Szmigiel Agnieszka, da Rocha Miguel Monteiro, Browne Kate, Morales Daniel, Olsen David Benee, Warren-Gash Charlotte, Douglas Ian, Bhaskaran Krishnan, Carreira Helena
Pharmacovigilance Office, European Medicines Agency, Amsterdam, the Netherlands.
Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK.
Pharmacoepidemiol Drug Saf. 2025 Apr;34(4):e70140. doi: 10.1002/pds.70140.
β-agonists and β-antagonists are among the most prescribed drugs worldwide. In 2018, studies suggesting a harmful association between propranolol and Parkinson's disease (PD) prompted a signal procedure by the European Medicines Agency's safety committee, which concluded with no update of product information. Several studies have been published since then. We aimed to systematically review, critically appraise, and meta-analyse all studies on the association between the use of β-antagonists (including propranolol) and β-agonists, and the risk of PD.
We searched Embase and Medline up to December 2024 for observational and intervention studies that reported relative risk estimates of the association between use of these medicines and PD. Two reviewers screened the records, extracted the data, and assessed the risk of bias. The restricted maximum likelihood method was used to compute pooled effect estimates and 95% confidence intervals (CIs).
Twenty-two studies were eligible. Overall, 20 had a high risk of bias in at least one domain. Twelve studies had medium to high risk of outcome misclassification. Of the 14 studies concerning β-antagonists, eleven had an unclear or high risk of protopathic bias, as propranolol is indicated for the treatment of essential tremor. Control for confounding by socio-economic status, area of residence (urban/rural), and smoking (a protective factor against PD) was deficient or lacking in 9/22, 15/22, and 12/22 studies, respectively. Lag times were applied in 9/22 studies. In meta-analysis, the summary relative risk (RR) of PD was 1.41 (95% CI: 1.18-1.68) for the class of β-antagonists (12 studies) and 0.93 (0.84-1.03) for β2-agonists (11 studies). Among specific β-antagonists, the summary RR of PD was 2.36 (1.66-3.36) for propranolol (7 studies), 0.84 (0.80-0.88) for carvedilol (3 studies) and 1.02 (0.87-1.18) for metoprolol (4 studies). For specific β2-agonists, summary RR was 0.88 (0.77-1.01) for salbutamol (7 studies), 0.91 (0.88-0.95) for short-acting β2-agonists (6 studies), and 0.85 (0.76-0.96) for long-acting β2 agonists (5 studies). Restricting to subgroups based on quality criteria resulted in weaker or non-statistically significant associations.
The quality and quantity of the available evidence do not support a causal association between use of β-adrenoreceptor modulators and PD. Significant associations are most likely explained by protopathic bias and confounding.
β受体激动剂和β受体拮抗剂是全球范围内处方量最大的药物之一。2018年，有研究表明普萘洛尔与帕金森病（PD）之间存在有害关联，这促使欧洲药品管理局安全委员会启动了信号程序，最终产品信息未更新。自那时以来，已经发表了几项研究。我们旨在系统地回顾、批判性评价并对所有关于使用β受体拮抗剂（包括普萘洛尔）和β受体激动剂与PD风险之间关联的研究进行荟萃分析。
我们检索了截至2024年12月的Embase和Medline数据库，以查找报告这些药物使用与PD关联的相对风险估计值的观察性和干预性研究。两名审阅者筛选记录、提取数据并评估偏倚风险。使用限制最大似然法计算合并效应估计值和95%置信区间（CI）。
22项研究符合条件。总体而言，20项研究在至少一个领域存在高偏倚风险。12项研究存在中到高的结果错误分类风险。在14项关于β受体拮抗剂的研究中，11项存在原发病偏倚不明确或高风险，因为普萘洛尔用于治疗特发性震颤。在9/22、15/22和12/22的研究中，分别缺乏或未充分控制社会经济地位、居住地区（城市/农村）和吸烟（PD的一个保护因素）的混杂因素。9/22的研究应用了滞后时间。在荟萃分析中，β受体拮抗剂类别（12项研究）的PD汇总相对风险（RR）为1.41（95%CI：1.18 - 1.68），β2受体激动剂（11项研究）为0.93（0.84 - 1.03）。在特定的β受体拮抗剂中，普萘洛尔（7项研究）的PD汇总RR为2.36（1.66 - 3.36），卡维地洛（3项研究）为0.84（0.80 - 0.88），美托洛尔（4项研究）为1.02（0.87 - 1.18）。对于特定的β2受体激动剂，沙丁胺醇（7项研究）的汇总RR为0.88（0.77 - 1.01），短效β2受体激动剂（
