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Randomized Controlled Trial
. 2024 Dec 1;184(12):1448-1456.
doi: 10.1001/jamainternmed.2024.5020.

Masked Taper With Behavioral Intervention for Discontinuation of Benzodiazepine Receptor Agonists: A Randomized Clinical Trial

Constance H Fung  1   2 , Cathy Alessi  1   2 , Jennifer L Martin  1   2 , Karen Josephson  1 , Lara Kierlin  3 , Joseph M Dzierzewski  4 , Alison A Moore  5 , M Safwan Badr  6   7 , Michelle Zeidler  2   8 , Monica Kelly  1   2 , Jason P Smith  9 , Ian A Cook  10 , Erin Der-Mcleod  1 , Sara Ghadimi  1   2 , Saadia Naeem  1 , Lisa Partch  1 , Andrew Guzman  1   2   11 , Austin Grinberg  1 , Michael Mitchell  1
Affiliations
Randomized Controlled Trial

Masked Taper With Behavioral Intervention for Discontinuation of Benzodiazepine Receptor Agonists: A Randomized Clinical Trial

Constance H Fung et al. JAMA Intern Med. .

Abstract

Importance: 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.

Objective: 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.

Interventions: Masked taper plus cognitive behavioral therapy-augmented program (MTcap); standard CBTI plus supervised (unmasked) gradual taper (SGT).

Main outcomes and measures: 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.

Results: 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).

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT03687086.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Fung reported nonfinancial support from Department of Veterans Affairs as a Department of Veteran's Affairs (VA)/ Department of Defense Clinical Practice Guideline committee member, with travel paid to attend guideline committee meeting outside the submitted work; in addition, Dr Fung had a patent for WO2021087456A1 pending. Dr Martin reported grants from VA Health Systems Research and grants from NIH/NHLBI during the conduct of the study. Dr Kierlin reported consulting fees from University of California, Los Angeles during the conduct of the study. Dr Dzierzewski reported personal fees from Eisai Pharmaceuticals outside the submitted work. Dr Kelly reported grants from NIH/NHLBI (HL157754) during the conduct of the study. Dr Cook reported employment at Los Angeles TMS Institute (private practice); previously chief medical officer and senior VP of NeuroSigma, Inc (a neuromodulation device company); previously CEO and Cofounder of HeartCloud, Inc (a remote patient monitoring company); research grants/contracts from NIH, grants to Stanford University and to University of Southern California (DSMB, consultant) (for neuromodulation research), Magnus Medical (for neuromodulation research), equity/shareholder in Los Angeles TMS Institute, HeartCloud, NeuroSigma, patents fromNeuroSigma, HeartCloud, or the regents of the University of California, volunteer positions including board of directors, Clinical TMS Society (a 501(c)(6) organization), board of directors and VP at the Foundation for the Advancement of Clinical TMS (a 501(c)(3) organization). Mrs Der-Mcleod reported grants from the Department of Veteran's Affairs during the conduct of the study. Dr Mitchell reported grants from the VA during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of Participants Through Each Stage of the Trial
CBTI indicates cognitive behavioral therapy for insomnia; MTcap, masked taper plus cognitive behavioral therapy–augmented program; SGT, standard CBTI plus supervised (unmasked) gradual taper. aSome individuals met multiple exclusion criteria. bDefined as 1 or more sessions with a research psychologist.
Figure 2.
Figure 2.. Benzodiazepine Receptor Agonist (BZRA) Outcomes, Insomnia Severity, and Beliefs and Attitudes About Hypnotics, by Study Phase With Comparisons Between Treatment Arms
BZRA frequency of use and dose, Insomnia Severity Index, and Dysfunctional Beliefs and Attitudes about Sleep-16 Medication Subscale at baseline, 1 week posttreatment, and 6 months after treatment for participants assigned to the MTcap and SGT arms. 6M indicates 6 months after treatment ended; BZRA, benzodiazepine receptor agonists; BL, baseline; DBAS, Dysfunctional Beliefs and Attitudes about Sleep-16 Medication Subscale; Post, 1 week posttreatment; MTcap, masked taper plus cognitive behavioral therapy-augmented program; SGT, standard cognitive behavioral therapy plus supervised (unmasked) gradual taper.
See this image and copyright information in PMC

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