{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T23:40:28Z","timestamp":1793317228881,"version":"4.5.0"},"reference-count":36,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Intern Med"],"published-print":{"date-parts":[[2024,12,1]]},"abstract":"<jats:sec><jats:title>Importance<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To compare a masked benzodiazepine receptor agonist taper plus augmented CBTI vs an unmasked taper plus standard CBTI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>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\u2013equivalent 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interventions<\/jats:title><jats:p>Masked taper plus cognitive behavioral therapy-augmented program (MTcap); standard CBTI plus supervised (unmasked) gradual taper (SGT).<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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\u2009=\u200992) or SGT (n\u2009=\u200996). Compared with SGT, MTcap resulted in greater benzodiazepine receptor agonist discontinuation at 6 months (MTcap\u2009=\u200964 [73.4%], SGT\u2009=\u200952 [58.6%]; odds ratio [OR], 1.95; 95% CI 1.03-3.70; <jats:italic>P<\/jats:italic>\u2009=\u2009.04) and 1 week posttreatment (MTcap\u2009=\u200976 [88.4%], SGT\u2009=\u2009 62 [67.4%]; OR, 3.68; 95% CI, 1.67-8.12; <jats:italic>P<\/jats:italic>\u2009=\u2009.001) and reduced frequency of benzodiazepine receptor agonist use (nights\/week) at 1 week posttreatment (\u22121.31; 95% CI, \u22122.05 to \u22120.57; <jats:italic>P<\/jats:italic>\u2009&amp;amp;lt;\u2009.001). Insomnia Severity Index improved with no significant between-group difference at follow-up (baseline to 1 week posttreatment, 1.38; <jats:italic>P<\/jats:italic>\u2009=\u2009.16; baseline to 6 months, 0.16; <jats:italic>P<\/jats:italic>\u2009=\u2009.88).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Relevance<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6822133\/\">NCT03687086<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamainternmed.2024.5020","type":"journal-article","created":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T15:00:43Z","timestamp":1728313243000},"page":"1448","source":"Crossref","is-referenced-by-count":24,"title":["Masked Taper With Behavioral Intervention for Discontinuation of Benzodiazepine Receptor Agonists"],"prefix":"10.1001","volume":"184","author":[{"given":"Constance H.","family":"Fung","sequence":"first","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"},{"name":"Department of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Alessi","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"},{"name":"Department of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Martin","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"},{"name":"Department of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Josephson","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Kierlin","sequence":"additional","affiliation":[{"name":"Northwest Sleep and Behavior, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Dzierzewski","sequence":"additional","affiliation":[{"name":"National Sleep Foundation, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison A.","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Diego, La Jolla"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Safwan","family":"Badr","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Wayne State University, Detroit, Michigan"},{"name":"Department of Medicine, John D. Dingell VA Medical Center, Detroit, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Zeidler","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, Los Angeles"},{"name":"Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Kelly","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"},{"name":"Department of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason P.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Veterans Affairs VISN 19, Glendale, Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A.","family":"Cook","sequence":"additional","affiliation":[{"name":"Los Angeles TMS Institute Inc, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Der-Mcleod","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Ghadimi","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"},{"name":"Department of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saadia","family":"Naeem","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Partch","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Guzman","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"},{"name":"Department of Medicine, University of California, Los Angeles"},{"name":"Department of Veterans Affairs VISN 21, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin","family":"Grinberg","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Geriatric, Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"8","key":"ioi240064r1","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.5665\/sleep.3914","article-title":"Trends in outpatient visits for insomnia, sleep apnea, and prescriptions for sleep medications among US adults: findings from the National Ambulatory Medical Care survey 1999-2010.","volume":"37","author":"Ford","year":"2014","journal-title":"Sleep"},{"issue":"7526","key":"ioi240064r2","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1136\/bmj.38623.768588.47","article-title":"Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits.","volume":"331","author":"Glass","year":"2005","journal-title":"BMJ"},{"issue":"1","key":"ioi240064r3","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1007\/s12603-011-0015-7","article-title":"Association between benzodiazepines and recurrent falls: a cross-sectional elderly population-based study.","volume":"15","author":"Rossat","year":"2011","journal-title":"J Nutr Health Aging"},{"issue":"9","key":"ioi240064r4","doi-asserted-by":"publisher","first-page":"749","DOI":"10.2165\/00002512-200522090-00004","article-title":"Postural instability and consequent falls and hip fractures associated with use of hypnotics in the elderly: A comparative review.","volume":"22","author":"Allain","year":"2005","journal-title":"Drugs Aging"},{"issue":"4","key":"ioi240064r5","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1111\/jgs.12226","article-title":"Choosing wisely.","volume":"61","author":"American Geriatrics Society Choosing Wisely Workgroup","year":"2013","journal-title":"J Am Geriatr Soc"},{"issue":"2","key":"ioi240064r6","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1192\/bjp.bp.113.126003","article-title":"Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials.","volume":"204","author":"Gould","year":"2014","journal-title":"Br J Psychiatry"},{"issue":"5","key":"ioi240064r7","article-title":"Psychosocial interventions for benzodiazepine harmful use, abuse or dependence.","volume":"2015","author":"Darker","year":"2015","journal-title":"Cochrane Database Syst Rev"},{"issue":"533","key":"ioi240064r8","first-page":"958","article-title":"Withdrawal from long-term benzodiazepine use: randomised trial in family practice.","volume":"56","author":"Vicens","year":"2006","journal-title":"Br J Gen Pract"},{"key":"ioi240064r9","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1002\/(SICI)1098-2299(199703)40:3<230::AID-DDR3>3.0.CO;2-L","article-title":"Double-blind, placebo-controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia.","volume":"40","author":"Leppik","year":"1997","journal-title":"Drug Dev Res"},{"issue":"5","key":"ioi240064r10","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.smrv.2005.05.001","article-title":"Placebo effects in primary insomnia.","volume":"9","author":"Perlis","year":"2005","journal-title":"Sleep Med Rev"},{"issue":"6","key":"ioi240064r11","first-page":"925","article-title":"Effect of placebo conditions on polysomnographic parameters in primary insomnia: a meta-analysis.","volume":"38","author":"Winkler","year":"2015","journal-title":"Sleep"},{"key":"ioi240064r12","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.smrv.2017.03.006","article-title":"A systematic review and meta-analysis of placebo versus no treatment for insomnia symptoms.","volume":"38","author":"Yeung","year":"2018","journal-title":"Sleep Med Rev"},{"issue":"6","key":"ioi240064r13","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.sleep.2011.03.008","article-title":"Dissection of the factors driving the placebo effect in hypnotic treatment of depressed insomniacs.","volume":"12","author":"McCall","year":"2011","journal-title":"Sleep Med"},{"issue":"2","key":"ioi240064r14","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1080\/07317115.2017.1356895","article-title":"Cognitive expectancies for hypnotic use among older adult veterans with chronic insomnia.","volume":"41","author":"Fung","year":"2018","journal-title":"Clin Gerontol"},{"issue":"4","key":"ioi240064r15","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1080\/15402002.2022.2115046","article-title":"Do placebos primarily affect subjective as opposed to objective measures? a meta-analysis of placebo responses in insomnia RCTs.","volume":"21","author":"Muench","year":"2023","journal-title":"Behav Sleep Med"},{"key":"ioi240064r17","doi-asserted-by":"crossref","first-page":"717","DOI":"10.3389\/fpsyt.2019.00717","article-title":"Hypnotic discontinuation using a blinded (masked) tapering approach: a case series.","volume":"10","author":"Fung","year":"2019","journal-title":"Front Psychiatry"},{"issue":"2","key":"ioi240064r18","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1037\/0278-6133.23.2.198","article-title":"The placebo puzzle: putting together the pieces.","volume":"23","author":"Stewart-Williams","year":"2004","journal-title":"Health Psychol"},{"issue":"5","key":"ioi240064r19","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1093\/sleep\/34.5.601","article-title":"The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response.","volume":"34","author":"Morin","year":"2011","journal-title":"Sleep"},{"issue":"11","key":"ioi240064r20","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/sleep\/30.11.1547","article-title":"Dysfunctional beliefs and attitudes about sleep (DBAS): validation of a brief version (DBAS-16).","volume":"30","author":"Morin","year":"2007","journal-title":"Sleep"},{"issue":"2","key":"ioi240064r21","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1176\/appi.ajp.161.2.332","article-title":"Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia.","volume":"161","author":"Morin","year":"2004","journal-title":"Am J Psychiatry"},{"issue":"10","key":"ioi240064r22","first-page":"1015","article-title":"Discontinuation of benzodiazepines among older insomniac adults treated with cognitive-behavioural therapy combined with gradual tapering: a randomized trial.","volume":"169","author":"Baillargeon","year":"2003","journal-title":"CMAJ"},{"key":"ioi240064r23","doi-asserted-by":"crossref","DOI":"10.1038\/s41380-024-02445-4","article-title":"Discontinuation of psychotropic medication: a synthesis of evidence across medication classes.","author":"Vinkers","year":"2024","journal-title":"Mol Psychiatry"},{"issue":"8","key":"ioi240064r24","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1007\/s00228-017-2257-8","article-title":"A systematic review of interventions to deprescribe benzodiazepines and other hypnotics among older people.","volume":"73","author":"Reeve","year":"2017","journal-title":"Eur J Clin Pharmacol"},{"issue":"2","key":"ioi240064r25","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1037\/0022-006X.75.2.325","article-title":"Hypnotic taper with or without self-help treatment of insomnia: a randomized clinical trial.","volume":"75","author":"Belleville","year":"2007","journal-title":"J Consult Clin Psychol"},{"issue":"497","key":"ioi240064r26","first-page":"923","article-title":"Psychological treatment for insomnia in the management of long-term hypnotic drug use: a pragmatic randomised controlled trial.","volume":"53","author":"Morgan","year":"2003","journal-title":"Br J Gen Pract"},{"issue":"1","key":"ioi240064r27","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/j.1360-0443.2008.02364.x","article-title":"Effectiveness of current treatment approaches for benzodiazepine discontinuation: a meta-analysis.","volume":"104","author":"Parr","year":"2009","journal-title":"Addiction"},{"key":"ioi240064r28","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1192\/bjp.182.6.498","article-title":"Tapering off long-term benzodiazepine use with or without group cognitive-behavioural therapy: three-condition, randomised controlled trial.","volume":"182","author":"Voshaar","year":"2003","journal-title":"Br J Psychiatry"},{"key":"ioi240064r29","doi-asserted-by":"crossref","DOI":"10.1016\/j.smrv.2019.101214","article-title":"Psychosocial intervention for discontinuing benzodiazepine hypnotics in patients with chronic insomnia: a systematic review and meta-analysis.","volume":"48","author":"Takaesu","year":"2019","journal-title":"Sleep Med Rev"},{"key":"ioi240064r30","article-title":"Use of a blinded hypnotic tapering strategy to promote hypnotic discontinuation.","author":"Edinger","journal-title":"Sleep"},{"key":"ioi240064r31","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.e8343","article-title":"Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration.","volume":"345","author":"Huedo-Medina","year":"2012","journal-title":"BMJ"},{"issue":"2","key":"ioi240064r32","first-page":"225","article-title":"Meta-analysis of benzodiazepine use in the treatment of insomnia.","volume":"162","author":"Holbrook","year":"2000","journal-title":"CMAJ"},{"issue":"10","key":"ioi240064r33","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1185\/03007990903167415","article-title":"Interpreting score differences in the Insomnia Severity Index: using health-related outcomes to define the minimally important difference.","volume":"25","author":"Yang","year":"2009","journal-title":"Curr Med Res Opin"},{"issue":"26","key":"ioi240064r34","first-page":"459","article-title":"Nocebo phenomena in medicine: their relevance in everyday clinical practice.","volume":"109","author":"H\u00e4user","year":"2012","journal-title":"Dtsch Arztebl Int"},{"issue":"2","key":"ioi240064r35","doi-asserted-by":"crossref","DOI":"10.1002\/prp2.208","article-title":"The nocebo effect of drugs.","volume":"4","author":"Plan\u00e8s","year":"2016","journal-title":"Pharmacol Res Perspect"},{"issue":"4","key":"ioi240064r36","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/acps.12422","article-title":"Do cultures influence placebo response?","volume":"132","author":"Bhugra","year":"2015","journal-title":"Acta Psychiatr Scand"},{"key":"ioi240064r16","unstructured":"Governor Gavin Newsom Issues Stay at Home Order. Office of Governor Gavin Newsom. Updated March 19, 2020. Accessed February 15, 2024, https:\/\/www.gov.ca.gov\/2020\/03\/19\/governor-gavin-newsom-issues-stay-at-home-order\/"}],"container-title":["JAMA Internal Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamainternalmedicine\/articlepdf\/2824755\/jamainternal_fung_2024_oi_240064_1732212183.6617.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T16:03:00Z","timestamp":1733155380000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamainternalmedicine\/fullarticle\/2824755"}},"subtitle":["A Randomized Clinical Trial"],"short-title":[],"issued":{"date-parts":[[2024,12,1]]},"references-count":36,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamainternmed.2024.5020","relation":{},"ISSN":["2168-6106"],"issn-type":[{"value":"2168-6106","type":"print"}],"subject":[],"published":{"date-parts":[[2024,12,1]]}}}