{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T07:57:12Z","timestamp":1762070232379,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T00:00:00Z","timestamp":1665187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Introduction: Benzodiazepines (BZDs) are used in the management of anxiety and sleep disorders; however, chronic use is associated with tolerance and dependence. During withdrawal, symptoms of anxiety are often severe and problematic for patients and may lead to relapse or maintenance on low doses of BZDs. Low, continuous doses of flumazenil reduce BZD withdrawal symptoms in several studies; however, bolus doses are known to induce anxiety and precipitate panic. Accordingly, this study aimed to determine whether continuous low-dose flumazenil is anxiogenic like bolus doses. Method: In a randomised control cross over design, participants received a continuous low-dose flumazenil infusion for eight days at an approximate rate of 4 mg\/24 h or placebo before crossing over to the alternate study arm. Participants were able to request diazepam as needed. The primary outcome was the change in state anxiety levels. Trait anxiety was also recorded at baseline and one month after the flumazenil\/placebo infusion period. Results: BZD use was significantly reduced in both groups. There were no significant differences between state anxiety and the 95% confidence interval showed no evidence of a clinically significant anxiogenic effect from low-dose flumazenil. Trait anxiety was significantly reduced one month after the infusion period. Conclusion: There is no evidence that continuous low-dose flumazenil infusion significantly increases state anxiety levels to a clinically significant level. Interestingly, flumazenil may decrease state anxiety during BZD withdrawal, unlike bolus doses of flumazenil. Flumazenil may have an anxiolytic effect on trait anxiety, which was evident one month after treatment.<\/jats:p>","DOI":"10.3390\/jcm11195948","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T23:39:31Z","timestamp":1665272371000},"page":"5948","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Is the Precipitation of Anxiety Symptoms Associated with Bolus Doses of Flumazenil a Barrier to Its Use at Low Continuous Doses in Benzodiazepine Withdrawal?"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8647-4968","authenticated-orcid":false,"given":"Alexander","family":"Gallo","sequence":"first","affiliation":[{"name":"Division of Psychiatry, Medical School, The University of Western Australia, Nedlands 6009, Australia"},{"name":"Fresh Start Recovery Programme, Subiaco 6008, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6810-8956","authenticated-orcid":false,"given":"Tim","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Currumbin Clinic, Currumbin 4223, Australia"},{"name":"School of Medicine, Griffith University, Gold Coast 4215, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kellie","family":"Bennett","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, Medical School, The University of Western Australia, Nedlands 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gioiamia","family":"Basso-Hulse","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, Medical School, The University of Western Australia, Nedlands 6009, Australia"},{"name":"Fresh Start Recovery Programme, Subiaco 6008, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary","family":"Hulse","sequence":"additional","affiliation":[{"name":"Division of Psychiatry, Medical School, The University of Western Australia, Nedlands 6009, Australia"},{"name":"Fresh Start Recovery Programme, Subiaco 6008, Australia"},{"name":"School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0740-5472(91)90024-5","article-title":"Pharmacologic aspects of benzodiazepine tolerance and dependence","volume":"8","author":"Busto","year":"1991","journal-title":"J. Subst. Abus. Treat."},{"key":"ref_2","first-page":"28","article-title":"Benzodiazepine use, abuse, and dependence","volume":"66","year":"2005","journal-title":"J. Clin. Psychiatry"},{"key":"ref_3","first-page":"501","article-title":"Benzodiazepines revisited","volume":"5","author":"Mehdi","year":"2012","journal-title":"Br. J. Med. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1097\/01.yco.0000165594.60434.84","article-title":"The diagnosis and management of benzodiazepine dependence","volume":"18","author":"Ashton","year":"2005","journal-title":"Curr. Opin. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1056\/NEJMra1611832","article-title":"Treatment of benzodiazepine dependence","volume":"376","author":"Soyka","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_6","first-page":"416864","article-title":"Mechanisms underlying tolerance after long-term benzodiazepine use: A future for subtype-selective GABAA receptor modulators?","volume":"2012","author":"Vinkers","year":"2012","journal-title":"Adv. Pharm. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"18595","DOI":"10.1073\/pnas.1204994109","article-title":"Benzodiazepine treatment induces subtype-specific changes in GABAA receptor trafficking and decreases synaptic inhibition","volume":"109","author":"Jacob","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5","DOI":"10.2174\/1381612023396681","article-title":"Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal","volume":"8","author":"Bateson","year":"2002","journal-title":"Curr. Pharm. Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0163-7258(03)00029-9","article-title":"Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence","volume":"98","author":"Allison","year":"2003","journal-title":"Pharm. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1111\/j.1360-0443.2011.03563.x","article-title":"Benzodiazepines revisited\u2014Will we ever learn?","volume":"106","author":"Lader","year":"2011","journal-title":"Addiction"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1016\/j.pharma.2009.07.001","article-title":"Benzodiazepine dependence: Focus on withdrawal syndrome","volume":"67","author":"Authier","year":"2009","journal-title":"Ann. Pharm. Fran\u00e7aises"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1111\/j.1360-0443.1994.tb03743.x","article-title":"The benzodiazepine withdrawal syndrome","volume":"89","author":"Petursson","year":"1994","journal-title":"Addiction"},{"key":"ref_13","first-page":"7","article-title":"Issues in the clinical use of benzodiazepines: Potency, withdrawal, and rebound","volume":"65","author":"Chouinard","year":"2004","journal-title":"J. Clin. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brat.2003.12.002","article-title":"Long-term outcome after discontinuation of benzodiazepines for insomnia: A survival analysis of relapse","volume":"43","author":"Morin","year":"2005","journal-title":"Behav. Res. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s11920-015-0642-5","article-title":"Withdrawing Benzodiazepines in Patients with Anxiety Disorders","volume":"18","author":"Lader","year":"2016","journal-title":"Curr. Psychiatry Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"273","DOI":"10.3109\/08039481003624173","article-title":"Benzodiazepine tapering: A prospective study","volume":"64","author":"Vikander","year":"2010","journal-title":"Nord. J. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2165\/00003088-198814010-00001","article-title":"Pharmacokinetics and Clinical Use of Flumazenil (Ro 15-1788)","volume":"14","author":"Klotz","year":"1988","journal-title":"Clin. Pharmacokinet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1007\/s002130051161","article-title":"A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users","volume":"147","author":"Mintzer","year":"1999","journal-title":"Psychopharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1177\/026988119801200205","article-title":"Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users","volume":"12","author":"Bernik","year":"1998","journal-title":"J. Psychopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1177\/026988119100500306","article-title":"Flumazenil-precipitated withdrawal symptoms in chronic users of therapeutic doses of diazepam","volume":"5","author":"Bernik","year":"1991","journal-title":"J. Psychopharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1177\/026988119601000201","article-title":"Flumazenil-precipitated panic and dysphoria in patients dependent on benzodiazepines: A possible aid to abstinence","volume":"10","author":"Tyrer","year":"1996","journal-title":"J. Psychopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s00213-004-2009-1","article-title":"Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure","volume":"178","author":"Mintzer","year":"2005","journal-title":"Psychopharmacology"},{"key":"ref_23","first-page":"1163","article-title":"Intravenous flumazenil following acute and repeated exposure to lorazepam in healthy volunteers: Antagonism and precipitated withdrawal","volume":"265","author":"Griffiths","year":"1993","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1001\/archpsyc.1990.01810220033004","article-title":"Flumazenil provocation of panic attacks: Evidence for altered benzodiazepine receptor sensitivity in panic disorder","volume":"47","author":"Nutt","year":"1990","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1177\/0269881120981390","article-title":"Pharmacological uses of flumazenil in benzodiazepine use disorders: A systematic review of limited data","volume":"35","author":"Gallo","year":"2021","journal-title":"J. Psychopharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1080\/0167482X.2019.1624951","article-title":"Anxiety of myoma patients: Results of standardized interviews with the State Trait Anxiety Inventory and the Kessler 10 questionnaire","volume":"41","author":"Knudsen","year":"2020","journal-title":"J. Psychosom. Obstet. Gynecol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e024719","DOI":"10.1136\/bmjopen-2018-024719","article-title":"Health-related quality of life and anxiety in the PAN-CAN lung cancer screening cohort","volume":"9","author":"Taghizadeh","year":"2019","journal-title":"BMJ Open"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"109501","DOI":"10.1016\/j.drugalcdep.2022.109501","article-title":"A double-blind randomised crossover trial of low-dose flumazenil for benzodiazepine withdrawal: A proof of concept","volume":"236","author":"MacDonald","year":"2022","journal-title":"Drug Alcohol. Depend."},{"key":"ref_29","unstructured":"Government of South Australia (2014). Benzodiazepine Equivalents."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1177\/0269881117714050","article-title":"Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence","volume":"31","author":"Tamburin","year":"2017","journal-title":"J. Psychopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1177\/0269881112446532","article-title":"Withdrawal and psychological sequelae, and patient satisfaction associated with subcutaneous flumazenil infusion for the management of benzodiazepine withdrawal: A case series","volume":"27","author":"Hulse","year":"2013","journal-title":"J. Psychopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1097\/00004714-198912000-00005","article-title":"A clinical scale to assess benzodiazepine withdrawal","volume":"9","author":"Busto","year":"1989","journal-title":"J. Clin. Psychopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Spielberger, C., Gorsuch, R., and Lushene, R. (1983). Manual for the State-Trait Anxiety Inventory, Consulting Psychologists Press.","DOI":"10.1037\/t06496-000"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1177\/02698811221082466","article-title":"A theory of the anxiolytic action of flumazenil in anxiety disorders","volume":"36","author":"Gallo","year":"2022","journal-title":"J. Psychopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3844\/amjbsp.2015.1.6","article-title":"Methods for Computing Missing Item Response in Psychometric Scale Construction","volume":"5","author":"Siddiqui","year":"2015","journal-title":"Curr. Res. Biostat."},{"key":"ref_36","first-page":"20451253221082386","article-title":"Experiences with benzodiazepine use, tapering, and discontinuation: An Internet survey","volume":"12","author":"Macoubrie","year":"2022","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1002\/hup.470040105","article-title":"Saturation analysis of specific 11C Ro 15-1788 binding to the human neocortex using positron emission tomography","volume":"4","author":"Persson","year":"1989","journal-title":"Hum. Psychopharmacol. Clin. Exp."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/0140-6736(91)90799-U","article-title":"Feasibility of reversing benzodiazepine tolerance with flumazenil","volume":"337","author":"Savic","year":"1991","journal-title":"Lancet"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.2165\/00003495-199142060-00010","article-title":"Flumazenil","volume":"42","author":"Brogden","year":"1991","journal-title":"Drugs"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.brainresbull.2015.11.015","article-title":"Flumazenil decreases surface expression of \u03b14\u03b22\u03b4 GABAA receptors by increasing the rate of receptor internalization","volume":"120","author":"Kuver","year":"2016","journal-title":"Brain Res. Bull."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"109517","DOI":"10.1016\/j.drugalcdep.2022.109517","article-title":"Outcomes of patients treated with low-dose flumazenil for benzodiazepine detoxification: A description of 26 participants","volume":"237","author":"MacDonald","year":"2022","journal-title":"Drug Alcohol. Depend."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1177\/0269881108100322","article-title":"The role of flumazenil in the treatment of benzodiazepine dependence: Physiological and psychological profiles","volume":"23","author":"Hood","year":"2009","journal-title":"J. Psychopharmacol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/19\/5948\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:48:24Z","timestamp":1760143704000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/19\/5948"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,8]]},"references-count":42,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["jcm11195948"],"URL":"https:\/\/doi.org\/10.3390\/jcm11195948","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2022,10,8]]}}}