Kopsky David J, Szadek Karolina M, Schober Patrick, Vrancken Alexander F J E, Steegers Monique A H
Department of Anesthesiology, Amsterdam University Medical Center, Amsterdam, 1081 HV, the Netherlands.
Institute for Neuropathic Pain, Amsterdam, 1056 SN, the Netherlands.
J Pain Res. 2022 Feb 17;15:479-496. doi: 10.2147/JPR.S334840. eCollection 2022.
Enriched enrollment randomized withdrawal (EERW) pain trials are designed to include only responders with considerable pain relief without unacceptable side effects into the randomized phase. There are no recommendations for primary endpoints in such trials. Our objective was to propose recommendations based on assessment of trial characteristics, endpoints and effect sizes in EERW pain trials. We conducted a systematic review by searching electronic databases up to June 2020 for EERW trials comparing an analgesic with a placebo in adults suffering from chronic pain. A total of 28 trials met our criteria, involving 13662 patients in the open or single-blind phase and 7937 patients in the double-blind phase. As primary endpoint 18 trials used pain intensity measured with the visual analogue scale (VAS) or the 11-point numerical rating scale (NRS); 1 trial used a 4-point NRS. Loss of therapeutic response (LTR) was used in 1 trial and time to LTR was used in 8 trials as primary endpoint. Definitions of time to LTR differed considerably between trials. Only 2 out of 8 trials using time to LTR as primary endpoint reported the percentage of patients experiencing a minimum pain relief of 50%, compared to 14 out of 18 trials using NRS or VAS. Due to the complexity and diversity of time to LTR in EERW pain trials, we propose to use the NRS as primary endpoint with conservative imputation methods, and to use time to LTR as secondary endpoint.
富集入组随机撤药（EERW）疼痛试验旨在仅将疼痛得到显著缓解且无不可接受副作用的应答者纳入随机阶段。此类试验中对于主要终点尚无推荐意见。我们的目标是基于对EERW疼痛试验的试验特征、终点和效应大小的评估提出推荐意见。我们通过检索截至2020年6月的电子数据库，对比较镇痛药与安慰剂用于慢性疼痛成人患者的EERW试验进行了系统评价。共有28项试验符合我们的标准，开放或单盲阶段涉及13662例患者，双盲阶段涉及7937例患者。作为主要终点，18项试验使用视觉模拟量表（VAS）或11点数字评定量表（NRS）测量疼痛强度；1项试验使用4点NRS。1项试验使用治疗反应丧失（LTR），8项试验使用至LTR时间作为主要终点。各试验中至LTR时间的定义差异很大。在使用至LTR时间作为主要终点的8项试验中，只有2项报告了疼痛至少缓解50%的患者百分比，而在使用NRS或VAS的18项试验中有14项报告了该百分比。由于EERW疼痛试验中至LTR时间的复杂性和多样性，我们建议使用NRS作为主要终点并采用保守的插补方法，将至LTR时间作为次要终点。
