Trends in Older versus Newer Antiseizure Medications Consumption and Cost in 73 countries, 2012-2022

Trends in Older versus Newer Antiseizure Medications Consumption and Cost in 73 countries, 2012-2022 | 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 Trends in Older versus Newer Antiseizure Medications Consumption and Cost in 73 countries, 2012-2022 Cuiling Wei, Caige Huang, Vincent Ka Chun Yan, Rachel Yui Ki Chu, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7182416/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Background Epilepsy affects over 50 million people globally, with antiseizure medications (ASMs) as the main pharmacotherapies. Understanding disparities in ASM use and costs across income levels is critical to address inequities in epilepsy care and reduce its global burden. Objective To examine recent global and regional patterns and trends of ASM consumption and costs across high-, upper-middle-, and lower-middle-income countries (HICs, UMICs, LMICs). Methods We analyzed country-level pharmaceutical sales data from the IQVIA Multinational Integrated Data Analysis System (IQVIA-MIDAS) database spanning 73 countries, stratified by geographical regions (Africa, Asia, Europe, Latin America and the Caribbean, Northern America, Oceania), World Bank income levels (HICs, UMICs, LMICs) and ASM generations (older- and newer-generation). Drug consumption was measured using defined daily doses per 1000 inhabitants per day (DDDTID) and drug cost was calculated in USD and international dollars per DDD to account for differences in purchasing power parity (PPP). Results Global ASM consumption rose steadily from 3.10 to 3.95 DDDTID between 2012 and 2022 with a compound annual growth rate of 2.34%. Regionally, Northern America led with the highest consumption at 15.48 DDDTID in 2022, followed by Oceania at 11.19 and Europe at 8.73, whileAfrica lagged at 4.78 and Asia recorded the lowest at 1.98. HICs consumed more ASMs and transitioned to newer-generationASM by 2017, whereas MICs continued to rely heavily on older ASMs. Costs of older-generation ASMs remained low across all regions, while newer-generation ASMs showed significantly higher and more variable costs, especially when adjusted for purchasing power parity. Notably, the PPP-adjusted costs of newer-generation ASMs were substantially higher in UMICs than in HICs or LMICs. Conclusions Newer ASMs consumption has surpassed older ASMs in the mid-2010s in HICs, while UMICs and LMICs rely on older ASMs due to cost barriers. Global health policies must prioritize affordable access to newer ASMs in middle-income countries to enhance equity in epilepsy and broader neurological care. Health sciences/Health care/Public health Health sciences/Diseases/Neurological disorders/Epilepsy Health sciences/Health care/Therapeutics Figures Figure 1 Figure 2 Figure 3 Figure 4 Key points The global use of antiseizure medications has increased steadily, with high-income countries leading in both volume and diversity of consumption, while upper- and lower-middle-income countries have shown significant growth from lower starting levels. Newer antiseizure medication consumption has surpassed older-generation antiseizure medications in high-income countries since the mid-2010s, while upper- and lower-middle-income countries continue to rely on older ones, largely due to cost-related barriers. Introduction Epilepsy is a major neurological disorder that affects over 50 million individuals worldwide and accounts for 13.9 million disability-adjusted life years (DALYs) in 2021. 1 Given its similar underlying causes, shared diagnostic methods and treatments with other frequently co-occurring neurological conditions, epilepsy is widely considered as a key focus for addressing broader neurological health issues and their associated global health burden. 2 Antiseizure medicines (ASMs) are currently the first-line pharmacotherapy for epilepsy and are generally classified into older and newer generations based on their date of introduction, with older-generation ASMs (first- and second- generation) being developed before the 1990s and newer-generation ASMs (third-generation) introduced thereafter. 3 The efficacy of both older and newer generations of ASMs are well supported by solid clinical evidence. 4 Nevertheless, newer ASMs offer improved safety and tolerability over older ones, showing up to 20% fewer cases of acute side effects like drowsiness and severe cutaneous adverse drug reactions and reduced long-term risks such as cognitive impairment and bone density loss. 5,6 Moreover, newer-generation ASMs may have higher efficacy in specific epilepsy syndromes, including the management for Dravet syndrome. 7,8 These advantages contribute to better adherence and treatment outcomes, underscoring the importance of ensuring the availability and accessibility of newer ASMs to help reduce the global burden of epilepsy. The International League Against Epilepsy’s (ILAE) global ASM availability survey in 2022 reported notable disparities in ASM availability across different countries of various income levels. 9 Although older-generation ASMs such as carbamazepine and phenobarbital are included on the World Health Organization Model List of Essential Medicines (WHO EML) and are theoretically more affordable and accessible, 10,11 the global survey found that access to these medicines remains inconsistent in some middle-income countries (MICs), largely due to supply chain issues, regulatory obstacles, and pricing barriers. 9 Access to newer-generation ASMs like lamotrigine and levetiracetam are plausibly limited by greater access challenges in MICs and low-income countries (LICs) due to their higher cost, recency of marketing, and delays in medical guideline updates. Existing regional studies of ASM consumption, such as those conducted in the United States and Japan, 12,13 provided valuable insights into local challenges. However, they are limited to specific geographic areas and often rely on differing measures and data sources, which makes cross-country comparisons difficult and potentially misleading. To date, there is no comprehensive analysis and comparison of the accessibility or availability of older versus newer generations of ASMs from a global perspective. To address this knowledge gap, we used the IQVIA Multinational Integrated Data Analysis System (IQVIA-MIDAS) database, a standardized and longitudinal data source that captures pharmaceutical sales across a broad range of countries to investigate the current global patterns of ASM use and costs. A particular focus was placed on comparing the consumption and costs of older-generation ASMs with newer-generation ASMs in high- versus middle-income countries. Methods Data sources Global ASM sales data for this study was sourced from the IQVIA-MIDAS database, from January 1, 2012 up to December 31, 2022. This global database comprehensively captures pharmaceutical product sales to retail and hospital pharmacies, enabling standardized national sales audits. Data collection varies by country, primarily incorporating direct sales from manufacturers and wholesalers, supplemented by retail and hospital pharmacy data in some regions. With an 88% average coverage, MIDAS estimates total sales volume by adjusting for market share. Its data are internally validated and widely used for global medicine consumption patterns. 14 Since patient-level information was unavailable, institutional review board, approval was deemed not required for this study. Classification of ASMs The sales data on ASMs were extracted from the IQVIA-MIDAS database using Anatomical Therapeutic Chemical (ATC) code groups beginning with N03A. For ASMs without an assigned ATC code, we included them based on their molecule name, to ensure a comprehensive representation of ASMs in the analysis. The older-generation ASMs in the database included 4-aminobutyric acid, barbexaclone, beclamide, carbamazepine, clonazepam, ethosuximide, ethotoin, felbamate, fenfluramine, fosphenytoin, methylphenobarbital, oxcarbazepine, pheneturide, phenobarbital, phenytoin, primidone and valproic acid. The newer-generation ASMs included brivaracetam, cannabidiol, cenobamate, eslicarbazepine acetate, lacosamide, lamotrigine, levetiracetam, mesuximide, perampanel, retigabine, rufinamide, stiripentol, sultiame, tiagabine, topiramate, trimethadione, vigabatrin, and zonisamide. Income-level stratification Our analysis included 73 countries and regions, categorized by World Bank 2024 income levels 15 : 43 high-income countries (HICs), and 30 middle-income countries [comprising 11 upper-middle-income countries (UMICs) and 19 lower-middle-income countries (LMICs)]. Data for low-income countries was not available. The detailed country list was provided in eTable in Supplement . Data analysis We utilized the Defined Daily Dose (DDD) per 1000 inhabitants per day (DDDTID), 16 a WHO-recommended metric, to quantify drug consumption. This metric offers a reasonably reliable estimate of the proportion of the study population treated daily with a specific drug. Population estimates were obtained from the World Population Prospects 2024 published by United Nations. 17 Annual drug sales were provided in US dollars (USD) and local currency dollars (LCD) by IQVIA-MIDAS. Using this data, average drug cost was expressed in both US dollar (USD) per DDD and international dollar (Int$) per DDD by dividing the total annual sales in USD or Int$ by the total drug consumption in DDD. 16 For the Int$ calculation, the annual drug cost in LCD was converted to Int$ by multiplying it by the purchasing power parities (PPPs) factor of obtained from the World Bank. 18 Importantly, the use of Int$ per DDD facilitates fairer comparisons of drug costs across countries by adjusting differences in purchasing power. We conducted a stratified descriptive statistical analysis of both consumption and cost. This stratification was performed across countries, geographic regions, income levels, and by older- and newer-generation ASMs. Countries lacking reliable PPP data or experiencing severe PPP fluctuations due to factors such as war or economic instability, including Argentina, Lebanon, Puerto Rico, Russia, Venezuela, Vietnam and Pakistan, were excluded from the income level stratification involving cost analyses in Int$. Moreover, pairwise post-hoc comparisons were performed using Dunn’s test with Bonferroni correction to identify specific group differences (HICs versus UMICs; HICs versus LMICs). Statistical significance was set at p < 0.05. All data analyses were performed using R 4.4.1. CW and CH conducted the same but independent analytic procedures for cross-checking purposes to ensure the accuracy of the results. Results Global and regional trends of ASM consumption As shown in Table 1 , global consumption of ASMs increased from 3.10 DDDTID to 3.95 DDDTID with a CAGR of 2.34% from 2012 to 2022. World maps in Figure 1 showed ASM consumption by country for the years 2012 and 2022. Among all regions, Northern America exhibited the highest consumption through this period, rising from 12.77 DDDTID to 15.48 DDDTID, with its CAGR decreasing from 4.25% (2012-2014) to 0.86% (2020-2022). Oceania followed with a substantial consumption of ASMs over the decade, with values recorded at 10.17 DDDTID in 2012 and 11.19 DDDTID in 2022, accompanied by CAGRs shifting from slightly negative to positive after 2016. Europe, consumption increased steadily from 6.96 DDDTID in 2012 to 8.73 DDDTID in 2022, sustained by positive CAGRs ranging from 1.05% to 3.04%. Within Europe, there were large differences in consumption between subregions. Southern Europe recorded the highest consumption, increasing from 9.60 DDDTID in 2012 to 11.92 DDDTID in 2022, whereas Eastern Europe maintained lower levels, rising from 3.67 DDDTID to 4.79 DDDTID over the same timeframe. Among regions with comparatively lower consumption, Asia displayed the lowest levels, with a gradual rise from 1.43 DDDTID in 2012 to 1.98 DDDTID in 2022. Consumption in Africa showed notable fluctuation, ranging from 3.36 to 4.78 DDDTID. Latin America and the Caribbean experienced a consistent increase from 3.62 DDDTID to 4.49 DDDTID, though the growth slowing slightly after 2020. Consumption trends of older - versus newer-generation ASMs Between 2012 and 2022, the consumption of older-generation ASMs varied across regions, with some showing marked declines and others maintaining stability or slight increases, as shown in Table 1 and eFigure in Supplement . The most significant declines in older ASM consumption occurred in Northern America, Western Europe and Northern Europe, corresponding to CAGRs of -3.4%, -3.3% and -3.2% from 2012 to 2022, respectively. The consumption in Oceania and other subregions in Europe also experienced a mild decrease. Conversely, South-Eastern Asia and Central Asia recorded a gentle uptick. South-Eastern Asia’s older ASM consumption rose from a low base of 0.56 DDDTID in 2012 to 0.82 DDDTID in 2022 (CAGR of 3.9%), while Central Asia’s increased from 1.17 DDDTID in 2012 to 1.53 DDDTID in 2022 (CAGR of 2.7%). Other regions sustained a near-steady level, with changes aligning with an absolute CAGR below 1.0%. While the consumption of older-generation ASMs exhibited a mixed pattern of declines and modest increases across regions, newer ASMs demonstrated a consistent upward trend in consumption globally from 2012 to 2022. Compared to older-generation ones, the consumption of newer-generation ASMs was minimal across most regions in 2012, except for Northern America, where consumption was already relatively high. Northern America maintained the highest levels, with consumption rising from 6.36 DDDTID in 2012 to 10.94 DDDTID in 2022, though its growth decelerated in later years, with a CAGR shifting from 9.15% (2012-2014) to 3.22% (2020-2022). In Africa, particularly Northern Africa, consumption surged from a very low starting point of 0.18 DDDTID in 2012 to 1.35 DDDTID in 2022, reflecting a peak CAGR of 28.0% between 2012 and 2014. Similar rapid increases also occurred in Asia and Latin America and the Caribbean. Meanwhile, Europe and Oceania exhibited stable and sustained increases over the decade. Figure 2 showed the consumption trends of older- and newer-generation ASMs across HICs, UMICs and LMICs between 2012 and 2022. A notable transition occurred in HICs during 2016-2017, when consumption of newer-generation ASM exceeded that of older-generation ones, subsequently maintaining dominance with an upward trend thereafter. Nevertheless, this transition has yet to be seen in UMICs and LMICs, where older-generation ASMs remained at higher consumption levels throughout the decade despite the gradual uptake of newer-generation ones. As demonstrated in Figure 3 , HICs not only consumed the largest volumes of ASMs but also the widest variety in both 2012 and 2022, regardless of older- or newer-generation. In 2012, older ASMs such as carbamazepine, valproic acid, clonazepam, oxcarbazepine, phenobarbital and phenytoin were the most common older-generation ASMs across different income level countries. Carbamazepine and phenytoin led the consumption in HICs and LMICs respectively, while the consumption of several commonly used older ASMs in UMICs was similar. Newer-generation ASMs like levetiracetam and lamotrigine were less common in 2012, though these drugs had started to emerge as the most consumed among the newer agents in HICs. By 2022, while common older ASMs remained widely used, some of them had generally declined in consumption, particularly in HICs. The most notable shift was the sharp rise in the consumption of levetiracetam in both HICs and LMICs, which surpassed other ASMs regardless of generation. Costs of older- versus newer-generation ASM Significant variations in ASM cost patterns across countries categorized by income level in 2012 and 2022, as detailed in Table 2 and Figure 4 . For older-generation ASMs, the median cost in USD per DDD decreased slightly in HICs from 0.75 in 2012 to 0.64 in 2022, and in UMICs from 0.63 to 0.51, while a modest increase was noted in LMICs from 0.38 to 0.42. In both years, LMICs demonstrated significantly lower costs compared to HICs (p < 0.01), and a significant difference between HICs and UMICs was observed in 2012 (p = 0.04). When assessed using Int$ per DDD, older ASM cost patterns were different from those using nominal costs. In 2012 and 2022, median costs in UMICs (1.64 and 1.96, respectively) were higher than those in HICs (0.74 and 0.66) and LMICs (0.43 and 1.13), though no statistically significant differences were observed between HICs and LMICs. For newer-generation ASMs, LMICs consistently exhibited lower costs in USD per DDD (median: 1.77 in 2011 and 1.16 in 2022) compared to UMICs (3.31 and 2.22) and HICs (3.59 and 2.77). Significant differences were observed between HICs and LMICs in both years (p < 0.01), and between HICs and UMICs in 2011 (p = 0.03). However, in Int$ terms, newer-generation ASM costs were substantially higher in UMICs (median: 15.2 in 2011 and 11.52 in 2022) than in both HICs (3.15 and 2.74) and LMICs (1.99 and 3.72). There are no statistically significant differences in the costs of newer ASMs between HICs and LMICs in both years (2012: p = 1; 2022: p = 0.21). Discussion Overall, our data showed a global increase in ASM consumption with a CAGR of 2.34%, with notable regional variations. While HICs consistently consumed the highest volumes and widest variety of ASMs, UMICs and LMICs showed notable growth, albeit from a lower baseline. A notable trend was the rising global adoption of newer-generation ASMs, alongside persistent and varied patterns in the use of older-generation ones - some regions saw declines, while others maintained stable or slightly increased consumption. One of our key findings is that in HICs, consumption of newer ASMs surpassed that of older ones around 2016-2017, while in UMICs and LMICs, newer ASMs saw increasing use but older agents remain dominant with no clear sign of decline. In terms of ASM costs, there was a cost gradient by income level nominally, with HICs paying more overall. However, when adjusted for purchasing power, UMICs faced higher costs than both HICs and LMICs, especially for newer-generation ASMs. Our findings on the older- to newer-generation ASM transition in HICs align with existing evidence from several national ASM use studies, including those from Japan and United States, which reported a similar shift toward newer ASMs. 12,13,19 Notably, we further observed such a transition occurring around 2016-2017, a period that coincided with the inclusion of lamotrigine as the first newer-generation ASM in the EML. Levetiracetam, a newer ASM that has seen rapid growth in use among HICs, also experienced a 40-fold increase in consumption over the past 10 years in LMICs by 2022, after which it was added to the EML. Positive evidence on the safety and tolerability of newer-generation ASMs continued to emerge since 2010, 20-22 driving their clinical adoption. Moreover, the broader spectrum of action, simplified dosing regimens, and fewer medication interactions of newer drugs likely contribute to their growing consumption, particularly in pediatric and elderly populations. 23,24 Apart from clinical advantages, this notable uptake of newer ASMs in HICs is likely due to a combination of factors: advanced healthcare infrastructure, substantial ability and willingness to pay, streamlined regulatory with rigorous health technology assessments, and robust pharmaceutical marketing efforts that effectively promote these newer options. 25-27 The temporal alignment suggests a potential bidirectional relationship between global health policy and ASM consumption trends. The inclusion of newer ASMs in the EML likely encouraged their increased adoption in HICs, while their prior and growing use in HICs provided clinical evidence supporting their designation as essential medicines. In contrast to the shift toward newer-generation ASMs observed in HICs, a continued reliance on older-generation drugs, such as carbamazepine and phenobarbital, was observed in UMICs and LMICs. These medications, despite potential disadvantages in side-effect profiles, remain highly cost-effective options in the short run, 28,29 with significantly lower costs incurred compared to newer-generation ASMs in MICs. Our study further demonstrated that although the use of newer ASMs in MICs is increasing, older ASMs continue to dominate, largely because the high drug acquisition cost of newer options remains a significant barrier to their widespread adoption. Specifically, the PPP-adjusted cost of newer-generation ASMs in UMICs was notably 5 times higher than that in HICs, highlighting a substantial economic burden in these regions relative to their purchasing power and reinforcing dependence on older, more affordable alternatives. The widespread availability of off-patent older ASMs also enhances their economic appeal, enabling broader treatment coverage within constrained resources. 30 The sustained use of older-generation ASM is further supported by well-established supply chains for them, which ensure consistent availability even in regions with limited pharmaceutical infrastructure. 9 Additionally, clinicians in resource-limited settings may rely on their own clinical experience in practice with older ASMs due to limited professional training on the adoption of less familiar treatments, such as newer ASMs. 31 Such a reliance on older agents may result in a vicious cycle: their inferior tolerability leads to poor adherence and early discontinuation, resulting in additional unmet needs and a greater disease burden. This in turn necessitates superior therapeutic treatments, further straining already limited resources. Ultimately, this cycle perpetuates a heavier burden on healthcare systems and exacerbates inequities in access to optimal treatment. This study is, to our knowledge, one of the first analysis of multinational data to provide a global perspective on ASM consumption and cost patterns across 73 countries over a decade, covering 17 older ASMs and 18 newer ASMs. It highlights marked disparities by region and income level, as well as evolving trends in the use of older- and newer-generation ASMs. However, several limitations should be considered when interpreting the findings of this study. First, the absence of consumption data from many low-income countries restricts the generalizability of our global estimates and may lead to an underestimation of the global epilepsy treatment gap. Second, there may be underreporting or inconsistencies in distinguishing between generic and brand-name ASM consumption, especially in regions with informal or fragmented pharmaceutical supply chains, which could have affected the accuracy of our consumption and cost estimates. Additionally, this longitudinal ecological study relied on country-level data excluding individual factors (e.g., age, gender, diagnosis) that may affect ASM consumption. However, our findings were unlikely to be affected by these limitations since IQVIA-MIDAS is currently the most comprehensive database with broad coverage with respect to drug sales data. 32 Conclusion In conclusion, our findings provide valuable insights into the evolving landscape of global ASM consumption from 2012 to 2022. The steady increase in newer-generation ASM use, especially in HICs, highlights a meaningful transition in global epilepsy treatment. More efforts on the global health policy level are much needed to facilitate and accelerate the transition to the use of newer ASMs in MICs and probably LICs, which are widely considered a preferred treatment option in various aspects. Declarations Acknowledgment Author Contributions : EWYC and FTTL had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: EWYC, FTTL, CW. Acquisition, analysis, or interpretation of data: CW, CH. Drafting of the manuscript: CW. Critical review of the manuscript for important intellectual content: All authors. Statistical analysis: CW, CH. Obtained funding: EWYC. Supervision: EWYC, FTTL. Conflict of Interest Disclosures : CSLC has received grants from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grant Council, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA and Amgen and personal fees from Primevigilance Ltd., outside the submitted work. XL received research grants or contracts from the Health and Medical Research Fund (HMRF Main Scheme, HMRF Fellowship Scheme, and Hong Kong Special Administrative Region), and from the Research Grants Council Early Career Scheme (HKSAR); is also the former non-executive director of ADAMS Hong Kong; received commission grants from Hospital Authority of Hong Kong, and internal funding from the University of Hong Kong; received consultancy fees from Merck Sharp & Dohme, Pfizer, Open Health, and The Office of Health Economics; and received honoraria for associate editorship from Nature Springer. EWYC reports grants from the Health Bureau (Hong Kong), the Research Grants Council Hong Kong, National Natural Science Fund of China, Bayer, AstraZeneca, Novartis, RGA Reinsurance Company, Pfizer, and Narcotics Division of the Security Bureau of HKSAR; consulting fees from Pfizer, Novartis, and AstraZeneca; and honorarium from Hospital Authority (Hong Kong) and Pfizer. FTTL has been supported by the RGC Postdoctoral Fellowship under the Hong Kong Research Grants Council and has received research grants from the Health Bureau of the Government of the Hong Kong Special Administrative Region, outside the submitted work. The remaining authors declare no competing interests. Data Availability Statement : Source data was obtained under license from IQVIA: IQVIA-MIDAS monthly sales data, 2012-2022; all rights reserved. The aggregated datasets generated and analyzed during the current study will be available from the corresponding author upon request. 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CSLC has received grants from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grant Council, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA and Amgen and personal fees from Primevigilance Ltd., outside the submitted work. XL received research grants or contracts from the Health and Medical Research Fund (HMRF Main Scheme, HMRF Fellowship Scheme, and Hong Kong Special Administrative Region), and from the Research Grants Council Early Career Scheme (HKSAR); is also the former non-executive director of ADAMS Hong Kong; received commission grants from Hospital Authority of Hong Kong, and internal funding from the University of Hong Kong; received consultancy fees from Merck Sharp & Dohme, Pfizer, Open Health, and The Office of Health Economics; and received honoraria for associate editorship from Nature Springer. EWYC reports grants from the Health Bureau (Hong Kong), the Research Grants Council Hong Kong, National Natural Science Fund of China, Bayer, AstraZeneca, Novartis, RGA Reinsurance Company, Pfizer, and Narcotics Division of the Security Bureau of HKSAR; consulting fees from Pfizer, Novartis, and AstraZeneca; and honorarium from Hospital Authority (Hong Kong) and Pfizer. FTTL has been supported by the RGC Postdoctoral Fellowship under the Hong Kong Research Grants Council and has received research grants from the Health Bureau of the Government of the Hong Kong Special Administrative Region, outside the submitted work. The remaining authors declare no competing interests. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-7182416","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":496124239,"identity":"8506fb7b-5d3d-4728-acc5-6a646874f84f","order_by":0,"name":"Cuiling Wei","email":"","orcid":"","institution":"The University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Cuiling","middleName":"","lastName":"Wei","suffix":""},{"id":496124240,"identity":"c3a538b2-b7fe-4c3c-929a-6156c2ffb8e0","order_by":1,"name":"Caige Huang","email":"","orcid":"","institution":"The University of Hong 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05:35:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":635256,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7182416/v1/149973f259f50aaeb8114c08.png"},{"id":88393964,"identity":"b8043c36-3d37-4b89-9aa5-710a504738f5","added_by":"auto","created_at":"2025-08-06 05:35:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":447443,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7182416/v1/215bfb6d652e23c136965a13.png"},{"id":88393967,"identity":"9b643a29-db4c-46b3-acd7-20c5d32245a0","added_by":"auto","created_at":"2025-08-06 05:35:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":946768,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7182416/v1/e4f83b50361c8f4e3f23b3cb.png"},{"id":88393966,"identity":"059a5108-d34f-4b67-9fc4-f730269d9df4","added_by":"auto","created_at":"2025-08-06 05:35:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":357925,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7182416/v1/34fcbdc329893facdabb70c6.png"},{"id":88448367,"identity":"5909a127-838f-426a-be08-9a5e79c2b2d6","added_by":"auto","created_at":"2025-08-06 14:03:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2788110,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7182416/v1/98e8ae92-2cd5-4fa1-a76a-4599ec0a4eab.pdf"},{"id":88393961,"identity":"07d03a07-05be-4be1-8b45-97eee71b835d","added_by":"auto","created_at":"2025-08-06 05:35:57","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":37080,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7182416/v1/6f3e02105cf456996fd2d7e0.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nCSLC has received grants from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grant Council, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA and Amgen and personal fees from Primevigilance Ltd., outside the submitted work. XL received research grants or contracts from the Health and Medical Research Fund (HMRF Main Scheme, HMRF Fellowship Scheme, and Hong Kong Special Administrative Region), and from the Research Grants Council Early Career Scheme (HKSAR); is also the former non-executive director of ADAMS Hong Kong; received commission grants from Hospital Authority of Hong Kong, and internal funding from the University of Hong Kong; received consultancy fees from Merck Sharp \u0026 Dohme, Pfizer, Open Health, and The Office of Health Economics; and received honoraria for associate editorship from Nature Springer. EWYC reports grants from the Health Bureau (Hong Kong), the Research Grants Council Hong Kong, National Natural Science Fund of China, Bayer, AstraZeneca, Novartis, RGA Reinsurance Company, Pfizer, and Narcotics Division of the Security Bureau of HKSAR; consulting fees from Pfizer, Novartis, and AstraZeneca; and honorarium from Hospital Authority (Hong Kong) and Pfizer. FTTL has been supported by the RGC Postdoctoral Fellowship under the Hong Kong Research Grants Council and has received research grants from the Health Bureau of the Government of the Hong Kong Special Administrative Region, outside the submitted work. The remaining authors declare no competing interests.","formattedTitle":"Trends in Older versus Newer Antiseizure Medications Consumption and Cost in 73 countries, 2012-2022","fulltext":[{"header":"Key points","content":"\u003cp\u003eThe global use of antiseizure medications has increased steadily, with high-income countries leading in both volume and diversity of consumption, while upper- and lower-middle-income countries have shown significant growth from lower starting levels.\u003c/p\u003e\n\u003cp\u003eNewer antiseizure medication consumption has surpassed older-generation antiseizure medications in high-income countries since the mid-2010s, while upper- and lower-middle-income countries continue to rely on older ones, largely due to cost-related barriers.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eEpilepsy is a major neurological disorder\u0026nbsp;that affects over 50 million individuals worldwide and accounts for 13.9 million disability-adjusted life years (DALYs) in 2021.\u003csup\u003e1\u003c/sup\u003e Given its similar underlying causes, shared diagnostic methods and treatments with other frequently co-occurring neurological conditions, epilepsy is widely considered as a key focus for addressing broader neurological health issues and their associated global health burden.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAntiseizure medicines (ASMs) are currently the first-line pharmacotherapy for epilepsy and are generally classified into older and newer generations based on their date of introduction, with older-generation ASMs (first- and second- generation) being developed before the 1990s and newer-generation ASMs (third-generation) introduced thereafter.\u003csup\u003e3\u003c/sup\u003e The efficacy of both older and newer generations of ASMs are well supported by solid clinical evidence.\u003csup\u003e4\u003c/sup\u003e Nevertheless, newer ASMs offer improved safety and tolerability over older ones, showing up to 20% fewer cases of acute side effects like drowsiness and severe cutaneous adverse drug reactions and reduced long-term risks such as cognitive impairment and bone density loss.\u003csup\u003e5,6\u003c/sup\u003e Moreover, newer-generation ASMs may have higher efficacy in specific epilepsy syndromes, including the management for Dravet syndrome.\u003csup\u003e7,8\u003c/sup\u003e These advantages contribute to better adherence and treatment outcomes, underscoring the importance of ensuring the availability and accessibility of newer ASMs to help reduce the global burden of epilepsy.\u003c/p\u003e\n\u003cp\u003eThe International League Against Epilepsy\u0026rsquo;s (ILAE) global ASM availability survey in 2022 reported notable disparities in ASM availability across different countries of various income levels.\u003csup\u003e9\u003c/sup\u003e Although older-generation ASMs such as carbamazepine and phenobarbital are included on the World Health Organization Model List of Essential Medicines (WHO EML) and are theoretically more affordable and accessible,\u003csup\u003e10,11\u003c/sup\u003e the global survey found that access to these medicines remains inconsistent in some middle-income countries (MICs), largely due to supply chain issues, regulatory obstacles, and pricing barriers.\u003csup\u003e9\u003c/sup\u003e Access to newer-generation ASMs like lamotrigine and levetiracetam are plausibly limited by greater access challenges in MICs and low-income countries (LICs) due to their higher cost, recency of marketing, and delays in medical guideline updates. Existing regional studies of ASM consumption, such as those conducted in the United States and Japan,\u003csup\u003e12,13\u003c/sup\u003e provided valuable insights into local challenges. However, they are limited to specific geographic areas and often rely on differing measures and data sources, which makes cross-country comparisons difficult and potentially misleading. To date, there is no comprehensive analysis and comparison of the accessibility or availability of older versus newer generations of ASMs from a global perspective.\u003c/p\u003e\n\u003cp\u003eTo address this knowledge gap, we used the IQVIA Multinational Integrated Data Analysis System (IQVIA-MIDAS) database, a standardized and longitudinal data source that captures pharmaceutical sales across a broad range of countries to investigate the current global patterns of ASM use and costs. A particular focus was placed on comparing the consumption and costs of older-generation ASMs with newer-generation ASMs in high- versus middle-income countries.\u0026nbsp;\u003c/p\u003e\n"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eData sources\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eGlobal ASM sales data for this study was sourced from the IQVIA-MIDAS database, from January 1, 2012 up to December 31, 2022. This global database comprehensively captures pharmaceutical product sales to retail and hospital pharmacies, enabling standardized national sales audits. Data collection varies by country, primarily incorporating direct sales from manufacturers and wholesalers, supplemented by retail and hospital pharmacy data in some regions. With an 88% average coverage, MIDAS estimates total sales volume by adjusting for market share. Its data are internally validated and widely used for global medicine consumption patterns.\u003csup\u003e14\u003c/sup\u003e Since patient-level information was unavailable, institutional review board, approval was deemed not required for this study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClassification of ASMs\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe sales data on ASMs were extracted from the IQVIA-MIDAS database using Anatomical Therapeutic Chemical (ATC) code groups beginning with N03A. For ASMs without an assigned ATC code, we included them based on their molecule name, to ensure a comprehensive representation of ASMs in the analysis. The older-generation ASMs in the database included 4-aminobutyric acid, barbexaclone, beclamide, carbamazepine, clonazepam, ethosuximide, ethotoin, felbamate, fenfluramine, fosphenytoin, methylphenobarbital, oxcarbazepine, pheneturide, phenobarbital, phenytoin, primidone and valproic acid. The newer-generation ASMs included brivaracetam, cannabidiol, cenobamate, eslicarbazepine acetate, lacosamide, lamotrigine, levetiracetam, mesuximide, perampanel, retigabine, rufinamide, stiripentol, sultiame, tiagabine, topiramate, trimethadione, vigabatrin, and zonisamide.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIncome-level stratification\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOur analysis included 73 countries and regions, categorized by World Bank 2024 income levels\u003csup\u003e15\u003c/sup\u003e: 43 high-income countries (HICs), and 30 middle-income countries [comprising 11 upper-middle-income countries (UMICs) and 19 lower-middle-income countries (LMICs)]. Data for low-income countries was not available. The detailed country list was provided in \u003cstrong\u003eeTable\u003c/strong\u003e in\u003cstrong\u003e\u0026nbsp;Supplement\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe utilized the Defined Daily Dose (DDD) per 1000 inhabitants per day (DDDTID),\u003csup\u003e16\u003c/sup\u003e a WHO-recommended metric, to quantify drug consumption. This metric offers a reasonably reliable estimate of the proportion of the study population treated daily with a specific drug. Population estimates were obtained from the World Population Prospects 2024 published by United Nations.\u003csup\u003e17\u003c/sup\u003e Annual drug sales were provided in US dollars (USD) and local currency dollars (LCD) by IQVIA-MIDAS. Using this data, average drug cost was expressed in both US dollar (USD) per DDD and international dollar (Int$) per DDD by dividing the total annual sales in USD or Int$ by the total drug consumption in DDD.\u003csup\u003e16\u003c/sup\u003e For the Int$ calculation, the annual drug cost in LCD was converted to Int$ by multiplying it by the purchasing power parities (PPPs) factor of obtained from the World Bank.\u003csup\u003e18\u003c/sup\u003e Importantly, the use of Int$ per DDD facilitates fairer comparisons of drug costs across countries by adjusting differences in purchasing power. We conducted a stratified descriptive statistical analysis of both consumption and cost. This stratification was performed across countries, geographic regions, income levels, and by older- and newer-generation ASMs. Countries lacking reliable PPP data or experiencing severe PPP fluctuations due to factors such as war or economic instability, including Argentina, Lebanon, Puerto Rico, Russia, Venezuela,\u0026nbsp;Vietnam and Pakistan,\u0026nbsp;were excluded from the\u0026nbsp;income\u0026nbsp;level stratification involving cost analyses in Int$.\u0026nbsp;Moreover, pairwise post-hoc comparisons were performed using Dunn\u0026rsquo;s test with Bonferroni correction to identify specific group differences (HICs versus UMICs; HICs versus LMICs). Statistical significance was set at p \u0026lt; 0.05.\u003c/p\u003e\n\u003cp\u003eAll data analyses were performed using R 4.4.1. CW and CH conducted the same but independent analytic procedures for cross-checking purposes to ensure the accuracy of the results.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003eGlobal and regional trends of ASM consumption\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in\u003cstrong\u003e\u0026nbsp;Table 1\u003c/strong\u003e, global consumption of ASMs increased from 3.10 DDDTID to 3.95 DDDTID with a CAGR of 2.34% from 2012 to 2022. World maps in\u0026nbsp;\u003cstrong\u003eFigure 1\u003c/strong\u003e showed\u0026nbsp;ASM consumption by country\u0026nbsp;for the years 2012 and\u0026nbsp;2022.\u0026nbsp;Among all regions, Northern\u0026nbsp;America\u0026nbsp;exhibited\u0026nbsp;the highest consumption\u0026nbsp;through\u0026nbsp;this period, rising from 12.77\u0026nbsp;DDDTID to 15.48\u0026nbsp;DDDTID,\u0026nbsp;with\u0026nbsp;its\u0026nbsp;CAGR\u0026nbsp;decreasing\u0026nbsp;from 4.25% (2012-2014) to 0.86% (2020-2022). Oceania followed with a substantial consumption of ASMs\u0026nbsp;over\u0026nbsp;the decade, with values recorded at 10.17 DDDTID in 2012 and 11.19 DDDTID in 2022,\u0026nbsp;accompanied by CAGRs\u0026nbsp;shifting from slightly negative to positive after 2016. Europe, consumption\u0026nbsp;increased\u0026nbsp;steadily from 6.96\u0026nbsp;DDDTID in 2012 to 8.73\u0026nbsp;DDDTID in 2022, sustained by positive\u0026nbsp;CAGRs\u0026nbsp;ranging from 1.05% to 3.04%. Within Europe,\u0026nbsp;there were large differences in consumption between subregions.\u0026nbsp;Southern Europe recorded the highest consumption, increasing from 9.60\u0026nbsp;DDDTID in 2012 to 11.92\u0026nbsp;DDDTID in 2022, whereas\u0026nbsp;Eastern Europe maintained lower levels, rising from 3.67\u0026nbsp;DDDTID to 4.79\u0026nbsp;DDDTID over the same\u0026nbsp;timeframe. Among\u0026nbsp;regions with\u0026nbsp;comparatively\u0026nbsp;lower consumption, Asia\u0026nbsp;displayed\u0026nbsp;the lowest levels, with\u0026nbsp;a gradual rise\u0026nbsp;from 1.43\u0026nbsp;DDDTID in 2012 to 1.98\u0026nbsp;DDDTID in 2022.\u0026nbsp;Consumption in Africa showed notable fluctuation, ranging from 3.36\u0026nbsp;to\u0026nbsp;4.78\u0026nbsp;DDDTID. Latin America\u0026nbsp;and the Caribbean\u0026nbsp;experienced a\u0026nbsp;consistent\u0026nbsp;increase from 3.62\u0026nbsp;DDDTID to 4.49\u0026nbsp;DDDTID, though the growth slowing\u0026nbsp;slightly after 2020.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsumption trends of older\u003c/em\u003e\u003cem\u003e- versus\u0026nbsp;\u003c/em\u003e\u003cem\u003enewer-generation ASMs\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBetween 2012 and 2022, the consumption of older-generation ASMs varied across regions, with some showing marked declines and others maintaining stability or slight increases, as shown in \u003cstrong\u003eTable 1\u003c/strong\u003e and \u003cstrong\u003eeFigure\u0026nbsp;\u003c/strong\u003ein\u003cstrong\u003e\u0026nbsp;Supplement\u003c/strong\u003e. The most significant declines in older ASM consumption occurred in Northern America, Western Europe and Northern Europe, corresponding to CAGRs of -3.4%, -3.3% and -3.2% from 2012 to 2022, respectively. The consumption in Oceania and other subregions in Europe also experienced a mild decrease. Conversely, South-Eastern Asia and Central Asia recorded a gentle uptick. South-Eastern Asia\u0026rsquo;s older ASM consumption rose from a low base of 0.56 DDDTID in 2012 to 0.82 DDDTID in 2022 (CAGR of 3.9%), while Central Asia\u0026rsquo;s increased from 1.17 DDDTID in 2012 to 1.53 DDDTID in 2022 (CAGR of 2.7%). Other regions sustained a near-steady level, with changes aligning with an absolute CAGR below 1.0%. While the consumption of older-generation ASMs exhibited a mixed pattern of declines and modest increases across regions, newer ASMs demonstrated a consistent upward trend in consumption globally from 2012 to 2022. Compared to older-generation ones, the consumption of newer-generation ASMs was minimal across most regions in 2012, except for Northern America, where consumption was already relatively high. Northern America maintained the highest levels, with consumption rising from 6.36 DDDTID in 2012 to 10.94 DDDTID in 2022, though its growth decelerated in later years, with a CAGR shifting from 9.15% (2012-2014) to 3.22% (2020-2022). In Africa, particularly Northern Africa, consumption surged from a very low starting point of 0.18 DDDTID in 2012 to 1.35 DDDTID in 2022, reflecting a peak CAGR of 28.0% between 2012 and 2014. Similar rapid increases also occurred in Asia and Latin America and the Caribbean. Meanwhile, Europe and Oceania exhibited stable and sustained increases over the decade.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2\u003c/strong\u003e showed the consumption trends of older- and newer-generation ASMs across HICs, UMICs and LMICs between 2012 and 2022. A notable transition occurred in HICs during 2016-2017, when consumption of newer-generation ASM exceeded that of older-generation ones, subsequently maintaining dominance with an upward trend thereafter. Nevertheless, this transition has yet to be seen in UMICs and LMICs, where older-generation ASMs remained at higher consumption levels throughout the decade despite the gradual uptake of newer-generation ones.\u003c/p\u003e\n\u003cp\u003eAs demonstrated in \u003cstrong\u003eFigure 3\u003c/strong\u003e, HICs not only consumed the largest volumes of ASMs but also the widest variety in both 2012 and 2022, regardless of older- or newer-generation. In 2012, older ASMs such as carbamazepine, valproic acid, clonazepam, oxcarbazepine, phenobarbital and phenytoin were the most common older-generation ASMs across different income level countries. Carbamazepine and phenytoin led the consumption in HICs and LMICs respectively, while the consumption of several commonly used older ASMs in UMICs was similar. Newer-generation ASMs like levetiracetam and lamotrigine were less common in 2012, though these drugs had started to emerge as the most consumed among the newer agents in HICs. By 2022, while common older ASMs remained widely used, some of them had generally declined in consumption, particularly in HICs. The most notable shift was the sharp rise in the consumption of levetiracetam in both HICs and LMICs, which surpassed other ASMs regardless of generation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCosts of older- versus newer-generation\u0026nbsp;\u003c/em\u003e\u003cem\u003eASM\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSignificant variations in ASM cost patterns across countries categorized by income level in 2012 and 2022, as detailed in \u003cstrong\u003eTable 2\u003c/strong\u003e and \u003cstrong\u003eFigure 4\u003c/strong\u003e. For older-generation ASMs, the median cost in USD per DDD decreased slightly in HICs from 0.75 in 2012 to 0.64 in 2022, and in UMICs from 0.63 to 0.51, while a modest increase was noted in LMICs from 0.38 to 0.42. In both years, LMICs demonstrated significantly lower costs compared to HICs (p \u0026lt; 0.01), and a significant difference between HICs and UMICs was observed in 2012 (p = 0.04). When assessed using Int$ per DDD, older ASM cost patterns were different from those using nominal costs. In 2012 and 2022, median costs in UMICs (1.64 and 1.96, respectively) were higher than those in HICs (0.74 and 0.66) and LMICs (0.43 and 1.13), though no statistically significant differences were observed between HICs and LMICs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor newer-generation ASMs, LMICs consistently exhibited lower costs in USD per DDD (median: 1.77 in 2011 and 1.16 in 2022) compared to UMICs (3.31 and 2.22) and HICs (3.59 and 2.77). Significant differences were observed between HICs and LMICs in both years (p \u0026lt; 0.01), and between HICs and UMICs in 2011 (p = 0.03). However, in Int$ terms, newer-generation ASM costs were substantially higher in UMICs (median: 15.2 in 2011 and 11.52 in 2022) than in both HICs (3.15 and 2.74) and LMICs (1.99 and 3.72). There are no statistically significant differences in the costs of newer ASMs between HICs and LMICs in both years (2012: p = 1; 2022: p = 0.21).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOverall, our data showed a global increase in ASM consumption with a CAGR of 2.34%, with notable regional variations. While HICs consistently consumed the highest volumes and widest variety of ASMs, UMICs and LMICs showed notable growth, albeit from a lower baseline. A notable trend was the rising global adoption of newer-generation ASMs, alongside persistent and varied patterns in the use of older-generation ones - some regions saw declines, while others maintained stable or slightly increased consumption. One of our key findings is that in HICs, consumption of newer ASMs surpassed that of older ones around 2016-2017, while in UMICs and LMICs, newer ASMs saw increasing use but older agents remain dominant with no clear sign of decline. In terms of ASM costs, there was a cost gradient by income level nominally, with HICs paying more overall. However, when adjusted for purchasing power, UMICs faced higher costs than both HICs and LMICs, especially for newer-generation ASMs.\u003c/p\u003e\n\u003cp\u003eOur findings on the older- to newer-generation ASM transition in HICs align with existing evidence from several national ASM use studies, including those from Japan and United States, which reported a similar shift toward newer ASMs.\u003csup\u003e12,13,19\u003c/sup\u003e Notably, we further observed such a transition occurring around 2016-2017, a period that coincided with the inclusion of lamotrigine as the first newer-generation ASM in the EML. Levetiracetam, a newer ASM that has seen rapid growth in use among HICs, also experienced a 40-fold increase in consumption over the past 10 years in LMICs by 2022, after which it was added to the EML. Positive evidence on the safety and tolerability of newer-generation ASMs continued to emerge since 2010,\u003csup\u003e20-22\u003c/sup\u003e driving their clinical adoption. Moreover, the broader spectrum of action, simplified dosing regimens, and fewer medication interactions of newer drugs likely contribute to their growing consumption, particularly in pediatric and elderly populations.\u003csup\u003e23,24\u003c/sup\u003e Apart from clinical advantages, this notable uptake of newer ASMs in HICs is likely due to a combination of factors: advanced healthcare infrastructure, substantial ability and willingness to pay, streamlined regulatory with rigorous health technology assessments, and robust pharmaceutical marketing efforts that effectively promote these newer options.\u003csup\u003e25-27\u003c/sup\u003e The temporal alignment suggests a potential bidirectional relationship between global health policy and ASM consumption trends. The inclusion of newer ASMs in the EML likely encouraged their increased adoption in HICs, while their prior and growing use in HICs provided clinical evidence supporting their designation as essential medicines.\u003c/p\u003e\n\u003cp\u003eIn contrast to the shift toward newer-generation ASMs observed in HICs, a continued reliance on older-generation drugs, such as carbamazepine and phenobarbital, was observed in UMICs and LMICs. These medications, despite potential disadvantages in side-effect profiles, remain highly cost-effective options in the short run,\u003csup\u003e28,29\u003c/sup\u003e with significantly lower costs incurred compared to newer-generation ASMs in MICs. Our study further demonstrated that although the use of newer ASMs in MICs is increasing, older ASMs continue to dominate, largely because the high drug acquisition cost of newer options remains a significant barrier to their widespread adoption. Specifically, the PPP-adjusted cost of newer-generation ASMs in UMICs was notably 5 times higher than that in HICs, highlighting a substantial economic burden in these regions relative to their purchasing power and reinforcing dependence on older, more affordable alternatives. The widespread availability of off-patent older ASMs also enhances their economic appeal, enabling broader treatment coverage within constrained resources.\u003csup\u003e30\u003c/sup\u003e The sustained use of older-generation ASM is further supported by well-established supply chains for them, which ensure consistent availability even in regions with limited pharmaceutical infrastructure.\u003csup\u003e9\u003c/sup\u003e Additionally, clinicians in resource-limited settings may rely on their own clinical experience in practice with older ASMs due to limited professional training on the adoption of less familiar treatments, such as newer ASMs.\u003csup\u003e31\u003c/sup\u003e Such a reliance on older agents may result in a vicious cycle: their inferior tolerability leads to poor adherence and early discontinuation, resulting in additional unmet needs and a greater disease burden. This in turn necessitates superior therapeutic treatments, further straining already limited resources. Ultimately, this cycle perpetuates a heavier burden on healthcare systems and exacerbates inequities in access to optimal treatment.\u003c/p\u003e\n\u003cp\u003eThis study is, to our knowledge, one of the first analysis of multinational data to provide a global perspective on ASM consumption and cost patterns across 73 countries over a decade, covering 17 older ASMs and 18 newer ASMs. It highlights marked disparities by region and income level, as well as evolving trends in the use of older- and newer-generation ASMs. However, several limitations should be considered when interpreting the findings of this study. First, the absence of consumption data from many low-income countries restricts the generalizability of our global estimates and may lead to an underestimation of the global epilepsy treatment gap. Second, there may be underreporting or inconsistencies in distinguishing between generic and brand-name ASM consumption, especially in regions with informal or fragmented pharmaceutical supply chains, which could have affected the accuracy of our consumption and cost estimates. Additionally, this longitudinal ecological study relied on country-level data excluding individual factors (e.g., age, gender, diagnosis) that may affect ASM consumption. However, our findings were unlikely to be affected by these limitations since IQVIA-MIDAS is currently the most comprehensive database with broad coverage with respect to drug sales data.\u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our findings provide valuable insights into the evolving landscape of global ASM consumption from 2012 to 2022. The steady increase in newer-generation ASM use, especially in HICs, highlights a meaningful transition in global epilepsy treatment. More efforts on the global health policy level are much needed to facilitate and accelerate the transition to the use of newer ASMs in MICs and probably LICs, which are widely considered a preferred treatment option in various aspects.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e: EWYC and FTTL had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.\u003c/p\u003e\n\u003cp\u003eConcept and design: EWYC, FTTL, CW.\u003c/p\u003e\n\u003cp\u003eAcquisition, analysis, or interpretation of data: CW, CH.\u003c/p\u003e\n\u003cp\u003eDrafting of the manuscript: CW.\u003c/p\u003e\n\u003cp\u003eCritical review of the manuscript for important intellectual content: All authors.\u003c/p\u003e\n\u003cp\u003eStatistical analysis: CW, CH.\u003c/p\u003e\n\u003cp\u003eObtained funding: EWYC.\u003c/p\u003e\n\u003cp\u003eSupervision: EWYC, FTTL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures\u003c/strong\u003e: CSLC has received grants from the Food and Health Bureau of the Hong Kong Government, Hong Kong Research Grant Council, Hong Kong Innovation and Technology Commission, Pfizer, IQVIA and Amgen and personal fees from Primevigilance Ltd., outside the submitted work. XL received research grants or contracts from the Health and Medical Research Fund (HMRF Main Scheme, HMRF Fellowship Scheme, and Hong Kong Special Administrative Region), and from the Research Grants Council Early Career Scheme (HKSAR); is also the former non-executive director of ADAMS Hong Kong; received commission grants from Hospital Authority of Hong Kong, and internal funding from the University of Hong Kong; received consultancy fees from Merck Sharp \u0026amp; Dohme, Pfizer, Open Health, and The Office of Health Economics; and received honoraria for associate editorship from Nature Springer. EWYC reports grants from the Health Bureau (Hong Kong), the Research Grants Council Hong Kong, National Natural Science Fund of China, Bayer, AstraZeneca, Novartis, RGA Reinsurance Company, Pfizer, and Narcotics Division of the Security Bureau of HKSAR; consulting fees from Pfizer, Novartis, and AstraZeneca; and honorarium from Hospital Authority (Hong Kong) and Pfizer. FTTL has been supported by the RGC Postdoctoral Fellowship under the Hong Kong Research Grants Council and has received research grants from the Health Bureau of the Government of the Hong Kong Special Administrative Region, outside the submitted work. The remaining authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e: Source data was obtained under license from IQVIA: IQVIA-MIDAS monthly sales data, 2012-2022; all rights reserved. The aggregated datasets generated and analyzed during the current study will be available from the corresponding author upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFeigin VL, Vos T, Nair BS, et al. 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Survey on the worldwide availability and affordability of antiseizure medications: report of the ILAE task force on access to treatment. \u003cem\u003eEpilepsia\u003c/em\u003e. 2022;63(2):335-351. \u003c/li\u003e\n\u003cli\u003eAsadi‐Pooya AA, Guekht A. Antiseizure medications in the World Health Organization list of\u0026quot; essential medicines\u0026quot;. \u003cem\u003eEpilepsia (Series 4)\u003c/em\u003e. 2023;64(7)\u003c/li\u003e\n\u003cli\u003eWorld Health Organization. WHO Model List of Essential Medicines - 23rd list, 2023. World Health Organization; 26 July 2023. Accessed June 27, 2025. https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2023.02. \u003c/li\u003e\n\u003cli\u003eJin K, Obara T, Hirano K, et al. 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Effectiveness and Safety of Antiepileptic Medications in Patients With Epilepsy. 2011;\u003c/li\u003e\n\u003cli\u003ePatsalos PN. Clinical pharmacokinetics of levetiracetam. \u003cem\u003eClinical pharmacokinetics\u003c/em\u003e. 2004;43:707-724. \u003c/li\u003e\n\u003cli\u003eZhang L-L, Zeng L-N, Li Y-P. Side effects of phenobarbital in epilepsy: a systematic review. \u003cem\u003eEpileptic disorders\u003c/em\u003e. 2011;13:349-365. \u003c/li\u003e\n\u003cli\u003eRohracher A, Kalss G, Kuchukhidze G, et al. New anti-seizure medication for elderly epilepsy patients-a critical narrative review. \u003cem\u003eExpert Opinion on Pharmacotherapy\u003c/em\u003e. 2021;22(5):621-634. \u003c/li\u003e\n\u003cli\u003eSinghi S, Gupta A. A review of the selected and newer antiseizure medications used in childhood epilepsies. \u003cem\u003eIndian Journal of Pediatrics\u003c/em\u003e. 2021;88(10):993-999. \u003c/li\u003e\n\u003cli\u003eRoach M, Land N, Hernandez J, et al. The Role of Pharmaceutical Innovation in Clinical Practice Guidelines for Chronic Diseases. \u003cem\u003eInternational Journal of Clinical Practice\u003c/em\u003e. 2024;2024(1):5877687. \u003c/li\u003e\n\u003cli\u003eMulcahy AW. Comparing new prescription drug availability and launch timing in the United States and other OECD countries. \u003cem\u003eRand Health Quarterly\u003c/em\u003e. 2024;11(3):4. \u003c/li\u003e\n\u003cli\u003eWouters OJ, Naci H, Papanicolas I. Availability and coverage of new drugs in 6 high-income countries with health technology assessment bodies. \u003cem\u003eJAMA internal medicine\u003c/em\u003e. 2024;184(3):328-330. \u003c/li\u003e\n\u003cli\u003eBeghi E, Atzeni L, Garattini L. Economic analysis of newer antiepileptic drugs. \u003cem\u003eCNS drugs\u003c/em\u003e. 2008;22:861-875. \u003c/li\u003e\n\u003cli\u003eHu Y, Chen S, Mao F, et al. Which is the most cost‐effective antiseizure medication for initial monotherapy for focal epilepsy? \u003cem\u003eEpilepsia\u003c/em\u003e. 2025;\u003c/li\u003e\n\u003cli\u003eFong SL, Thuy Le MA, Lim KS, et al. Affordability of newer antiseizure medications in Asian resource‐limited countries. \u003cem\u003eEpilepsia\u003c/em\u003e. 2023;64(8):2116-2125. \u003c/li\u003e\n\u003cli\u003ePugh MJV, Foreman PJ, Berlowitz DR. Prescribing antiepileptics for the elderly: differences between guideline recommendations and clinical practice. \u003cem\u003eDrugs \u0026amp; aging\u003c/em\u003e. 2006;23:861-875. \u003c/li\u003e\n\u003cli\u003eYan VK, Li H-L, Wei L, Knapp MR, Wong IC, Chan EW. Evolving trends in consumption of direct oral anticoagulants in 65 countries/regions from 2008 to 2019. \u003cem\u003eDrugs\u003c/em\u003e. 2023;83(4):315-340. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"},{"header":"Supplementary file","content":"\u003cp\u003eSupplementary file is not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7182416/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7182416/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\n\u003cp\u003eEpilepsy affects over 50 million people globally, with antiseizure medications (ASMs) as the main pharmacotherapies. Understanding disparities in ASM use and costs across income levels is critical to address inequities in epilepsy care and reduce its global burden.\u003c/p\u003e\n\u003cp\u003eObjective\u003c/p\u003e\n\u003cp\u003eTo examine recent global and regional patterns and trends of ASM consumption and costs across high-, upper-middle-, and lower-middle-income countries (HICs, UMICs, LMICs).\u003c/p\u003e\n\u003cp\u003eMethods\u003c/p\u003e\n\u003cp\u003eWe analyzed country-level pharmaceutical sales data from the IQVIA Multinational Integrated Data Analysis System (IQVIA-MIDAS) database spanning 73 countries, stratified by geographical regions (Africa, Asia, Europe, Latin America and the Caribbean, Northern America, Oceania), World Bank income levels (HICs, UMICs, LMICs) and ASM generations (older- and newer-generation). Drug consumption was measured using defined daily doses per 1000 inhabitants per day (DDDTID) and drug cost was calculated in USD and international dollars per DDD to account for differences in purchasing power parity (PPP).\u003c/p\u003e\n\u003cp\u003eResults\u003c/p\u003e\n\u003cp\u003eGlobal ASM consumption rose steadily from 3.10 to 3.95 DDDTID between 2012 and 2022 with a compound annual growth rate of 2.34%. Regionally, Northern America led with the highest consumption at 15.48 DDDTID in 2022, followed by Oceania at 11.19 and Europe at 8.73, whileAfrica lagged at 4.78 and Asia recorded the lowest at 1.98. HICs consumed more ASMs and transitioned to newer-generationASM by 2017, whereas MICs continued to rely heavily on older ASMs. Costs of older-generation ASMs remained low across all regions, while newer-generation ASMs showed significantly higher and more variable costs, especially when adjusted for purchasing power parity. Notably, the PPP-adjusted costs of newer-generation ASMs were substantially higher in UMICs than in HICs or LMICs.\u003c/p\u003e\n\u003cp\u003eConclusions\u003c/p\u003e\n\u003cp\u003eNewer ASMs consumption has surpassed older ASMs in the mid-2010s in HICs, while UMICs and LMICs rely on older ASMs due to cost barriers. Global health policies must prioritize affordable access to newer ASMs in middle-income countries to enhance equity in epilepsy and broader neurological care.\u003c/p\u003e","manuscriptTitle":"Trends in Older versus Newer Antiseizure Medications Consumption and Cost in 73 countries, 2012-2022","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-06 05:35:53","doi":"10.21203/rs.3.rs-7182416/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a57036cb-91ed-449c-96c4-206ba07f5aa0","owner":[],"postedDate":"August 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":52693427,"name":"Health sciences/Health care/Public health"},{"id":52693428,"name":"Health sciences/Diseases/Neurological disorders/Epilepsy"},{"id":52693429,"name":"Health sciences/Health care/Therapeutics"}],"tags":[],"updatedAt":"2026-04-14T17:27:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-06 05:35:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7182416","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7182416","identity":"rs-7182416","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}