Fung Constance H, Alessi Cathy, Martin Jennifer L, Josephson Karen, Kierlin Lara, Dzierzewski Joseph M, Moore Alison A, Badr M Safwan, Zeidler Michelle, Kelly Monica, Smith Jason P, Cook Ian A, Der-Mcleod Erin, Ghadimi Sara, Naeem Saadia, Partch Lisa, Guzman Andrew, Grinberg Austin, Mitchell Michael
Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California.
Department of Medicine, University of California, Los Angeles.
JAMA Intern Med. 2024 Dec 1;184(12):1448-1456. doi: 10.1001/jamainternmed.2024.5020.
Placebo effects are commonly observed in benzodiazepine receptor agonist hypnotic clinical trials. Clinical guidelines recommend discontinuing benzodiazepine receptor agonist hypnotics (particularly in older adults) and administering cognitive behavioral therapy for insomnia (CBTI) as first-line therapy for insomnia. It is unknown whether a novel intervention that masks the daily dose of benzodiazepine receptor agonist during tapering and augments CBTI with novel cognitive and behavioral exercises targeting placebo effect mechanisms improves benzodiazepine receptor agonist discontinuation.
To compare a masked benzodiazepine receptor agonist taper plus augmented CBTI vs an unmasked taper plus standard CBTI.
DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial conducted at an academic medical center and a Department of Veterans Affairs medical center included adults aged 55 years or older who had used lorazepam, alprazolam, clonazepam, temazepam, and/or zolpidem for current or prior insomnia, at doses of less than 8-mg diazepam-equivalent 2 or more nights per week for at least 3 months. Data were collected between December 2018 and November 2023. Data analyses were conducted between November 2023 and July 2024.
Masked taper plus cognitive behavioral therapy-augmented program (MTcap); standard CBTI plus supervised (unmasked) gradual taper (SGT).
The primary efficacy outcome was percentage achieving benzodiazepine receptor agonist discontinuation 6 months after treatment ended (6-month; intention-to-treat) measured with 7-day self-reported medication logs and for a subset, urine tests. Secondary outcomes were Insomnia Severity Index scores at 1 week posttreatment and 6 months posttreatment, percentage of participants that have discontinued benzodiazepine receptor agonist use at 1 week posttreatment, and benzodiazepine receptor agonist dose and the Dysfunctional Beliefs About Sleep-Medication subscale at 1 week and 6 months posttreatment.
Of 338 participants who underwent in-depth screening, 188 participants (mean [SD] age, 69.8 [8.3] years, 123 male [65.4%] and 65 female [35.6%]) were randomly assigned to MTcap (n = 92) or SGT (n = 96). Compared with SGT, MTcap resulted in greater benzodiazepine receptor agonist discontinuation at 6 months (MTcap = 64 [73.4%], SGT = 52 [58.6%]; odds ratio [OR], 1.95; 95% CI 1.03-3.70; P = .04) and 1 week posttreatment (MTcap = 76 [88.4%], SGT = 62 [67.4%]; OR, 3.68; 95% CI, 1.67-8.12; P = .001) and reduced frequency of benzodiazepine receptor agonist use (nights/week) at 1 week posttreatment (-1.31; 95% CI, -2.05 to -0.57; P < .001). Insomnia Severity Index improved with no significant between-group difference at follow-up (baseline to 1 week posttreatment, 1.38; P = .16; baseline to 6 months, 0.16; P = .88).
This randomized clinical trial found that a program combining masked tapering with novel cognitive and behavioral exercises targeting placebo mechanisms improved the percentage of long-term benzodiazepine receptor agonist discontinuation compared with standard CBTI plus an unmasked taper.
ClinicalTrials.gov Identifier: NCT03687086.
在苯二氮䓬受体激动剂催眠临床试验中，安慰剂效应普遍存在。临床指南建议停用苯二氮䓬受体激动剂催眠药（尤其是在老年人中），并将失眠认知行为疗法（CBTI）作为失眠的一线治疗方法。目前尚不清楚一种新型干预措施，即在逐渐减量过程中掩盖苯二氮䓬受体激动剂的每日剂量，并通过针对安慰剂效应机制的新型认知和行为练习增强CBTI，是否能改善苯二氮䓬受体激动剂的停用情况。
比较掩盖式苯二氮䓬受体激动剂逐渐减量加增强型CBTI与非掩盖式逐渐减量加标准CBTI的效果。
设计、设置和参与者：这项随机临床试验在一家学术医疗中心和一家退伍军人事务部医疗中心进行，纳入了55岁及以上的成年人，他们因当前或既往失眠使用过劳拉西泮、阿普唑仑、氯硝西泮、替马西泮和/或唑吡坦，剂量低于等效于8毫克地西泮，每周至少两晚，持续至少3个月。数据收集于2018年12月至2023年11月之间。数据分析于2023年11月至2024年7月之间进行。
掩盖式逐渐减量加认知行为疗法增强方案（MTcap）；标准CBTI加监督（非掩盖式）逐渐减量（SGT）。
主要疗效结局是治疗结束6个月后（6个月；意向性治疗）实现停用苯二氮䓬受体激动剂的百分比，通过7天自我报告的用药记录以及部分尿液检测来测量。次要结局包括治疗后1周和6个月时的失眠严重程度指数得分、治疗后1周停用苯二氮䓬受体激动剂的参与者百分比、治疗后1周和6个月时的苯二氮䓬受体激动剂剂量以及关于睡眠 - 药物的功能失调信念子量表。
在338名接受深入筛查的参与者中，188名参与者（平均[标准差]年龄，69.8[8.3]岁，123名男性[65.4%]和65名女性[35.6%]）被随机分配到MTcap组（n = 92）或SGT组（n = 96）。与SGT组相比，MTcap组在6个月时停用苯二氮䓬受体激动剂的比例更高（MTcap组 = 64[73.4%]，SGT组 = 52[58.6%]；优势比[OR]，1.95；95%置信区间1.03 - 3.70；P = 0.04），在治疗后1周时也是如此（MTcap组 = 76[88.4%]，SGT组 = 62[67.4%]；OR，3.68；95%置信区间，1.67 - 8.12；P = 0.001），并且在治疗后1周时苯二氮䓬受体激动剂的使用频率（每周夜晚数）降低（-1.31；95%置信区间，-2.05至-0.57；P < 0.001）。失眠严重程度指数有所改善，随访期间组间无显著差异（从基线到治疗后1周，改善1.38；P = 0.16；从基线到6个月，改善0.16；P = 0.88）。
这项随机临床试验发现，与标准CBTI加非掩盖式逐渐减量相比，并针对安慰剂机制进行新型认知和行为练习的掩盖式逐渐减量方案，提高了长期停用苯二氮䓬受体激动剂的百分比。
ClinicalTrials.gov标识符：NCT03687086。
