Spanou Ioanna, Mavridis Theodoros, Mitsikostas Dimos D
1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Front Pharmacol. 2019 Jul 24;10:809. doi: 10.3389/fphar.2019.00809. eCollection 2019.
Nocebo refers to adverse events related to patients' negative expectations and previous experiences, mediated by several neurobiological pathways within the brain. It is common among neurological patients and affects adherence and treatment outcomes, representing a real clinical challenge. We conducted a systematic search based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines in MEDLINE database, using several keywords for studies that can be processed to investigate the magnitude of nocebo in generics and biosimilars used in the most common neurological diseases. The aim was to estimate its size and suggest strategies to minimize its prevalence in clinical trials and practice. Of a total of 2,606 identified articles, after criteria-based selection, 35 studies were included for analysis. Overall, there was vast heterogeneity across the studies concerning population, study design, and outcomes. Nocebo response could be estimated only in one double-blind randomized trial of generic glatiramer acetate in relapsing remitting multiple sclerosis that included a placebo arm. In this trial, no significant differences observed between the three arms (innovator, bioequivalent, and placebo) in favorable and unfavorable outcomes. In the open-label phase of the trial, an increased withdrawal rate was recorded in patients switched from placebo to bioequivalent (8.4%) that may be related to nocebo. In other open-label and real-world studies evaluating biosimilars or generics for brain disorders, a similar indirect nocebo effect is assuming by several investigators. Also, knowledge gaps between health-care providers and patients exist towards generics and biosimilars. Despite its presence, the true burden of the nocebo response and effect cannot be accurately estimated in existing studies with generics and biosimilars in neurological diseases. Targeted strategies for clinical trials' design are needed in order to measure the exact nocebo's size.
反安慰剂效应是指与患者的负面期望和既往经历相关的不良事件，由大脑内的多种神经生物学途径介导。它在神经系统疾病患者中很常见，会影响依从性和治疗效果，是一个实际的临床挑战。我们根据PRISMA（系统评价和Meta分析的首选报告项目）指南在MEDLINE数据库中进行了系统检索，使用了几个关键词来查找可用于研究最常见神经系统疾病中使用的仿制药和生物类似药的反安慰剂效应程度的研究。目的是估计其规模，并提出在临床试验和实践中尽量降低其发生率的策略。在总共识别出的2606篇文章中，经过基于标准的筛选，纳入35项研究进行分析。总体而言，这些研究在人群、研究设计和结果方面存在很大异质性。只有一项关于复发缓解型多发性硬化症中醋酸格拉替雷仿制药的双盲随机试验（该试验设有安慰剂组）能够估计反安慰剂反应。在该试验中，三组（原研药、生物等效药和安慰剂）在有利和不利结果方面未观察到显著差异。在试验的开放标签阶段，从安慰剂转换为生物等效药的患者中记录到更高的退出率（8.4%），这可能与反安慰剂效应有关。在其他评估用于脑部疾病的生物类似药或仿制药的开放标签和真实世界研究中，一些研究人员也假设存在类似的间接反安慰剂效应。此外，医疗保健提供者和患者之间对仿制药和生物类似药也存在知识差距。尽管存在反安慰剂效应，但在现有关于神经系统疾病中仿制药和生物类似药的研究中，无法准确估计反安慰剂反应和效应的真实负担。需要制定针对临床试验设计的策略，以测量反安慰剂效应的确切规模。
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