Benzodiazepines and Z-drugs: descriptive analysis of reported paradoxical reactions
Vigil Sanit Debate, Rio de Janeiro, 2026, v.14: e02544| Published on: 2026-05-05
DOI:
https://doi.org/10.22239/2317-269X.02544Keywords:
Drug-Related Side Effects and Adverse Reactions, Pharmacovigilance, Hypnotics and SedativesAbstract
Introduction: Benzodiazepines (BZD) and Z-drugs have been increasingly prescribed and used. In addition to well-recognized adverse events, these classes may trigger paradoxical reactions, which are rarely explored in the literature and are characterized by effects opposite to those expected. Objective: To evaluate the profile of reports of paradoxical reactions to BZD and Z-drugs in the Brazilian electronic spontaneous reporting system (VigiMed). Method: Cross-sectional analytical study based on reports of potential adverse drug events (ADEs) indicative of paradoxical reactions, classified according to MedDRA terminology and recorded in VigiMed between January 2018 and April 2023. The analysis included anxiolytics (N05BA), hypnotics and sedatives (N05CF, N05CD), and benzodiazepine-derived antiepileptics (N03AE). Disproportionality analysis was performed using the Reporting Odds Ratio (ROR). Results: A total of 466 reports of potential paradoxical reactions were identified. Most reports were submitted by consumers (65.9%) and pharmacists (26.6%) and involved women (54.5%) and older adults (34.9%). The majority were classified as non-serious (59.4%), with outcomes unknown (36%) or resolved (28.5%). The most frequently reported reactions were insomnia (29.8%), anxiety (18.9%), agitation (18.2%), and hallucination (13.7%). Disproportionality analysis showed significant associations for both BZD and Z-drugs. Agitation, insomnia, and anxiety stood out as paradoxical reactions associated with all drugs. Zolpidem and clonazepam were the medications with the highest number of significant associations. Conclusions: The signals of potential paradoxical reactions in widely prescribed drugs, especially zolpidem and clonazepam, highlight the need to reassess routine use. The findings reinforce the importance of pharmacovigilance and critical prescribing, particularly in older adults and women.
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Author Biographies
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Rafaela Lourenço Spoti , Escola de Enfermagem de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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Lara Riboli Bortolato, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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João Paulo Alves Cunha, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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Fabiana Rossi Varallo, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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Leonardo Régis Leira Pereira, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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Maria Olívia Barboza Zanetti, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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Data Availability Statement
The variables were obtained from a open database (VigiMed) and, as so, are available for anyone interessed through the link: https://app.powerbi.com/view?r=eyJrIjoiZGJiZjVjZmQtZGFkNC00ZjI1LWIxYmQtNDg5YmU1ZGEwNjQ0IiwidCI6ImI2N2FmMjNmLWMzZjMtNGQzNS04MGM3LWI3MDg1ZjVlZGQ4MSJ9
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