CGRP mAbs reduced the risk of migraine-related return visits in patients with hypertension (HR: 0.862, 95% CI: 0.801–0.927) but not in those with diabetes (HR: 0.918, 95% CI: 0.817–1.031). These findings indicate a clinical trade-off, with botulinum toxin offering advantages for acute medication control in patients with comorbidities and CGRP mAbs providing potential benefits for reducing health-care utilization in patients with hypertension. Age-Related Heterogeneity Subgroup analyses revealed age-dependent treatment effects. CGRP mAbs were associated with higher migraine-related return visit rates in younger adults aged 20–64 years (HR: 1.048, 95% CI 1.013–1.083) but lower return visit rates in older adults aged ≥65 years (HR: 0.893, 95% CI: 0.825–0.966). By contrast, botulinum toxin was associated with a more pronounced reduction in acute triptan prescription risk among older adults (HR: 0.392, 95% CI: 0.315–0.488; Figure 9). Previous real-world studies have reported robust efficacy of botulinum toxin in adolescents and young adults (aged 13–21 years), with a ≥50% reduction in symptoms observed in up to 69% of severe cases [25–27]. In comparison, CGRP mAbs have demonstrated consistent efficacy in midlife adults, with mean ages typically ranging from 40 to 50 years; however, data in older populations remain limited, indicating the need for age-stratified analyses [28–30]. Direct age-based head-to-head comparisons between these therapies remain scarce. Age-related declines in baseline CGRP and substance P levels in trigeminal neurons [31] may render residual CGRP signaling more critical for migraine generation among older adults, thereby enhancing the relative effectiveness of CGRP mAb therapy. By contrast, younger patients with more active multineuropeptide signaling pathways may derive greater benefit from the broad-spectrum inhibitory effects of botulinum toxin. Collectively, these findings support age-stratified, phenotype-driven personalization of preventive migraine therapy. Advantages of Real-World, Multicenter, Big Data Analysis Using TriNetX Our use of the TriNetX global research platform enabled access to a large, diverse, multiethnic patient population across multiple health-care systems, thereby enhancing the external validity of our findings. This approach helped us overcome the sample size and population spectrum limitations typical of single-center studies and helped improve the generalizability of our findings to real-world clinical practice. Limitations and Future Directions This study has several limitations that should be acknowledged. First, the TriNetX database primarily includes data from specific health-care systems, which may limit the generalizability of the findings across different ethnic, socioeconomic, and health-care system contexts [13, 21]. Second, the small sample sizes in subgroups with rare comorbidities or headache types restricted our ability to draw robust conclusions for these populations. Third, the reliance on administrative coding and prescription records may have introduced misclassification bias, particularly in cases receiving care outside the contributing networks. Fourth, the retrospective study design and limited follow-up duration precluded assessments of long-term safety, disease progression, and patient-reported outcomes, such as migraine severity and quality of life, which are central to headache research [32]. Finally, although TriNetX offers access to a large and diverse dataset, its predominantly US-based representation necessitates caution when extrapolating the findings to global populations [13, 21]. Future research should incorporate prospective trials and pragmatic cohort studies to validate these findings, clarify mechanisms underlying differential treatment responses, and evaluate long-term outcomes across diverse patient populations. In particular, prospective studies focused on high-risk subgroups, such as patients with medication-overuse headache or refractory migraine, are warranted because these populations are underrepresented in existing trials despite having a disproportionate disease burden [33]. Generating robust evidence in these populations is essential for optimizing clinical management strategies and informing health policy decisions [34, 35]. In addition, future clinical research and policy initiatives should prioritize patient-centered approaches for individuals with high acute medication requirements or complex comorbidities to more effectively address their specific clinical needs. Conclusion This multicenter real-world study provides the first direct head-to-head comparison of botulinum toxin versus CGRP mAbs in chronic migraine, demonstrating a lower risk of acute triptan prescription with botulinum toxin (HR: 0.513, 95% CI: 0.481–0.546) and comparable migraine-related return visit rates between the two treatments (HR: 1.008, 95% CI: 0.977–1.039). Subgroup analyses suggested that CGRP mAbs were preferable for older adults aged ≥65 years (return visit HR: 0.893) and for patients with hypertension (HR: 0.862), whereas botulinum toxin exhibited an advantage in acute medication control across most examined strata. These comparative findings, derived from propensity score–matched cohorts, should be interpreted in the context of the retrospective study design, and prospective studies are required for validation. Declarations Availability of data and materials The data supporting the findings of this study are available from TriNetX; however, restrictions apply to the availability of these data, which were used under license for the current study and are not publicly available. The data may be made available from the authors upon reasonable request and with permission from TriNetX. Ethics approval and consent to participate This study was approved by the Taipei Medical University Joint Institutional Review Board (Approval No. N202512042). Due to the retrospective nature and use of deidentified data, the requirement for informed consent was waived. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Authors’ Contributions Chun-Fu Lin: conceptualization, study design, manuscript drafting, and overall project coordination. Hung-En Huang: primary data analysis, including TriNetX data processing, propensity score matching, Kaplan–Meier curve generation, and hazard ratio calculations. James Cheng-Chung Wei: methodology, analytical supervision, figure/table review, and leadership of intellectual contributions. Hsun-Hua Lee: supervision, correspondence, and critical revision of the manuscript. Chen-Chih Chung, Jia-Hung Chen, Nai-Fang Chi, Chaur-Jong Hu, Chih-Chung Chen, Tu-Hsueh Yeh: critical revision of the manuscript for intellectual content. All authors have read and approved the final manuscript. Acknowledgements This manuscript was edited by Wallace Academic Editing. Competing Interest The authors declare that they have no competing interests. References GBD 2021 Nervous System Disorders Collaborators. Global, regional, and national burden of disorders affecting the nervous system, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024 Apr;23(4):344-381. doi: 10.1016/S1474-4422(24)00038-3. Epub 2024 Mar 14. Erratum in: Lancet Neurol. 2024 May;23(5):e9. doi: 10.1016/S1474-4422(24)00114-5. Erratum in: Lancet Neurol. 2024 Jul;23(7):e11. doi: 10.1016/S1474-4422(24)00231-X. PMID: 38493795; PMCID: PMC10949203. Kung D, Rodriguez G, Evans R. Chronic Migraine: Diagnosis and Management. Neurol Clin. 2023 Feb;41(1):141-159. doi: 10.1016/j.ncl.2022.05.005. Epub 2022 Oct 31. PMID: 36400552. Lu J, Zhang Q, Guo X, Liu W, Xu C, Hu X, Ni J, Lu H, Zhao H. Calcitonin Gene-Related Peptide Monoclonal Antibody Versus Botulinum Toxin for the Preventive Treatment of Chronic Migraine: Evidence From Indirect Treatment Comparison. Front Pharmacol. 2021 May 3;12:631204. doi: 10.3389/fphar.2021.631204. PMID: 34012392; PMCID: PMC8126691. Ashina M, Mitsikostas DD, Amin FM, Kokturk P, Schankin CJ, Sahin G, Pozo-Rosich P, Dorman PJ, Nežádal T, Poole AC, Martins IP, Sumelahti ML, Ramirez Campos V, Ahn AH, Lyras L, Tassorelli C. Real-world effectiveness of fremanezumab for the preventive treatment of migraine: Interim analysis of the pan-European, prospective, observational, phase 4 PEARL study. Cephalalgia. 2023 Nov;43(11):3331024231214987. doi: 10.1177/03331024231214987. PMID: 37987641. Montisano DA, Giossi R, Canella M, Altamura C, Marcosano M, Vernieri F, Raggi A, Grazzi L. Reducing the Impact of Headache and Allodynia Score in Chronic Migraine: An Exploratory Analysis from the Real-World Effectiveness of Anti-CGRP Monoclonal Antibodies Compared to Onabotulinum Toxin A (RAMO) Study. Toxins (Basel). 2024 Apr 7;16(4):178. doi: 10.3390/toxins16040178. PMID: 38668603; PMCID: PMC11054793. Mohammad Alabdali M, Rafique N, AlDossary DA, Alalloush RS, AlHemli HA, Zeerak M, Latif R, Ibrahim Al-Asoom L, Abdulrahman AlSunni A, Mohammed Salem A, Alshurem M, Aljaafari D, Obaid S, Alabdulhadi A. Direct Comparison of Treatment Outcome Between the Botulinum Toxin and Calcitonin Gene-Related Peptide Monoclonal Antibody in Migraine Patients. J Clin Med Res. 2024 Dec;16(11):527-535. doi: 10.14740/jocmr6054. Epub 2024 Nov 30. PMID: 39635334; PMCID: PMC11614408. Pellesi L. Combining onabotulinumtoxin A with a CGRP antagonist for chronic migraine prophylaxis: where do we stand? Front Pain Res (Lausanne). 2023 Oct 27;4:1292994. doi: 10.3389/fpain.2023.1292994. PMID: 37965209; PMCID: PMC10641512. Corasaniti MT, Lawrence GW, Bagetta G, Iannacchero R, Tarsitano A, Monteleone A, Pagliaro M, Tonin P, Sandrini G, Nicotera P, Scuteri D. Combination of anti-CGRP/CGRP-R mAbs with onabotulinumtoxin A as a novel therapeutic approach for refractory chronic migraine: a retrospective study of real-world clinical evidence and a protocol for a double-blind, randomized clinical trial to establish the efficacy and safety. Front Pharmacol. 2023 Dec 13;14:1296577. doi: 10.3389/fphar.2023.1296577. PMID: 38152694; PMCID: PMC10751376. Salim A, Hennessy E, Sonneborn C, Hogue O, Biswas S, Mays M, Suneja A, Ahmed Z, Mata IF. Synergism of Anti-CGRP Monoclonal Antibodies and OnabotulinumtoxinA in the Treatment of Chronic Migraine: A Real-World Retrospective Chart Review. CNS Drugs. 2024 Jun;38(6):481-491. doi: 10.1007/s40263-024-01086-z. Epub 2024 Apr 7. PMID: 38583127; PMCID: PMC11098928. Wu JW, Yang CP; Treatment Guideline Subcommittee of the Taiwan Headache Society. 2022 Taiwan Guidelines for Preventive Treatment of Migraine. Acta Neurol Taiwan. 2022 Sep 30;31(3):164-202. PMID: 36089629. Aguilar-Shea AL, Membrilla Md JA, Diaz-de-Teran J. Migraine review for general practice. Aten Primaria. 2022 Feb;54(2):102208. doi: 10.1016/j.aprim.2021.102208. Epub 2021 Nov 16. PMID: 34798397; PMCID: PMC8605054. Tzankova V, Becker WJ, Chan TLH. Pharmacologic prevention of migraine. CMAJ. 2023 Feb 6;195(5):E187-E192. doi: 10.1503/cmaj.221607. PMID: 36746481; PMCID: PMC9904820. Ludwig RJ, Anson M, Zirpel H, Thaci D, Olbrich H, Bieber K, Kridin K, Dempfle A, Curman P, Zhao SS, Alam U. A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX. Front Pharmacol. 2025 Mar 10;16:1516126. doi: 10.3389/fphar.2025.1516126. PMID: 40129946; PMCID: PMC11931024. Lin TL, Fan YH, Fan KS, Juan CK, Chen YJ, Wu CY. Reduced atopic march risk in pediatric atopic dermatitis patients prescribed dupilumab versus conventional immunomodulatory therapy: A population-based cohort study. J Am Acad Dermatol. 2024 Sep;91(3):466-473. doi: 10.1016/j.jaad.2024.05.029. Epub 2024 Jun 14. PMID: 38878041. Grazzi L, Giossi R, Montisano DA, Canella M, Marcosano M, Altamura C, Vernieri F. Real-world effectiveness of Anti-CGRP monoclonal antibodies compared to OnabotulinumtoxinA (RAMO) in chronic migraine: a retrospective, observational, multicenter, cohort study. J Headache Pain. 2024 Feb 2;25(1):14. doi: 10.1186/s10194-024-01721-6. PMID: 38308209; PMCID: PMC10836018. Siddiqui M, Shah PV, Balani P, Lopez AR, Nobleza CMN, Khan S. Comparing the Efficacy, Safety, and Superiority of Calcitonin Gene-Related Peptide Monoclonal Antibodies and Botox in Preventing and Treating Migraines. Cureus. 2021 Jan 30;13(1):e13002. doi: 10.7759/cureus.13002. Erratum in: Cureus. 2021 Feb 12;13(2):c41. doi: 10.7759/cureus.c41. PMID: 33542885; PMCID: PMC7847775. Blumenfeld AM, Kaur G, Mahajan A, Shukla H, Sommer K, Tung A, Knievel KL. Effectiveness and Safety of Chronic Migraine Preventive Treatments: A Systematic Literature Review. Pain Ther. 2023 Feb;12(1):251-274. doi: 10.1007/s40122-022-00452-3. Epub 2022 Nov 22. PMID: 36417165; PMCID: PMC9845441. Pallapothu MR, Quintana Mariñez MG, Chakkera M, Ravi N, Ramaraju R, Vats A, Nair AR, Bandhu AK, Koirala D, Mohammed L. Long-Term Management of Migraine With OnabotulinumtoxinA (Botox) vs Calcitonin Gene-Related Peptide Antibodies (Anti-CGRP). Cureus. 2023 Oct 8;15(10):e46696. doi: 10.7759/cureus.46696. PMID: 38021691; PMCID: PMC10630153. Gooriah R, Ahmed F. OnabotulinumtoxinA for chronic migraine: a critical appraisal. Ther Clin Risk Manag. 2015 Jun 29;11:1003-13. doi: 10.2147/TCRM.S76964. PMID: 26170679; PMCID: PMC4492656. Frank F, Ulmer H, Sidoroff V, Broessner G. CGRP-antibodies, topiramate and botulinum toxin type A in episodic and chronic migraine: A systematic review and meta-analysis. Cephalalgia. 2021 Oct;41(11-12):1222-1239. doi: 10.1177/03331024211018137. Epub 2021 Jun 15. PMID: 34130525; PMCID: PMC8506070. Pellesi L. Editorial: Novel migraine therapies: consolidating evidence from the real world. Front Pain Res (Lausanne). 2023 Dec 5;4:1340268. doi: 10.3389/fpain.2023.1340268. PMID: 38116186; PMCID: PMC10728816. Durham PL, Cady R. Insights into the mechanism of onabotulinumtoxinA in chronic migraine. Headache. 2011 Nov-Dec;51(10):1573-7. doi: 10.1111/j.1526-4610.2011.02022.x. PMID: 22082429; PMCID: PMC3306767. Ramachandran R, Yaksh TL. Therapeutic use of botulinum toxin in migraine: mechanisms of action. Br J Pharmacol. 2014 Sep;171(18):4177-92. doi: 10.1111/bph.12763. PMID: 24819339; PMCID: PMC4241086. Burstein R, Blumenfeld AM, Silberstein SD, Manack Adams A, Brin MF. Mechanism of Action of OnabotulinumtoxinA in Chronic Migraine: A Narrative Review. Headache. 2020 Jul;60(7):1259-1272. doi: 10.1111/head.13849. Epub 2020 Jun 30. PMID: 32602955; PMCID: PMC7496564. Goenka A, Grace Yu S, Chikkannaiah M, George MC, MacDonald S, Stolfi A, Kumar G. Generalized Anxiety Disorder: A Predictor for Poor Responsiveness to Botulinum Toxin Type A Therapy for Pediatric Migraine. Pediatr Neurol. 2022 May;130:21-27. doi: 10.1016/j.pediatrneurol.2022.02.002. Epub 2022 Mar 4. PMID: 35305510. Horvat DE, Shields JM, Young WWC, Eye PG. Botulinum Toxin for Pediatric Migraine: A Retrospective Multisite Cohort Study. Pediatr Neurol. 2023 Oct;147:68-71. doi: 10.1016/j.pediatrneurol.2023.07.005. Epub 2023 Jul 13. PMID: 37562172. Gómez-Dabó L, Caronna E, Mas-de-Les-Valls R, Gallardo VJ, Alpuente A, Torres-Ferrus M, Pozo-Rosich P. Effectiveness and Safety of OnabotulinumtoxinA in Adolescent Patients with Chronic Migraine. Toxins (Basel). 2024 May 11;16(5):221. doi: 10.3390/toxins16050221. PMID: 38787073; PMCID: PMC11126010. Ray JC, Dalic L, Baker J, Cheng S, Hutton EJ, Matharu M. Twelve-month efficacy of CGRP monoclonal antibodies and predictive value of short-term response: results of an Australian multicentre study. BMJ Neurol Open. 2024 Jan 10;6(1):e000547. doi: 10.1136/bmjno-2023-000547. PMID: 38268750; PMCID: PMC10806998. Wang YF, Yang FC, Chen LA, Chang TY, Su HC, Yang CP, Tu YH, Tzeng YS, Chen SP, Fuh JL, Lai KL, Ling YH, Chen WT, Wang SJ. Comparative effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies and onabotulinumtoxinA in chronic migraine: A multicenter, real-world study in Taiwan. Eur J Neurol. 2024 Sep;31(9):e16372. doi: 10.1111/ene.16372. Epub 2024 Jun 5. PMID: 38837528; PMCID: PMC11295178. Salim A, Biswas S, Sonneborn C, Hogue O, Hennessy E, Mays M, Suneja A, Ahmed Z, Mata IF. Efficacy and Tolerability of Anti-CGRP Monoclonal Antibodies in Patients Aged ≥ 65 Years With Daily or Nondaily Migraine. Neurol Clin Pract. 2025 Feb;15(1):e200373. doi: 10.1212/CPJ.0000000000200373. Epub 2024 Oct 8. PMID: 39399553; PMCID: PMC11464238. Fila M, Pawlowska E, Szczepanska J, Blasiak J. Different Aspects of Aging in Migraine. Aging Dis. 2023 Dec 1;14(6):2028-2050. doi: 10.14336/AD.2023.0313. PMID: 37199585; PMCID: PMC10676778. Orlando B, Egeo G, Aurilia C, Fiorentini G, Barbanti P. Calcitonin Gene-Related Peptide Monoclonal Antibodies: Key Lessons from Real-World Evidence. Brain Sci. 2024 Sep 22;14(9):948. doi: 10.3390/brainsci14090948. PMID: 39335442; PMCID: PMC11429799. Wang X, Sun Y, Zhang Y, Zhi Z, Wang S, Li J, Sun Y, Sun Y. Research trends and hotspots in clinical trials of migraine in the past 20 years: bibliometric analysis. Front Neurol. 2024 Oct 25;15:1430138. doi: 10.3389/fneur.2024.1430138. PMID: 39524909; PMCID: PMC11543406. Bentivegna E, Galastri S, Onan D, Martelletti P. Unmet Needs in the Acute Treatment of Migraine. Adv Ther. 2024 Jan;41(1):1-13. doi: 10.1007/s12325-023-02650-7. Epub 2023 Nov 9. PMID: 37943442; PMCID: PMC10796525. Katsuki M, Matsumori Y, Ichihara T, Yamada Y, Kaneko K, Kobayashi Y, Kawamura S, Kashiwagi K, Koh A, Goto T, Kaneko K, Wada N, Hanaoka Y, Yamagishi F. Treatment Patterns, Characteristics, and Probable Acute Medication Overprescription Among Patients With Migraine in Japan: A Retrospective Cross-Sectional and Longitudinal Analysis of Health Insurance Claims Data. Cureus. 2024 Dec 18;16(12):e75928. doi: 10.7759/cureus.75928. PMID: 39830552; PMCID: PMC11739997. Table Table 1 is available in the Supplementary Files section. 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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-8506523","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":578347907,"identity":"1d9ee8b6-b530-4316-9c4e-68a2db187b27","order_by":0,"name":"Chun-Fu Lin","email":"","orcid":"","institution":"Taipei Medical University Hospital, Taipei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chun-Fu","middleName":"","lastName":"Lin","suffix":""},{"id":578347912,"identity":"21909156-2b04-424d-89d5-8b845718d634","order_by":1,"name":"Chen-Chih Chung","email":"","orcid":"","institution":"Taipei Medical University-Shuang Ho 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00:02:22","extension":"doc","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":902656,"visible":true,"origin":"","legend":"","description":"","filename":"ImpactofBotulinumToxinVersusCGRPMonoclonalAntibodiesonReturnVisitsandAcuteMedicationUseinChronicMigraine.doc","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/68d2afdbc250ffe2d0ee527b.doc"},{"id":101207433,"identity":"1536a8e1-e53e-43b0-b575-65c8b872bdc0","added_by":"auto","created_at":"2026-01-27 10:04:06","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12068,"visible":true,"origin":"","legend":"","description":"","filename":"734f408e1a5c452abc7feb5d45b5fc58.json","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/e1ef3ed765ac2ebb49cc099a.json"},{"id":101206681,"identity":"f9c45ce4-d9f8-4b6f-a506-4b89e9226221","added_by":"auto","created_at":"2026-01-27 09:56:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":243712,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow diagram of cohort selection for patients with chronic migraine treated with botulinum toxin or CGRP mAbs in the TriNetX database. The diagram presents the number of patients assessed for eligibility, excluded at each step, and included in the final 1:1 propensity score–matched cohorts. \u003c/strong\u003eCGRP, calcitonin gene-related peptide; mAbs, monoclonal antibodies.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/409107af0f55d7574a5d01d9.png"},{"id":101207458,"identity":"90bc66d1-e6da-4297-841b-835a65484951","added_by":"auto","created_at":"2026-01-27 10:04:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":62082,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCumulative incidence of acute triptan prescriptions and migraine-related return visits during the 1-year follow-up, stratified by preventive treatment with botulinum toxin or CGRP mAbs. Curves were estimated using Kaplan–Meier methods, and HRs with 95% CIs were derived from Cox proportional hazards models. \u003c/strong\u003eCGRP, calcitonin gene-related peptide; mAbs, monoclonal antibodies; HR, hazard ratio; CI, confidence interval.\u003c/p\u003e\n\u003cp\u003e\u003cimg height=\"329\" 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09:56:25","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":76380,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier cumulative risk curves for time to migraine-related return visit in patients with chronic migraine treated with botulinum toxin or CGRP mAbs. \u003c/strong\u003eCGRP, calcitonin gene-related peptide; mAbs, monoclonal antibodies; HR, hazard ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/09ee487cee3ca0c1c38fdb05.png"},{"id":101206463,"identity":"ebe4f4f0-1b73-4230-821f-5346020451ad","added_by":"auto","created_at":"2026-01-27 09:56:16","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":61453,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIncidence of acute triptan prescriptions and migraine-related return visits in the expanded cohort including patients with headache symptoms (\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eICD-10-CM\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e code R51), stratified by preventive treatment with botulinum toxin or CGRP mAbs. \u003c/strong\u003eCGRP, calcitonin gene-related peptide; mAbs, monoclonal antibodies; HR, hazard ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/6963663a2e0d1775467aba67.png"},{"id":101170351,"identity":"6f5961e3-2c8a-4fcf-afa8-1869602a6265","added_by":"auto","created_at":"2026-01-27 00:02:22","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":68126,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier cumulative risk curves for time to first acute triptan prescription in the expanded headache cohort (\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eICD-10-CM\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003ecode R51). \u003c/strong\u003eCGRP, calcitonin gene-related peptide; mAbs, monoclonal antibodies.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/b008a905615e494649326c5f.png"},{"id":101170352,"identity":"d0838b67-ae5f-4a96-b9dc-9024695a0068","added_by":"auto","created_at":"2026-01-27 00:02:22","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":76161,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier cumulative risk curves for migraine-related return visits in the expanded headache cohort (\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eICD-10-CM\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e code R51). \u003c/strong\u003eCGRP, calcitonin gene-related peptide; mAbs, monoclonal antibodies.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/dd8b322c00d1a448936ef6f8.png"},{"id":101170358,"identity":"39b23aee-6934-4af4-b692-40176828a047","added_by":"auto","created_at":"2026-01-27 00:02:22","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":173566,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubgroup analyses of the association between preventive treatment (botulinum toxin vs. CGRP mAbs) and the risk of acute triptan prescriptions. Forest plots display HRs with 95% CIs across strata defined by age, sex, and major comorbidities. \u003c/strong\u003eCGRP, calcitonin gene-related peptide; mAbs, monoclonal antibodies; HR, hazard ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/3218ec8c3cab92642836ac16.png"},{"id":101170356,"identity":"0724b8a8-f32b-4bbf-89f0-a8f900bb1428","added_by":"auto","created_at":"2026-01-27 00:02:22","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":186056,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubgroup analyses of the association between preventive treatment (botulinum toxin versus CGRP mAbs) and the risk of migraine-related return visits. Treatment effects were broadly consistent across predefined subgroups.\u003c/strong\u003e CGRP, calcitonin gene-related peptide; mAbs, monoclonal antibodies; HR, hazard ratio; CI, confidence interval.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/2a588d6fd53d05687774a919.png"},{"id":104779978,"identity":"a030408e-b132-4a82-aa55-044d4d1c4ecc","added_by":"auto","created_at":"2026-03-17 07:48:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2515603,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/a9b6076c-57d1-43b3-84dd-7788fb605038.pdf"},{"id":101170349,"identity":"3cf7ff93-79ca-4dad-a71f-d726b9904148","added_by":"auto","created_at":"2026-01-27 00:02:22","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23674,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8506523/v1/af398e76e2b29cbeb3ddb84f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of Botulinum Toxin Versus CGRP Monoclonal Antibodies on Return Visits and Acute Medication Use in Chronic Migraine: First Real-World, Multicenter, Head-to-Head Analysis Using TriNetX","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic migraine is a prevalent and disabling neurological disorder that substantially impairs patients’ quality of life and imposes a substantial burden on health-care resources [1]. Preventive treatment strategies primarily include the administration of botulinum toxin type A and monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway [2]. Both therapies have demonstrated efficacy in reducing migraine frequency; however, their direct comparative effects on clinical outcomes, including headache recurrence, health-care utilization, and acute medication use, remain insufficiently clarified in large real-world populations.\u003c/p\u003e\n\u003cp\u003eA systematic review and meta-analysis demonstrated that both botulinum toxin and CGRP mAbs substantially reduced headache days and exhibited favorable safety profiles [3]. Recent large-scale real-world observational studies, including the pan-European PEARL study examining fremanezumab, a CGRP monoclonal antibody, reported substantial reductions in monthly migraine days and acute medication use, along with good tolerability over 6 months of treatment [4]. However, variations in patient responses and differences in cost-effectiveness underscore the need for head-to-head comparisons between preventive therapies [5, 6]. Emerging real-world evidence also reveals potential benefits of combining botulinum toxin with CGRP antagonists, indicating the possibility of synergistic effects [7–9].\u003c/p\u003e\n\u003cp\u003ePatient-centered indicators such as the frequency of return visits and use of acute pain medications, particularly nonsteroidal anti-inflammatory drugs and triptans, are crucial indirect measures of preventive treatment effectiveness and health-care resource utilization. These indicators are emphasized in both Taiwanese headache society guidelines and international studies [10–12]. However, large-scale comparative data on these outcomes in botulinum toxin versus CGRP mAb users are lacking.\u003c/p\u003e\n\u003cp\u003eTo address the aforementioned gaps, the present study used the TriNetX US Collaborative Network—a subset of the global TriNetX health-care database comprising approximately 70 health-care organizations, which predominantly represent the United States (80%), with limited European and Asian representation [13, 14]—to conduct the first large-scale, multicenter, head-to-head comparison of real-world outcomes in propensity score–matched cohorts of chronic migraine patients receiving botulinum toxin versus CGRP mAbs. We conducted binary time-to-event analyses over a 1-year follow-up period to examine migraine-related return visits and acute triptan prescriptions in order to determine differences in health-care utilization patterns between these preventive therapies. Despite inherent limitations in the availability of detailed dosing and visit-level information, these real-world data address critical evidence gaps and inform phenotype-driven preventive treatment selection and health-care resource allocation in migraine management.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design, Participants, and Data Collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective cohort study used deidentified patient data collected from the TriNetX global health-care research network, which aggregates electronic health records from several health-care organizations worldwide and supports large-scale population-based analyses. The study period was from January 1, 2018, to December 31, 2024. This study was approved by the Taipei Medical University Joint Institutional Review Board (TMU-JIRB No: N202512042). Eligible participants were adults aged ≥18 years with a diagnosis of chronic migraine (\u003cem\u003eInternational Classification of Diseases, Tenth Revision, Clinical Modification\u003c/em\u003e [\u003cem\u003eICD-10-CM\u003c/em\u003e] codes G43, G43.7, G43.70, and G43.709). The study cohorts comprised patients who received botulinum toxin type A or CGRP mAbs (erenumab, fremanezumab, galcanezumab, or eptinezumab) and initiated treatment within 1 month after their initial migraine diagnosis. Patients who received both therapies within 1 month before or after the index date were excluded to prevent overlapping exposures. All data were fully anonymized, and the study adhered to applicable ethical and privacy regulations governing secondary use of deidentified data.\u003c/p\u003e\n\u003cp\u003eThis study used the TriNetX research network, which aggregates real-time electronic health records from participating health-care organizations. To ensure data authenticity and transparency, particularly for laboratory parameters such as body mass index and immunoglobulin E, the platform applies no imputation or deletion procedures; missing values are retained in their original state for analysis. TriNetX does not implement a formal definition of loss to follow-up; instead, when no subsequent health-care encounters are recorded, the patient’s last documented visit is used as the endpoint of follow-up. All data undergo strict deidentification in accordance with the Health Insurance Portability and Accountability Act and the General Data Protection Regulation. To protect patient privacy, cell counts representing fewer than 10 individuals are masked in the reported results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExposure and Outcome Definitions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExposure cohorts were defined using prescription records. The botulinum toxin cohort was identified using RxNorm code 1712, and the CGRP mAb cohort was identified using the corresponding RxNorm codes.\u003c/p\u003e\n\u003cp\u003eThe primary outcomes were defined as binary events occurring during the follow-up period: (1) migraine recurrence (return visit), identified by the presence of a subsequent diagnostic record for migraine (\u003cem\u003eICD-10-CM\u003c/em\u003e code G43) in the electronic health records, including outpatient, emergency department, or inpatient encounters; and (2) acute medication use, defined as the prescription of any triptan-class medication (identified using RxNorm codes; e.g., sumatriptan or rizatriptan).\u003c/p\u003e\n\u003cp\u003eBecause of the inherent limitations of the TriNetX platform in capturing the precise dosage, days of supply, or cumulative prescription counts, acute medication use was analyzed as a time-to-event outcome, defined as the time to the first recorded triptan prescription, rather than as a quantitative measure of total medication consumption.\u003c/p\u003e\n\u003cp\u003eWe conducted sensitivity analyses by expanding the diagnostic definition to include all headache-related codes (\u003cem\u003eICD-10-CM\u003c/em\u003e code R51) and examining the robustness of the findings across key subgroups stratified by age, sex, and comorbidities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCovariates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe adjusted for covariates such as demographic variables (age, sex, and race), lifestyle characteristics (nicotine dependence, tobacco use, and alcohol-related disorders), comorbidities (including, but not limited to, hypertension, diabetes, sleep disorders, depression, and anxiety), health-care utilization measures (outpatient visits, emergency department visits, and inpatient admissions), concurrent medication use (opioids, psychoanaleptics, and glucocorticoids), and laboratory values (C-reactive protein, hemoglobin, and estimated glomerular filtration rate).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePropensity score matching was conducted using a 1:1 nearest-neighbor algorithm without replacement to balance covariates across cohorts. Covariate balance was examined using standardized mean differences, with values \u0026lt;0.1 indicating acceptable balance. Kaplan–Meier survival analyses were performed to estimate the cumulative incidence of the outcomes. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) between the treatment groups. A two-sided p value of \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity and Subgroup Analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted sensitivity analyses by expanding the diagnostic definition of migraine to include headache symptoms (\u003cem\u003eICD-10-CM\u003c/em\u003e code R51) and evaluating the robustness of the findings. Subgroup analyses were conducted to investigate treatment effects across groups stratified by age, sex, and key comorbidities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Taipei Medical University Joint Institutional Review Board (TMU-JIRB No: N202512042), and all data used were fully deidentified and aggregated.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCohort Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 29,938 patients with chronic migraine were identified in the TriNetX database after the application of the eligibility criteria (Figure 1). After propensity score matching to balance baseline characteristics, each treatment cohort (botulinum toxin or CGRP mAb cohort) comprised 10,140 patients. Table 1 presents a summary of the baseline demographic, clinical, and comorbidity characteristics of the matched cohorts. Both cohorts were well balanced in terms of age, sex, race, comorbidities, and key clinical parameters, with standardized mean differences of \u0026lt;0.1 for all covariates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcute Triptan Prescription Risk\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of receiving an acute triptan prescription within 1 year after the index treatment was significantly higher in the CGRP mAb cohort than in the botulinum toxin cohort. In the primary time-to-event analysis, the risk of receiving an acute triptan prescription was significantly lower in the botulinum toxin cohort than in the CGRP mAb cohort (HR: 0.513, 95% CI: 0.481\u0026ndash;0.546; Figure 2). This finding was consistent across complementary analytical approaches, including Kaplan\u0026ndash;Meier survival analyses and cumulative incidence estimates, which confirmed clear between-group differences (Figure 3).\u003c/p\u003e\n\u003cp\u003eFigure 3 displays the cumulative incidence of acute triptan prescriptions over a 3-year follow-up period among patients initiating CGRP mAbs or botulinum toxin. The CGRP mAb cohort had a consistently higher cumulative incidence, with the survival curves diverging early after the index date and remaining separated over time. By contrast, the botulinum toxin cohort exhibited a lower and more gradual increase in cumulative incidence. The log-rank test confirmed that these differences were statistically significant (p \u0026lt; 0.001), indicating that the CGRP mAb cohort required acute triptans more frequently than did the botulinum toxin cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of Migraine-Related Health-Care Visits\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the primary analysis, no statistically significant difference in the risk of migraine-related return visits was observed between the botulinum toxin and CGRP mAb cohorts (HR: 1.008, 95% CI: 0.977\u0026ndash;1.039; p \u0026gt; 0.05). Kaplan\u0026ndash;Meier curves revealed similar trajectories for both groups, characterized by a sharp increase in cumulative incidence during the initial months, followed by gradual plateauing with minimal divergence throughout the 1-year follow-up period (Figure 4). The CI closely centered around unity, indicating comparable rates of migraine-related health-care encounters between the two preventive treatments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo evaluate the robustness of our primary findings, we conducted a sensitivity analysis by expanding the migraine cohort to include patients with broader headache diagnoses defined by \u003cem\u003eICD-10-CM\u003c/em\u003e code R51. This enabled us to examine whether the inclusion of headache symptoms beyond strict chronic migraine criteria affected the observed outcomes.\u003c/p\u003e\n\u003cp\u003eThe results revealed that in the expanded cohort, patients treated with botulinum toxin continued to exhibit a significantly lower risk of receiving an acute triptan prescription than did those treated with CGRP mAbs (HR: 0.437, 95% CI: 0.409\u0026ndash;0.467; p \u0026lt; 0.01). Additionally, the risk of migraine-related return visits was significantly lower among patients treated with botulinum toxin than those treated with CGRP mAbs, suggesting a higher recurrence or breakthrough headache burden in the CGRP mAb cohort (HR: 0.741, 95% CI: 0.717\u0026ndash;0.766; p \u0026lt; 0.01; Figure 5).\u003c/p\u003e\n\u003cp\u003eKaplan\u0026ndash;Meier survival curves for time to first acute triptan prescription under the expanded diagnostic criteria were also consistent with the findings of our primary analyses, supporting the observation that patients treated with CGRP mAbs more frequently required acute medication despite receiving preventive therapy (Figure 6).\u003c/p\u003e\n\u003cp\u003eIn contrast to the primary cohort, in which migraine-related return visits were comparable between the treatment cohorts, the Kaplan\u0026ndash;Meier curves in the expanded cohort revealed a significant increase in migraine-related return visits among patients treated with CGRP mAbs compared with those treated with botulinum toxin. This increase may reflect the inclusion of less strictly defined headache cases in the expanded cohort and highlight potential differences in real-world effectiveness across a broader patient population (Figure 7).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup Analyses of Preventive Treatment: Botulinum Toxin Versus CGRP mAbs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe performed subgroup analyses (Figure 8) to examine acute triptan prescription risk across demographic, clinical, and lifestyle strata in patients treated with botulinum toxin or CGRP mAbs. In the propensity score\u0026ndash;matched cohort, the risk of receiving an acute triptan prescription was lower in the botulinum toxin cohort than in the CGRP mAb cohort (HR: 0.513, 95% CI: 0.481\u0026ndash;0.546; p \u0026lt; 0.001). This difference was consistent across the male (HR: 0.491, 95% CI: 0.417\u0026ndash;0.579; p \u0026lt; 0.001) and female (HR: 0.517, 95% CI: 0.483\u0026ndash;0.555; p \u0026lt; 0.001) subgroups and across the age subgroups. Specifically, this risk was lower in individuals aged 20\u0026ndash;64 years (HR: 0.530, 95% CI: 0.495\u0026ndash;0.566; p \u0026lt; 0.001), with a more pronounced reduction observed in those aged \u0026ge;65 years (HR: 0.392, 95% CI: 0.315\u0026ndash;0.488; p \u0026lt; 0.001). In the racial subgroup analyses, botulinum toxin treatment was associated with a significantly lower triptan prescription risk in the White subgroup (HR: 0.484, 95% CI: 0.450\u0026ndash;0.520; p \u0026lt; 0.001), with similar directional trends observed in the Black/African American and Asian subgroups; however, CIs were wider in these groups due to smaller sample sizes.\u003c/p\u003e\n\u003cp\u003eComorbidity subgroup analyses also demonstrated that botulinum toxin treatment was associated with a significantly reduced risk of acute triptan prescription in patients with hypertension (HR: 0.543, 95% CI: 0.455\u0026ndash;0.648; p \u0026lt; 0.001) and diabetes mellitus (HR: 0.579, 95% CI: 0.403\u0026ndash;0.781; p \u0026lt; 0.001). Similarly, lifestyle subgroup analysis results revealed that botulinum toxin treatment was associated with reduced triptan prescription risk among smokers (HR: 0.657, 95% CI: 0.478\u0026ndash;0.905; p \u0026lt; 0.05); however, results for alcohol-related disorders were limited and inconclusive.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup Analyses of Migraine-Related Return Visits\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted prespecified subgroup analyses to evaluate whether the comparative effectiveness of botulinum toxin type A versus CGRP mAbs regarding migraine-related return visits varied by demographic and clinical factors (Figure 9). Overall, the 1-year risk of migraine-related return visits remained comparable between CGRP mAb and botulinum toxin users (HR: 1.008, 95% CI: 0.977\u0026ndash;1.039). Sex did not modify this effect, with similar HRs observed in men (HR: 1.012, 95% CI: 0.942\u0026ndash;1.086) and women (HR: 1.014, 95% CI: 0.980\u0026ndash;1.048).\u003c/p\u003e\n\u003cp\u003eAge significantly moderated the outcomes. CGRP mAb therapy was associated with a higher risk of migraine-related return visits in adults aged 20\u0026ndash;64 years (HR: 1.048, 95% CI: 1.013\u0026ndash;1.083) but a lower risk in those aged \u0026ge;65 years (HR: 0.893, 95% CI: 0.825\u0026ndash;0.966), indicating age-specific benefits. Racial subgroups displayed no significant differences favoring either treatment. Among lifestyle factors, smoking yielded a nonsignificant HR (0.911, 95% CI: 0.793\u0026ndash;1.048), whereas alcohol-related disorders exhibited a trend toward lower return visit risk with CGRP mAbs (HR: 0.761, 95% CI: 0.523\u0026ndash;1.107). However, this finding was constrained by limited sample size.\u003c/p\u003e\n\u003cp\u003eComorbidity subgroup analyses revealed notable heterogeneity across conditions. Hypertension was associated with reduced migraine-related return visit risk among CGRP mAb users (HR: 0.862, 95% CI: 0.801\u0026ndash;0.927), whereas no significant difference was observed in patients with diabetes mellitus (HR: 0.918, 95% CI: 0.817\u0026ndash;1.031), suggesting a superior response of CGRP mAbs in cardiovascular phenotypes. Collectively, these results demonstrate equivalent overall effects but highlight improved outcomes with CGRP mAbs in older patients and those with hypertension, whereas younger adults may benefit more from botulinum toxin, emphasizing phenotype-driven therapy personalization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSummary of Findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBotulinum toxin was associated with a significantly lower risk of receiving an acute triptan prescription (HR: 0.513, 95% CI: 0.481\u0026ndash;0.546) compared with CGRP mAbs across matched chronic migraine cohorts, although migraine-related return visit rates were equivalent between the cohorts (HR: 1.008, 95% CI: 0.977\u0026ndash;1.039). This difference in triptan prescription risk persisted in sensitivity analyses incorporating broader headache diagnoses and across subgroup analyses stratified by age, sex, and comorbidities. Together, these findings reveal mechanistic differences that support phenotype-driven preventive therapy selection to optimize acute medication control.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cstrong\u003eClinical Implications and Comparison With the Literature\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients treated with CGRP mAbs exhibited significantly higher acute triptan requirements after the initiation of preventive therapy, despite having migraine-related return visit risks comparable to those of patients treated with botulinum toxin.\u003c/p\u003e\n\u003cp\u003eThe present study also confirmed that CGRP mAbs were associated with a higher risk of acute triptan use. This finding is consistent with those of the RAMO study [15], which reported reductions in Headache Impact and Allodynia scores with both CGRP mAbs and botulinum toxin, thereby addressing a gap in real-world head-to-head evidence. Previous clinical trials and real-world studies have primarily evaluated preventive efficacy by using reductions in headache days or patient-reported disability measures, yielding inconsistent signals of superiority across treatments [3, 5, 6]. However, few studies have examined acute triptan utilization as a definitive outcome, despite its direct relevance to acute migraine management and health-care resource planning. Moreover, previous meta-analyses have primarily focused on reductions in headache days or indirect treatment comparisons and have lacked direct real-world evidence on acute medication use and health-care utilization [3, 5, 20]. By contrast, the present TriNetX-based study directly evaluated acute triptan prescription risk and migraine-related return visits and applied propensity score matching to enhance comparability between the treatment cohorts, thereby addressing a crucial gap in the literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNovel Contribution: Direct Comparison of Return Visits and Acute Medication Use\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn addition to our primary analysis, we conducted sensitivity analyses by broadening the diagnostic definition of migraine to include headache symptoms (\u003cem\u003eICD-10-CM\u003c/em\u003e code R51). The results of this approach confirm a higher risk of acute triptan use in the CGRP mAb cohort and additionally identified an increased risk of migraine recurrence (\u003cem\u003eICD-10-CM\u003c/em\u003e G43). To our knowledge, this is the first real-world study to directly compare return visit rates and acute triptan prescriptions as dual endpoints in a head-to-head study. These outcomes have been infrequently examined in previous research, which has predominantly focused on reductions in headache days. Our findings provide more actionable endpoints that reflect both patient burden and health-care system impact.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMechanisms and Clinical Applications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe higher acute triptan use observed among patients treated with CGRP mAbs likely reflects incomplete preventive efficacy or the occurrence of breakthrough attacks caused by non-CGRP triggers. CGRP mAbs target a single pathway by blocking the CGRP ligand or receptor, which reduces migraine frequency but may result in a persistent need for residual acute treatment [5, 15–18]. By contrast, botulinum toxin type A inhibits acetylcholine and multiple neuropeptides (CGRP, substance P, and glutamate), providing broader control of peripheral and central sensitization and reducing severe breakthrough attacks [3, 19, 20].\u003c/p\u003e\n\u003cp\u003eCGRP mAbs block peripheral CGRP signaling, whereas botulinum toxin inhibits multiple neuropeptides at the trigeminal ganglia [3, 15, 19, 21]. We observed that both therapies equivalently reduced the risk of migraine-related return visits (HR: 1.008), whereas botulinum toxin was associated with a lower risk of acute triptan prescription (HR: 0.513) across most subgroups (Figure 2). The age- and comorbidity-related heterogeneity observed in return visit risk (Figure 9) supports a phenotype-driven approach to therapy selection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComorbidity-Specific Insights\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the hypertension and diabetes subgroups, botulinum toxin reduced the risk of acute triptan prescription, likely due to its multitarget inhibition of neuropeptides (CGRP, substance P, and glutamate), mitigating sensitization and vascular or inflammatory effects in patients with comorbidities [22-24]. However, when compared with botulinum toxin, CGRP mAbs reduced the risk of migraine-related return visits in patients with hypertension (HR: 0.862, 95% CI: 0.801–0.927) but not in those with diabetes (HR: 0.918, 95% CI: 0.817–1.031). These findings indicate a clinical trade-off, with botulinum toxin offering advantages for acute medication control in patients with comorbidities and CGRP mAbs providing potential benefits for reducing health-care utilization in patients with hypertension.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAge-Related Heterogeneity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubgroup analyses revealed age-dependent treatment effects. CGRP mAbs were associated with higher migraine-related return visit rates in younger adults aged 20–64 years (HR: 1.048, 95% CI 1.013–1.083) but lower return visit rates in older adults aged ≥65 years (HR: 0.893, 95% CI: 0.825–0.966). By contrast, botulinum toxin was associated with a more pronounced reduction in acute triptan prescription risk among older adults (HR: 0.392, 95% CI: 0.315–0.488; Figure 9).\u003c/p\u003e\n\u003cp\u003ePrevious real-world studies have reported robust efficacy of botulinum toxin in adolescents and young adults (aged 13–21 years), with a ≥50% reduction in symptoms observed in up to 69% of severe cases [25–27]. In comparison, CGRP mAbs have demonstrated consistent efficacy in midlife adults, with mean ages typically ranging from 40 to 50 years; however, data in older populations remain limited, indicating the need for age-stratified analyses [28–30]. Direct age-based head-to-head comparisons between these therapies remain scarce.\u003c/p\u003e\n\u003cp\u003eAge-related declines in baseline CGRP and substance P levels in trigeminal neurons [31] may render residual CGRP signaling more critical for migraine generation among older adults, thereby enhancing the relative effectiveness of CGRP mAb therapy. By contrast, younger patients with more active multineuropeptide signaling pathways may derive greater benefit from the broad-spectrum inhibitory effects of botulinum toxin. Collectively, these findings support age-stratified, phenotype-driven personalization of preventive migraine therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdvantages of Real-World, Multicenter, Big Data Analysis Using TriNetX\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur use of the TriNetX global research platform enabled access to a large, diverse, multiethnic patient population across multiple health-care systems, thereby enhancing the external validity of our findings. This approach helped us overcome the sample size and population spectrum limitations typical of single-center studies and helped improve the generalizability of our findings to real-world clinical practice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations and Future Directions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has several limitations that should be acknowledged. First, the TriNetX database primarily includes data from specific health-care systems, which may limit the generalizability of the findings across different ethnic, socioeconomic, and health-care system contexts [13, 21]. Second, the small sample sizes in subgroups with rare comorbidities or headache types restricted our ability to draw robust conclusions for these populations. Third, the reliance on administrative coding and prescription records may have introduced misclassification bias, particularly in cases receiving care outside the contributing networks. Fourth, the retrospective study design and limited follow-up duration precluded assessments of long-term safety, disease progression, and patient-reported outcomes, such as migraine severity and quality of life, which are central to headache research [32]. Finally, although TriNetX offers access to a large and diverse dataset, its predominantly US-based representation necessitates caution when extrapolating the findings to global populations [13, 21].\u003c/p\u003e\n\u003cp\u003eFuture research should incorporate prospective trials and pragmatic cohort studies to validate these findings, clarify mechanisms underlying differential treatment responses, and evaluate long-term outcomes across diverse patient populations. In particular, prospective studies focused on high-risk subgroups, such as patients with medication-overuse headache or refractory migraine, are warranted because these populations are underrepresented in existing trials despite having a disproportionate disease burden [33]. Generating robust evidence in these populations is essential for optimizing clinical management strategies and informing health policy decisions [34, 35]. In addition, future clinical research and policy initiatives should prioritize patient-centered approaches for individuals with high acute medication requirements or complex comorbidities to more effectively address their specific clinical needs.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis multicenter real-world study provides the first direct head-to-head comparison of botulinum toxin versus CGRP mAbs in chronic migraine, demonstrating a lower risk of acute triptan prescription with botulinum toxin (HR: 0.513, 95% CI: 0.481\u0026ndash;0.546) and comparable migraine-related return visit rates between the two treatments (HR: 1.008, 95% CI: 0.977\u0026ndash;1.039). Subgroup analyses suggested that CGRP mAbs were preferable for older adults aged \u0026ge;65 years (return visit HR: 0.893) and for patients with hypertension (HR: 0.862), whereas botulinum toxin exhibited an advantage in acute medication control across most examined strata. These comparative findings, derived from propensity score\u0026ndash;matched cohorts, should be interpreted in the context of the retrospective study design, and prospective studies are required for validation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available from TriNetX; however, restrictions apply to the availability of these data, which were used under license for the current study and are not publicly available. The data may be made available from the authors upon reasonable request and with permission from TriNetX.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Taipei Medical University Joint Institutional Review Board (Approval No. N202512042). Due to the retrospective nature and use of deidentified data, the requirement for informed consent was waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChun-Fu Lin:\u003c/strong\u003e conceptualization, study design, manuscript drafting, and overall project coordination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHung-En Huang:\u0026nbsp;\u003c/strong\u003eprimary data analysis, including TriNetX data processing, propensity score matching, Kaplan–Meier curve generation, and hazard ratio calculations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJames Cheng-Chung Wei:\u003c/strong\u003e methodology, analytical supervision, figure/table review, and leadership of intellectual contributions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHsun-Hua Lee:\u0026nbsp;\u003c/strong\u003esupervision, correspondence, and critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eChen-Chih Chung, Jia-Hung Chen, Nai-Fang Chi, Chaur-Jong Hu, Chih-Chung Chen, Tu-Hsueh Yeh:\u003c/strong\u003e critical revision of the manuscript for intellectual content.\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript was edited by Wallace Academic Editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGBD 2021 Nervous System Disorders Collaborators. Global, regional, and national burden of disorders affecting the nervous system, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024 Apr;23(4):344-381. doi: 10.1016/S1474-4422(24)00038-3. Epub 2024 Mar 14. Erratum in: Lancet Neurol. 2024 May;23(5):e9. doi: 10.1016/S1474-4422(24)00114-5. Erratum in: Lancet Neurol. 2024 Jul;23(7):e11. doi: 10.1016/S1474-4422(24)00231-X. PMID: 38493795; PMCID: PMC10949203.\u003c/li\u003e\n\u003cli\u003eKung D, Rodriguez G, Evans R. Chronic Migraine: Diagnosis and Management. Neurol Clin. 2023 Feb;41(1):141-159. doi: 10.1016/j.ncl.2022.05.005. Epub 2022 Oct 31. PMID: 36400552.\u003c/li\u003e\n\u003cli\u003eLu J, Zhang Q, Guo X, Liu W, Xu C, Hu X, Ni J, Lu H, Zhao H. Calcitonin Gene-Related Peptide Monoclonal Antibody Versus Botulinum Toxin for the Preventive Treatment of Chronic Migraine: Evidence From Indirect Treatment Comparison. Front Pharmacol. 2021 May 3;12:631204. doi: 10.3389/fphar.2021.631204. PMID: 34012392; PMCID: PMC8126691.\u003c/li\u003e\n\u003cli\u003eAshina M, Mitsikostas DD, Amin FM, Kokturk P, Schankin CJ, Sahin G, Pozo-Rosich P, Dorman PJ, Než\u0026aacute;dal T, Poole AC, Martins IP, Sumelahti ML, Ramirez Campos V, Ahn AH, Lyras L, Tassorelli C. Real-world effectiveness of fremanezumab for the preventive treatment of migraine: Interim analysis of the pan-European, prospective, observational, phase 4 PEARL study. Cephalalgia. 2023 Nov;43(11):3331024231214987. doi: 10.1177/03331024231214987. PMID: 37987641.\u003c/li\u003e\n\u003cli\u003eMontisano DA, Giossi R, Canella M, Altamura C, Marcosano M, Vernieri F, Raggi A, Grazzi L. Reducing the Impact of Headache and Allodynia Score in Chronic Migraine: An Exploratory Analysis from the Real-World Effectiveness of Anti-CGRP Monoclonal Antibodies Compared to Onabotulinum Toxin A (RAMO) Study. Toxins (Basel). 2024 Apr 7;16(4):178. doi: 10.3390/toxins16040178. PMID: 38668603; PMCID: PMC11054793.\u003c/li\u003e\n\u003cli\u003eMohammad Alabdali M, Rafique N, AlDossary DA, Alalloush RS, AlHemli HA, Zeerak M, Latif R, Ibrahim Al-Asoom L, Abdulrahman AlSunni A, Mohammed Salem A, Alshurem M, Aljaafari D, Obaid S, Alabdulhadi A. Direct Comparison of Treatment Outcome Between the Botulinum Toxin and Calcitonin Gene-Related Peptide Monoclonal Antibody in Migraine Patients. J Clin Med Res. 2024 Dec;16(11):527-535. doi: 10.14740/jocmr6054. Epub 2024 Nov 30. PMID: 39635334; PMCID: PMC11614408.\u003c/li\u003e\n\u003cli\u003ePellesi L. Combining onabotulinumtoxin A with a CGRP antagonist for chronic migraine prophylaxis: where do we stand? Front Pain Res (Lausanne). 2023 Oct 27;4:1292994. doi: 10.3389/fpain.2023.1292994. PMID: 37965209; PMCID: PMC10641512.\u003c/li\u003e\n\u003cli\u003eCorasaniti MT, Lawrence GW, Bagetta G, Iannacchero R, Tarsitano A, Monteleone A, Pagliaro M, Tonin P, Sandrini G, Nicotera P, Scuteri D. Combination of anti-CGRP/CGRP-R mAbs with onabotulinumtoxin A as a novel therapeutic approach for refractory chronic migraine: a retrospective study of real-world clinical evidence and a protocol for a double-blind, randomized clinical trial to establish the efficacy and safety. Front Pharmacol. 2023 Dec 13;14:1296577. doi: 10.3389/fphar.2023.1296577. PMID: 38152694; PMCID: PMC10751376.\u003c/li\u003e\n\u003cli\u003eSalim A, Hennessy E, Sonneborn C, Hogue O, Biswas S, Mays M, Suneja A, Ahmed Z, Mata IF. Synergism of Anti-CGRP Monoclonal Antibodies and OnabotulinumtoxinA in the Treatment of Chronic Migraine: A Real-World Retrospective Chart Review. CNS Drugs. 2024 Jun;38(6):481-491. doi: 10.1007/s40263-024-01086-z. Epub 2024 Apr 7. PMID: 38583127; PMCID: PMC11098928.\u003c/li\u003e\n\u003cli\u003eWu JW, Yang CP; Treatment Guideline Subcommittee of the Taiwan Headache Society. 2022 Taiwan Guidelines for Preventive Treatment of Migraine. Acta Neurol Taiwan. 2022 Sep 30;31(3):164-202. PMID: 36089629.\u003c/li\u003e\n\u003cli\u003eAguilar-Shea AL, Membrilla Md JA, Diaz-de-Teran J. Migraine review for general practice. Aten Primaria. 2022 Feb;54(2):102208. doi: 10.1016/j.aprim.2021.102208. Epub 2021 Nov 16. PMID: 34798397; PMCID: PMC8605054.\u003c/li\u003e\n\u003cli\u003eTzankova V, Becker WJ, Chan TLH. Pharmacologic prevention of migraine. CMAJ. 2023 Feb 6;195(5):E187-E192. doi: 10.1503/cmaj.221607. PMID: 36746481; PMCID: PMC9904820.\u003c/li\u003e\n\u003cli\u003eLudwig RJ, Anson M, Zirpel H, Thaci D, Olbrich H, Bieber K, Kridin K, Dempfle A, Curman P, Zhao SS, Alam U. A comprehensive review of methodologies and application to use the real-world data and analytics platform TriNetX. Front Pharmacol. 2025 Mar 10;16:1516126. doi: 10.3389/fphar.2025.1516126. PMID: 40129946; PMCID: PMC11931024.\u003c/li\u003e\n\u003cli\u003eLin TL, Fan YH, Fan KS, Juan CK, Chen YJ, Wu CY. Reduced atopic march risk in pediatric atopic dermatitis patients prescribed dupilumab versus conventional immunomodulatory therapy: A population-based cohort study. J Am Acad Dermatol. 2024 Sep;91(3):466-473. doi: 10.1016/j.jaad.2024.05.029. Epub 2024 Jun 14. PMID: 38878041.\u003c/li\u003e\n\u003cli\u003eGrazzi L, Giossi R, Montisano DA, Canella M, Marcosano M, Altamura C, Vernieri F. Real-world effectiveness of Anti-CGRP monoclonal antibodies compared to OnabotulinumtoxinA (RAMO) in chronic migraine: a retrospective, observational, multicenter, cohort study. J Headache Pain. 2024 Feb 2;25(1):14. doi: 10.1186/s10194-024-01721-6. PMID: 38308209; PMCID: PMC10836018.\u003c/li\u003e\n\u003cli\u003eSiddiqui M, Shah PV, Balani P, Lopez AR, Nobleza CMN, Khan S. Comparing the Efficacy, Safety, and Superiority of Calcitonin Gene-Related Peptide Monoclonal Antibodies and Botox in Preventing and Treating Migraines. Cureus. 2021 Jan 30;13(1):e13002. doi: 10.7759/cureus.13002. Erratum in: Cureus. 2021 Feb 12;13(2):c41. doi: 10.7759/cureus.c41. PMID: 33542885; PMCID: PMC7847775.\u003c/li\u003e\n\u003cli\u003eBlumenfeld AM, Kaur G, Mahajan A, Shukla H, Sommer K, Tung A, Knievel KL. Effectiveness and Safety of Chronic Migraine Preventive Treatments: A Systematic Literature Review. Pain Ther. 2023 Feb;12(1):251-274. doi: 10.1007/s40122-022-00452-3. Epub 2022 Nov 22. PMID: 36417165; PMCID: PMC9845441.\u003c/li\u003e\n\u003cli\u003ePallapothu MR, Quintana Mari\u0026ntilde;ez MG, Chakkera M, Ravi N, Ramaraju R, Vats A, Nair AR, Bandhu AK, Koirala D, Mohammed L. Long-Term Management of Migraine With OnabotulinumtoxinA (Botox) vs Calcitonin Gene-Related Peptide Antibodies (Anti-CGRP). Cureus. 2023 Oct 8;15(10):e46696. doi: 10.7759/cureus.46696. PMID: 38021691; PMCID: PMC10630153.\u003c/li\u003e\n\u003cli\u003eGooriah R, Ahmed F. OnabotulinumtoxinA for chronic migraine: a critical appraisal. Ther Clin Risk Manag. 2015 Jun 29;11:1003-13. doi: 10.2147/TCRM.S76964. PMID: 26170679; PMCID: PMC4492656.\u003c/li\u003e\n\u003cli\u003eFrank F, Ulmer H, Sidoroff V, Broessner G. CGRP-antibodies, topiramate and botulinum toxin type A in episodic and chronic migraine: A systematic review and meta-analysis. Cephalalgia. 2021 Oct;41(11-12):1222-1239. doi: 10.1177/03331024211018137. Epub 2021 Jun 15. PMID: 34130525; PMCID: PMC8506070.\u003c/li\u003e\n\u003cli\u003ePellesi L. Editorial: Novel migraine therapies: consolidating evidence from the real world. Front Pain Res (Lausanne). 2023 Dec 5;4:1340268. doi: 10.3389/fpain.2023.1340268. PMID: 38116186; PMCID: PMC10728816.\u003c/li\u003e\n\u003cli\u003eDurham PL, Cady R. Insights into the mechanism of onabotulinumtoxinA in chronic migraine. Headache. 2011 Nov-Dec;51(10):1573-7. doi: 10.1111/j.1526-4610.2011.02022.x. PMID: 22082429; PMCID: PMC3306767.\u003c/li\u003e\n\u003cli\u003eRamachandran R, Yaksh TL. Therapeutic use of botulinum toxin in migraine: mechanisms of action. Br J Pharmacol. 2014 Sep;171(18):4177-92. doi: 10.1111/bph.12763. PMID: 24819339; PMCID: PMC4241086.\u003c/li\u003e\n\u003cli\u003eBurstein R, Blumenfeld AM, Silberstein SD, Manack Adams A, Brin MF. Mechanism of Action of OnabotulinumtoxinA in Chronic Migraine: A Narrative Review. Headache. 2020 Jul;60(7):1259-1272. doi: 10.1111/head.13849. Epub 2020 Jun 30. PMID: 32602955; PMCID: PMC7496564.\u003c/li\u003e\n\u003cli\u003eGoenka A, Grace Yu S, Chikkannaiah M, George MC, MacDonald S, Stolfi A, Kumar G. Generalized Anxiety Disorder: A Predictor for Poor Responsiveness to Botulinum Toxin Type A Therapy for Pediatric Migraine. Pediatr Neurol. 2022 May;130:21-27. doi: 10.1016/j.pediatrneurol.2022.02.002. Epub 2022 Mar 4. PMID: 35305510.\u003c/li\u003e\n\u003cli\u003eHorvat DE, Shields JM, Young WWC, Eye PG. Botulinum Toxin for Pediatric Migraine: A Retrospective Multisite Cohort Study. Pediatr Neurol. 2023 Oct;147:68-71. doi: 10.1016/j.pediatrneurol.2023.07.005. Epub 2023 Jul 13. PMID: 37562172.\u003c/li\u003e\n\u003cli\u003eG\u0026oacute;mez-Dab\u0026oacute; L, Caronna E, Mas-de-Les-Valls R, Gallardo VJ, Alpuente A, Torres-Ferrus M, Pozo-Rosich P. Effectiveness and Safety of OnabotulinumtoxinA in Adolescent Patients with Chronic Migraine. Toxins (Basel). 2024 May 11;16(5):221. doi: 10.3390/toxins16050221. PMID: 38787073; PMCID: PMC11126010.\u003c/li\u003e\n\u003cli\u003eRay JC, Dalic L, Baker J, Cheng S, Hutton EJ, Matharu M. Twelve-month efficacy of CGRP monoclonal antibodies and predictive value of short-term response: results of an Australian multicentre study. BMJ Neurol Open. 2024 Jan 10;6(1):e000547. doi: 10.1136/bmjno-2023-000547. PMID: 38268750; PMCID: PMC10806998.\u003c/li\u003e\n\u003cli\u003eWang YF, Yang FC, Chen LA, Chang TY, Su HC, Yang CP, Tu YH, Tzeng YS, Chen SP, Fuh JL, Lai KL, Ling YH, Chen WT, Wang SJ. Comparative effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies and onabotulinumtoxinA in chronic migraine: A multicenter, real-world study in Taiwan. Eur J Neurol. 2024 Sep;31(9):e16372. doi: 10.1111/ene.16372. Epub 2024 Jun 5. PMID: 38837528; PMCID: PMC11295178.\u003c/li\u003e\n\u003cli\u003eSalim A, Biswas S, Sonneborn C, Hogue O, Hennessy E, Mays M, Suneja A, Ahmed Z, Mata IF. Efficacy and Tolerability of Anti-CGRP Monoclonal Antibodies in Patients Aged \u0026ge; 65 Years With Daily or Nondaily Migraine. Neurol Clin Pract. 2025 Feb;15(1):e200373. doi: 10.1212/CPJ.0000000000200373. Epub 2024 Oct 8. PMID: 39399553; PMCID: PMC11464238.\u003c/li\u003e\n\u003cli\u003eFila M, Pawlowska E, Szczepanska J, Blasiak J. Different Aspects of Aging in Migraine. Aging Dis. 2023 Dec 1;14(6):2028-2050. doi: 10.14336/AD.2023.0313. PMID: 37199585; PMCID: PMC10676778.\u003c/li\u003e\n\u003cli\u003eOrlando B, Egeo G, Aurilia C, Fiorentini G, Barbanti P. Calcitonin Gene-Related Peptide Monoclonal Antibodies: Key Lessons from Real-World Evidence. Brain Sci. 2024 Sep 22;14(9):948. doi: 10.3390/brainsci14090948. PMID: 39335442; PMCID: PMC11429799.\u003c/li\u003e\n\u003cli\u003eWang X, Sun Y, Zhang Y, Zhi Z, Wang S, Li J, Sun Y, Sun Y. Research trends and hotspots in clinical trials of migraine in the past 20\u0026thinsp;years: bibliometric analysis. Front Neurol. 2024 Oct 25;15:1430138. doi: 10.3389/fneur.2024.1430138. PMID: 39524909; PMCID: PMC11543406.\u003c/li\u003e\n\u003cli\u003eBentivegna E, Galastri S, Onan D, Martelletti P. Unmet Needs in the Acute Treatment of Migraine. Adv Ther. 2024 Jan;41(1):1-13. doi: 10.1007/s12325-023-02650-7. Epub 2023 Nov 9. PMID: 37943442; PMCID: PMC10796525.\u003c/li\u003e\n\u003cli\u003eKatsuki M, Matsumori Y, Ichihara T, Yamada Y, Kaneko K, Kobayashi Y, Kawamura S, Kashiwagi K, Koh A, Goto T, Kaneko K, Wada N, Hanaoka Y, Yamagishi F. Treatment Patterns, Characteristics, and Probable Acute Medication Overprescription Among Patients With Migraine in Japan: A Retrospective Cross-Sectional and Longitudinal Analysis of Health Insurance Claims Data. Cureus. 2024 Dec 18;16(12):e75928. doi: 10.7759/cureus.75928. PMID: 39830552; PMCID: PMC11739997.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"chronic migraine, botulinum toxin, calcitonin gene-related peptide, monoclonal antibodies, drug therapy, triptan, medication adherence, medical visits, real-world evidence, propensity score matching","lastPublishedDoi":"10.21203/rs.3.rs-8506523/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8506523/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBotulinum toxin type A and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) are widely used preventive treatments for chronic migraine. However, real-world comparative evidence regarding their effects on health-care utilization and acute medication use remains lacking.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo directly compare the real-world effectiveness of botulinum toxin and CGRP mAbs in reducing migraine-related return visits and acute triptan medication prescription use among patients with chronic migraine across a large, multicenter cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective cohort analysis was conducted using data collected from the TriNetX global health-care database for the period from 2018 to 2024. Adults with a diagnosis of chronic migraine were assigned to botulinum toxin or CGRP mAb cohorts on the basis of prescription records. Propensity score matching was used to balance key demographic, clinical, and comorbidity variables between the cohorts. The primary outcomes were (1) migraine-related return visits and (2) acute triptan prescription risk within 1 year of treatment initiation. Sensitivity analyses were conducted by expanding diagnostic criteria to include broader headache codes (\u003cem\u003eInternational Classification of Diseases, Tenth Revision, Clinical Modification\u003c/em\u003e R51), and subgroup analyses were performed to examine outcome consistency across age, sex, and comorbidity strata.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter propensity score matching, each cohort comprised 10,140 patients. Botulinum toxin was associated with a significantly lower acute triptan prescription risk (hazard ratio: 0.513, 95% confidence interval: 0.481–0.546, p \u0026lt; 0.001), whereas migraine-related return visit rates were comparable between the cohorts. The increased triptan prescription risk observed in the CGRP mAb cohort persisted across sensitivity and subgroup analyses. In the expanded cohorts, higher migraine recurrence was observed among CGRP mAb users.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis multicenter real-world study demonstrated that botulinum toxin was associated with a superior reduction in acute triptan prescription risk compared with CGRP mAbs in patients with chronic migraine. These findings were robust across diverse subgroups and sensitivity analyses, supporting phenotype-driven preventive therapy selection to optimize acute medication control and health-care resource utilization.\u003c/p\u003e","manuscriptTitle":"Impact of Botulinum Toxin Versus CGRP Monoclonal Antibodies on Return Visits and Acute Medication Use in Chronic Migraine: First Real-World, Multicenter, Head-to-Head Analysis Using TriNetX","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-27 00:02:17","doi":"10.21203/rs.3.rs-8506523/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":"48bbdf7d-c98f-4d3c-b3b4-eac45fa5d329","owner":[],"postedDate":"January 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":61537014,"name":"Health sciences/Diseases"},{"id":61537015,"name":"Health sciences/Health care"},{"id":61537016,"name":"Health sciences/Medical research"},{"id":61537017,"name":"Health sciences/Neurology"}],"tags":[],"updatedAt":"2026-03-11T06:26:27+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-27 00:02:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8506523","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8506523","identity":"rs-8506523","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}