Silva Maria A, Duarte Gonçalo S, Camara Raquel, Rodrigues Filipe B, Fernandes Ricardo M, Abreu Daisy, Mestre Tiago, Costa João, Trenkwalder Claudia, Ferreira Joaquim J
From the Laboratory of Clinical Pharmacology and Therapeutics (M.A.S., G.S.D., R.C., F.B.R., R.M.F., D.A., J.C., J.J.F.), Portuguese Collaborating Center of the IberoAmerican Cochrane Network, Cochrane Portugal (G.S.D., R.M.F., J.C.), and Center for Evidence-Based Medicine (J.C.), Faculty of Medicine, University of Lisbon; Clinical Pharmacology Unit (M.A.S., G.S.D., R.C., F.B.R., R.M.F., D.A., J.C., J.J.F.), Instituto de Medicina Molecular, Lisbon, Portugal; Huntington's Disease Centre (F.B.R.), Institute of Neurology, University College London, UK; Parkinson's Disease and Movement Disorders Center (T.M.), Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa, Canada; Paracelsus-Elena Klinik (C.T.), Center of Parkinsonism and Movement Disorders, Kassel; and the Department of Neurosurgery (C.T.), University Medical Center, Göttingen, Germany.
Neurology. 2017 Jun 6;88(23):2216-2224. doi: 10.1212/WNL.0000000000004004. Epub 2017 May 10.
To estimate the placebo and nocebo responses in restless legs syndrome (RLS) and explore their determinants.
Databases were searched up to October 2015. Randomized, double-blind, placebo-controlled trials of patients with RLS were included if quantitative data were extractable in the placebo arm. Placebo response was defined as the within-group change from baseline, using any scale measuring RLS severity or disability. Nocebo response was defined as the proportion of patients experiencing adverse events in the placebo arm. Random-effects meta-analysis was used to pool data. Statistical heterogeneity was assessed with statistic. Several predetermined subgroup and sensitivity analysis were performed. PROSPERO registration number is CRD42015027992.
We included 85 randomized controlled trials (5,046 participants). Pooled placebo response effect size was -1.41 (95% confidence interval [CI] -1.56 to -1.25, 64 trials, = 88.1%), corresponding to -6.58 points in the International RLS Study Group Scale (IRLS). Pooled nocebo response was 45.36% (95% CI 40.47%-50.29%, 72 trials; = 89.8%). The placebo and nocebo responses were greater in trials with longer duration, evaluating pharmacologic interventions and idiopathic RLS, and in industry-funded and unpublished studies. The placebo response was considerably smaller in objective as compared to subjective outcomes. In addition, the nocebo response increases proportionally with the placebo response, and has the same predictors.
The magnitude of the placebo response in RLS is above the threshold of minimal clinical important difference, and the frequency of adverse events is also considerable. These results are relevant to inform the design and interpretation of future clinical trials.
评估不安腿综合征（RLS）中的安慰剂和反安慰剂反应，并探究其决定因素。
检索数据库至2015年10月。纳入RLS患者的随机、双盲、安慰剂对照试验，前提是安慰剂组可提取定量数据。安慰剂反应定义为使用任何测量RLS严重程度或残疾程度的量表，从基线开始的组内变化。反安慰剂反应定义为安慰剂组中经历不良事件的患者比例。采用随机效应荟萃分析汇总数据。用统计量评估统计异质性。进行了几项预先设定的亚组分析和敏感性分析。PROSPERO注册号为CRD42015027992。
我们纳入了85项随机对照试验（5046名参与者）。汇总的安慰剂反应效应量为-1.41（95%置信区间[CI]-1.56至-1.25，64项试验，I² = 88.1%），相当于国际RLS研究组量表（IRLS）中-6.58分。汇总的反安慰剂反应为45.36%（95%CI 40.47%-50.29%，72项试验；I² = 89.8%）。在持续时间较长、评估药物干预和特发性RLS的试验中，以及在行业资助和未发表的研究中，安慰剂和反安慰剂反应更大。与主观结果相比，客观结果中的安慰剂反应要小得多。此外，反安慰剂反应与安慰剂反应成比例增加，且具有相同的预测因素。
RLS中安慰剂反应的幅度高于最小临床重要差异的阈值，不良事件的发生率也相当可观。这些结果对于指导未来临床试验的设计和解释具有重要意义。
