All Things Being Equal,Global Antiseizure Medications Consumption Remains Unequal

Abstract

Antiseizure Medications Consumption in 73 Countries and Regions from 2012 to 2022: A Longitudinal Trend Study

Chan AYL, Yuen ASC, Hsia Y, Lau WCY, Cross JH, Walker MC, Besag FMC, Hung ATF, Iessa N, Chowdhary N, Man KKC, Wong ICK. EClinicalMedicine. 2025 Oct 9;89:103558. doi: 10.1016/j.eclinm.2025.103558. PMID: 41140454; PMCID: PMC12547185.

Background: International trends in antiseizure medication use across countries from different geographical regions and income levels remain underexplored. Valproic acid (valproate) use has raised concerns due to its teratogenic risks, with World Health Organization (WHO) guidelines recommending lamotrigine or levetiracetam as first-line therapy for epilepsy in women and girls of childbearing potential, advising against valproate use in this population. This study aimed to assess multinational trends in antiseizure medication (ASM) consumption from 2012 to 2022 in the context of evolving policy and regulatory actions. Methods: In this longitudinal trend study, we used pharmaceutical sales data of antiseizure medications from the IQVIA-Multinational Integrated Data Analysis System (MIDAS) between January 1, 2012 and December 31, 2022, covering 73 countries/regions. The list of ASMs included in this study was based on the Anatomical Therapeutic Chemical (ATC) Classification, N03A. We obtained the midyear national/regional population estimates of each country from the United Nations Population Division and the total epilepsy (active idiopathic and secondary epilepsy) population from the Global Burden of Disease Collaborative Network. In total, 41 high-income, 20 upper-middle income, and 12 lower-middle-income countries/regions were included in this study. Antiseizure medication consumption rate was expressed as defined daily doses per 10 000 inhabitants per day (DDD/TID). Linear mixed models were used to estimate multinational, regional, and income-level trends in consumption over time. Findings: Multinational antiseizure medication consumption increased throughout the study period, with an average annual percentage change of +2.58% (95% CI +1.85% to +3.32%), rising from 40.96 DDD/TID (31.94-52.52) in 2012 to 52.87 DDD/TID (42.17-66.27) in 2022. The highest change in consumption was in South-eastern Asia (+5.20%, +3.41% to +7.03%), followed by Western Asia (+4.70%, +0.58% to +8.99%) and Southern Asia (+3.80%, +1.52% to +6.14%). Newer generation antiseizure medications such as levetiracetam (+21.72%, +13.86% to +30.11%) and lamotrigine (+7.48%, +6.34% to +8.63%) showed growth in consumption, while consumption of older medications such as phenobarbital (−2.85%, −9.50% to +4.29%), phenytoin (−11.19%, −17.58% to −4.30%), and carbamazepine (−1.09%, −1.95% to −0.23%) declined. In 2022, the consumption rate of high-income countries (88.36 DDD/TID, 71.69-108.90) was more than 4 times of lower-middle-income countries (15.63 DDD/TID, 8.75-27.91). Valproate remained the most widely used antiseizure medication globally (10.93 DDD/TID, 8.68-13.77) in 2022, with stronger growth observed in lower- (+4.24%, +1.73% to +6.81%) and upper-middle-income (+3.10%, +0.95% to +5.29%) countries, compared with high-income countries (+0.86%, −0.07% to +1.79%). Interpretation: Multinational antiseizure medication use increased between 2012 and 2022, particularly for newer medications like levetiracetam and lamotrigine. Disparities in access to antiseizure medications across countries of varying income levels persist, with valproate consumption remaining predominant. This underscores the urgent need to align prescribing practice with safety guidelines, in order to optimize patient outcomes. Since patient-level characteristics are not available in IQVIA-MIDAS, further research is warranted to examine consumption rates across different population groups.

Commentary

Epilepsy is one of the most common brain disorders across the age spectrum and around the world. In 2021, it was estimated that 51.7 million people live with epilepsy globally, an increased prevalence of 10.8% compared to 1990. ¹ Approximately 80% of this disease burden resides in low- to middle-income countries (LMICs).^1,2 Epilepsy constitutes a public health concern with serious physical and psychological consequences to the families living with it, including poor quality of life, significant disability, increased mortality, and heightened healthcare needs and expenditure. ³

Antiseizure medications (ASMs) constitute mainstream treatment for epilepsy. The last 3 decades have witnessed a revolution in the discovery of pharmaceutical agents with novel mechanisms of action and favorable side-effect profile, enriching substantially our therapeutic armamentarium. ⁴ However, it is unclear whether these developments benefited all people with epilepsy worldwide.

The current study ⁵ addresses this knowledge gap. By means of analyzing pharmaceutical sales data from 73 countries from 2012 to 2022, the investigators estimated ASMs consumption, expressed as the defined daily dose per ten-thousand inhabitants per day (DDD/TID). ⁵ Further stratification was performed based on country income levels. They found that the multinational ASMs consumption increased throughout that decade with an average annual percentage change of +2.58%. ⁵ Yet, that consumption increased disproportionally with high-income countries (HICs) experiencing a greater than 4-fold growth compared to LMICs by the end of the study period. ⁵ Second-generation ASMs (eg, levetiracetam and lamotrigine) showed growth in consumption, contrary to first-generation ASMs (eg, phenobarbital, phenytoin, and carbamazepine) whose consumption declined. ⁵ Nevertheless, despite escalating admonition for its teratogenic potential, ⁶ valproate remained the most widely used ASM globally, with the stronger consumption growth observed in LMICs and modest decline in certain HICs. ⁵ Likewise, newly marketed and, hence, still patented third-generation ASMs (eg, lacosamide, perampanel, and brivaracetam) demonstrated impressive growth predominantly in HICs. ⁵

In the absence of a global, publicly funded, harmonized pharmaceutical surveillance system, this study ⁵ provides the most up-to-date, longitudinal evidence of ASMs utilization from a broad representation of countries/regions accounting together for approximately 77% of the world's population. In that sense, it provides a sound benchmark that informs policy formulation and can be used as a baseline to gauge future interventions. The Multinational Integrated Data Analysis System database (MIDAS) used incorporates sales volumes from various distributors accounting for an average national coverage of 88% and has been previously validated against external data sources and used effectively for other drug classes such as antibiotics, ⁷ opiates, ⁸ and psychotropic medications. ⁹

Yet, the use of pharmaceutical sales data as a proxy for medication consumption is imperfect as discrepancies could arise from wastage of drugs, stockpiling, or cross-border distribution of medications that remained unconsumed. ⁸ Moreover, the MIDAS database does not contain patient-level data. As such, there was no information of the exact indication for ASMs consumption. To counteract this drawback, the authors conducted a sensitivity analysis substituting the national population with the epilepsy population based on the Global Burden of Disease data (GBD collaborators), calculating the DDD per hundred patients with epilepsy (HED) instead. The consumption rates calculated as DDD/HED were consistent with the main analysis. ⁵ Still, no information was available on patient demographics (eg, age, gender, ethnicity, etc), epilepsy specifics (eg, etiology, duration, seizure type and frequency, comorbidities, etc), and prescribers’ constitution (eg, primary care vs specialists, pediatric vs adult healthcare providers, etc). As such, case ascertainment, sampling approach, the definitions of active epilepsy, and of adequate treatment cannot be reliably performed. Even at a micro- and macro-economic level stratification was solely based on country income lacking additional information (eg, national health expenditure, development index, urban vs rural, referral patterns, prescribing habits, reimbursement systems, etc).

These limitations notwithstanding, this study ⁵ highlights the global, albeit unequal, increase in ASMs consumption and the global, albeit unequal, trend toward newer generation ASMs adaptation. The question arises whether these findings are specific to epilepsy or reflect systemic healthcare access and provision issues pervasive to the countries/regions investigated that may have been further aggravated locally by socioeconomic unrest in some countries that have experienced considerable political and financial disruption during the study period or globally due to the COVID-19 pandemic. Without interindividual data to inform about potential underuse, overuse, or misuse of ASMs and a control group of another chronic neurological or medical disorder where longitudinal management is required, one would be hard pressed to draw safe conclusions. Nevertheless, as prior studies have insinuated, regulatory factors and policies related to cost, access, and quality assurance have a large effect on the demand side. ⁹ In epilepsy in particular, akin to mental health, ⁹ social and religious barriers related to discrimination and stigmatization may further widen the treatment gap.

Future research efforts at a national and international level should further evaluate the underpinnings of the disparities to inform on potential solutions to address them. That would facilitate radical rethinking of existing policies such as inclusion of ASMs on Essential Medicine Lists, advocacy and funding for data-driven and sustainable stewardship initiatives related to procurement and supply of medications, reimbursement schemes, medicine donation, and local production, ¹⁰ along with parallel assessment of the economic benefit of such investments. In addition to laws and guidelines pertaining to availability, accessibility, affordability, quality, and rational use of ASMs in each country, such endeavors should also include awareness campaigns and educational programs to address ingrained cultural and perceptual factors that relate to physicians’ and patients’ attitudes toward epilepsy treatment. ¹⁰

All things being equal, global ASMs consumption remains unequal. This study provides comprehensive evidence of highly unbalanced worldwide access that has been pervasive over decades ¹¹ and calls for collaborative, intersectoral action among all stakeholders to narrow the treatment gap.