As a part of the process of filling the gaps in evidence, the Alliance helps fund the scientists and researchers who do the research and document the results. Several papers have been published in this manner, including all of the papers listed below, and other papers still in development. Your donation helps fund this research.
Sponsored Research Project
The Alliance funded a 3-year research project at the University of Arizona School of Pharmacy. This study attempted to show the effect that benzodiazepines acting on Peripheral Benzodiazepine Receptors have on withdrawal and BIND. [Peripheral Benzodiazepine Receptors, also called TSPO receptors, are present in peripheral nervous system tissues, glial cells, in mitochondria (the cells’ energy factories) throughout the body.] This study is the subject of three papers listed below.
Prescribing and deprescribing guidance for benzodiazepine and benzodiazepine receptor agonist use in adults with depression, anxiety, and insomnia: an international scoping review
‘We need more support and doctors that understand the process of tapering …’:
Unpublished trials of alprazolam XR and their influence on its apparent efficacy for panic disorder
Long-term consequences of benzodiazepine-induced neurological dysfunction: A survey (New BIND Paper)
Cognitive Consequences of Benzodiazepine Use: Is it Worth Losing Our Mind Over?
Pilot Studies on the Novel Hypothesis that TSPO (Peripheral Benzodiazepine Receptor) Is Involved in Benzodiazepine/“Z-Drug” Physical Dependence and/or Withdrawal (Alliance-Sponsored University of Arizona Research Project)
Enduring neurological sequelae of benzodiazepine use: an Internet survey
The devil is in the detail: A critique of nine editorials published by the International Task Force on Benzodiazepines
A double-blind randomized crossover trial of low-dose flumazenil for benzodiazepine withdrawal: A proof of concept
Complex Persistent Benzodiazepine Dependence—When Benzodiazepine Deprescribing Goes Awry
Experiences with benzodiazepine use, tapering, and discontinuation: an Internet survey
Benzodiazepine and Z-hypnotic stewardship
Surviving Benzodiazepines: A Patient’s and Clinician’s Perspectives
I just thought that it was such an impossible thing’: A qualitative study of barriers and facilitators to discontinuing long‐term use of benzodiazepine receptor agonists using the Theoretical Domains Framework
The FDA Mandate to Reassess Benzodiazepines: Alprazolam Induces a Positive Conditioned Place-Preference in Male Rats
Benzodiazepines and Z Drugs for Pain Patients: the Problem of Protracted Withdrawal Symptoms (PWS)
Treating Insomnia in Older Adult Patients: Limiting Benzodiazepine Use.
Limited Utility for Benzodiazepines in Chronic Pain Management: A Narrative Review.
Alliance-affiliated authors are noted with yellow highlight.
Brandt J., Bressi, J., Le M., Neal D., Cadogan C., Witt-Doerring J., Witt-Doerring M., Wright S. Prescribing and deprescribing guidance for benzodiazepine and benzodiazepine receptor agonist use in adults with depression, anxiety, and insomnia: an international scoping review.
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Background
Many individuals worldwide continue to take benzodiazepine receptor agonists (BZRAs) long term (≥3 months). The aim of this study was to conduct a content analysis of the views and experiences of discontinuing long-term BZRA use as documented in the free-text responses of respondents to an online questionnaire examining mediators of behaviour change relating to the discontinuation of long-term BZRA use.
Lynch T., Ryan C., Huff C., Foster D., Cadogan C. ‘We need more support and doctors that understand the process of tapering …’: A content analysis of free-text responses to a questionnaire on discontinuing long-term benzodiazepine receptor agonist use. The Lancet: Volume 70, 2024
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Background
Clinical practice guidelines and guidance documents routinely offer prescribing clinicians’ recommendations and instruction on the use of psychotropic drugs for mental illness. We sought to characterise parameters relevant to prescribing and deprescribing of benzodiazepine (BZD) and benzodiazepine receptor agonist (BZRA), in clinical practice guidelines and guidance documents internationally, for adult patients with unipolar depression, anxiety disorders and insomnia to understand similarities and discrepancies between evidence-based expert opinion.
Ahn-Horst R., Turner E. Unpublished trials of alprazolam XR and their influence on its apparent efficacy for panic disorder. Psychological Medicine, 2023
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Background
To test for publication bias with alprazolam, the most widely prescribed benzodiazepine, by comparing its efficacy for panic disorder using trial results from (1) the published literature and (2) the US Food and Drug Administration (FDA).
Ritvo A., Foster D., Huff C., Finlayson R., Silvernail B., Martin P. Long-term consequences of benzodiazepine-induced neurological dysfunction: A survey. PLOS One, 2023
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Background
Acute benzodiazepine withdrawal has been described, but literature regarding the benzodiazepine-induced neurological injury that may result in enduring symptoms and life consequences is scant.
Neal D., Bressi J. Cognitive Consequences of Benzodiazepine Use: Is it Worth Losing Our Mind Over? Therapeutic Advances in Psychopharmacology. 2023;13
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Introduction
Benzodiazepines are a commonly prescribed class of medications used to manage conditions such as anxiety, insomnia, alcohol withdrawal, muscle spasms, and seizures. Due to the potential for dependence, withdrawal and long-term adverse effects (AEs), they’re only intended for short term use.
Largent-Milnes T., Kost K., Moffett C., Pergolizzi Jr J., Raffa R., Thompson A., Vanderah T. Pilot Studies on the Novel Hypothesis that TSPO (Peripheral Benzodiazepine Receptor) Is Involved in Benzodiazepine/“Z-Drug” Physical Dependence and/or Withdrawal. Therapeutic Advances in Psychopharmacology. 2023;13
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Abstract
Benzodiazepines and other benzodiazepine receptor agonists, such as the “Z” drugs, are widely prescribed medications mainly used for treating anxiety and seizures, and for inducing sedation. Unfortunately, despite their popularity, benzodiazepine prescribing often exceeds recommendations and the consequences can be severe. On September 23, 2020, the United States FDA announced a new requirement for a Boxed Warning for benzodiazepines prescribing. Along with this announcement, the FDA stated that relevant information regarding the initiation, continuation, and discontinuation of benzodiazepines is lacking. Here, we describe initial pilot studies intended to investigate the questions 1) can animal models be developed that demonstrate benzodiazepine physical dependence and/or withdrawal symptoms, and 2) determine whether translocator protein (TSPO) plays a role in benzodiazepine dependence and/or withdrawal processes. The former was demonstrated, methodological limitations prevented the latter.
Finlayson R., Huff C., Foster D., Martin P. Enduring neurological sequelae of benzodiazepine use: an Internet survey. Therapeutic Advances in Psychopharmacology. 2023;13
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Summary
Benzodiazepine tapering and cessation has been associated with diverse symptom constellations of varying duration. Although described in the literature decades ago, the mechanistic underpinnings of enduring symptoms that can last months or years have not yet been elucidated.
Brandt, J. (2023). The devil is in the detail: A critique of nine editorials published by the International Task Force on Benzodiazepines. BJPsych Advances, 1-7. January 2023.
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Summary
Since 2018, the International Task Force on Benzodiazepines (ITFB), a group of academic psychiatrists and academic psychologists, has advocated that clinical guidelines should change to promote benzodiazepines from second- to first-line treatment for anxiety disorders, accept their use as maintenance treatment for anxiety conditions (in particular, panic disorder) and increase their use in gastrointestinal disorders. There is merit in much of what the ITFB argues, but in this article I analyse four major claims it has made in opinion editorials that I believe are not fully supported by the available evidence.
MacDonald T., Gallo A.T., Basso-Hulse G., Bennett K.S., Hulse G.K. A double-blind randomised crossover trial of low-dose flumazenil for benzodiazepine withdrawal: A proof of concept. Drug and Alcohol Dependence. July 2022, Volume 236
Abstract
Benzodiazepines (BZD) are a class of anxiolytics with varying uses, which primarily act on the GABAA receptor resulting in hyperpolarisation. BZDs are often a difficult drug class to cease once neuroadaptation has occurred; recommendations usually involve gradual dose reductions at variable rates. A growing body of evidence has suggested that low-dose flumazenil, a GABAA receptor antagonist, may be a useful agent to allow for rapid detoxification.
Peng L., Meeks T., Blazes C. Complex Persistent Benzodiazepine Dependence—When Benzodiazepine Deprescribing Goes Awry. Therapeutic JAMA Psychiatry. 2022, Published online
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Abstract
Benzodiazepines were discovered serendipitously in the 1950s and later marketed as safer alternatives to barbiturates, leading to increased popularity over subsequent decades. Though touted as safe treatments for anxiety and insomnia, problems with benzodiazepines became more apparent by the 1980s, especially risks of physiological dependence, misuse, and addiction. Although clinicians’ enthusiasm for benzodiazepines has waned, they remain popular medications among patients owing to their rapid symptom relief and reinforcing effects. The opioid crisis has dominated headlines, yet benzodiazepines are an underrecognized and important contributor to the public health crisis of drug overdose deaths.
Finlayson R., Macoubrie J., Huff C., Foster D., Martin P. Experiences with benzodiazepine use, tapering, and discontinuation: an Internet survey. Therapeutic Advances in Psychopharmacology. 2022, Vol. 12: 1–10
Abstract
Over 92 million prescriptions for benzodiazepines are dispensed in the United States annually, yet little is known about the experiences of those taking and discontinuing them.
Wright S. Benzodiazepine and Z-hypnotic stewardship. Journal of Family Practice. 2022;103-107
Abstract
Benzodiazepines (BZDs) and Z-hypnotics have been available for decades, yet uncertainties about their use remain. They are prescribed and overprescribed most often for anxiety and insomnia, for which they have value but also the potential for significant adverse consequences, notably physiologic dependence. Use of these agents should be limited, and planned deprescribing is a fundamental aspect of prescribing.
Silvernail C, Wright S. Surviving Benzodiazepines: A Patient’s and Clinician’s Perspectives. Advances in Therapy. 2022;1871–1880
Abstract
Although benzodiazepines have been used for 6 decades, many questions remain unanswered by research. The lived experiences of those adversely affected long term can provide insights into how these agents might be more thoughtfully prescribed. Here, perspectives of one such experience encompassing benzodiazepine initiation, ongoing use with adverse consequences and difficult discontinuation are presented through the eyes of an affected individual and a clinician. This experience highlights the importance of limited initiation and duration of use (2–4 weeks) as well as a supported, slow tapering process led by patients. Because researched evidence about deprescribing benzodiazepines is insufficient and because individual experiences vary so widely, it is the patient’s expertise—that of her or his lived experience—that should assume a primary role in determining the course and pace of discontinuing these medications.
Lynch T, Cristín R, Cadogan C. ‘I just thought that it was such an impossible thing’: A qualitative study of barriers and facilitators to discontinuing long‐term use of benzodiazepine receptor agonists using the Theoretical Domains Framework. Health Expectations. 2021;1–11.
Abstract
Existing interventions to reduce long‐term benzodiazepine receptor agonist (BZRA) use lack theoretical underpinning and detailed descriptions. This creates difficulties in understanding how interventions work and how to replicate them in practice. The Theoretical Domains Framework (TDF) can be used to identify behaviour change determinants to target during intervention development.
Moffett C, Kost K, Thompson A, Ossipov M, Pergolizzi J, Umeda-Raffa S, Raffa R, Largent-Milnes T, Vanderah T. The FDA Mandate to Reassess Benzodiazepines: Alprazolam Induces a Positive Conditioned Place-Preference in Male Rats. Journal of Biosciences and Medicines, 2021, 9, 1-8.
Abstract
On September 23, 2020, in order “To address the serious risks of abuse, addiction, physical dependence, and withdrawal reactions, the U.S. Food and Drug Administration (FDA) is requiring the Boxed Warning be updated for all benzodiazepine medicines”. With this announcement, the FDA proclaimed that much more needs to be known about the initiation, continuation, and discontinuation of these widely-used drugs. Unfortunately, relevant information is lacking, since for many years, there has been a notable sparsity in the funding and conduct of basic and clinical research on these drugs. In order to begin to fill the void, it is valuable to (re)examine animal models. We here describe a model of conditioned place-preference (CPP) for rats and for the first time, to our knowledge, show that the representative benzodiazepine alprazolam induces positive place-preference in male rats.
Raffa R, Pergolizzi J, Wright S. Benzodiazepines and Z Drugs for Pain Patients: the Problem of Protracted Withdrawal Symptoms (PWS). PAINWeek Journal 2018 Q4 Vol6
Abstract
Despite the severity and notoriety of the opioid crisis, which began to receive national attention at least as early as the late 1990’s, the CDC (Centers for Disease Control and Prevention) did not produce a guideline for opioid prescription until March 2016. History might be repeating itself – the CDC has yet to produce prescription guidelines for benzodiazepines and ‘Z’ drugs, despite a strong signal of excessive prescription of these drugs and the difficulties identifying and treating the protracted withdrawal symptoms (PWS) that sometimes follow cessation of use.
Pergolizzi Jr., J. , Taylor Jr., R. , LeQuang, J. , Gould, E. and Raffa, R. (2019) Treating Insomnia in Older Adult Patients: Limiting Benzodiazepine Use. Pharmacology & Pharmacy, 10, 116-129. doi: 10.4236/pp.2019.103010.
Abstract
As aging comes, an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negatively impact sleep. Fortunately, good quality sleep can improve pain management. Because benzodiazepine receptor agonists (including the “Z” drugs) can reduce anxiety and improve sleep, they seem a convenient choice. However, their use in this population, particularly for more than short-term (guidelines range from 2 to 6 weeks max), is not recommended because of increased likelihood of falls, further disruption of sleep, dependence, and problems with discontinuation (withdrawal). Besides, this population is often likely to take concomitant medication for pain or other central nervous system depressants leading to potentially serious and even life-threatening interactions involving synergistic amplification of respiratory depression (opioids being a particularly dangerous interaction). Therefore, insomnia in older adults should ideally be treated with a non-benzodiazepine receptor agonist; if indicated, they may be used, but should be closely monitored and tapered to avoid long-term adverse problems (direct or from withdrawal). Older adult patients with insomnia may be more optimally treated with sleep aids that do not interact with the GABAA receptor.
Robert B. Raffa, Joseph V. Pergolizzi. Commentary: Benzodiazepine (BZD) and Related BZD-Receptor Agonists: Basic Science Reasons to Limit to Four Weeks or Less Pharmacology & Pharmacy, Vol.10 No.8, August 2019
Abstract
Benzodiazepines and related benzodiazepine-receptor agonists such as the pyrazolopyrimidinezalepl -on; the imidazopyridine zolpidem; and the cyclopyrroloneszopiclone and eszopiclone, are among the most widely prescribed drugs, and for a variety of conditions. Surprisingly: 1) there are only a few conditions for which there is a good evidence basis, 2) efficacy has only been well demonstrated for short-term use (i.e., less than 4 weeks), and 3) much less is known about the basic science of these drugs than is widely believed. We suggest that the use of these drugs beyond four or less weeks exceeds the available knowledge base, so best-practice use suggests that the prescribing of these drugs for most patients should be limited to only short-term use until more is known about the basic pharmacology of their actions in the brain and in the periphery.
Wright, Steven L. Limited Utility for Benzodiazepines in Chronic Pain Management: A Narrative Review. Advances in therapy vol. 37,6 (2020): 2604-2619. doi:10.1007/s12325-020-01354-6
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Abstract
Introduction
Controversy and uncertainty exist about the use of benzodiazepine receptor agonists (BZRAs) in pain management. BZRAs include benzodiazepines and the so-called Z-drugs. This article curates available research to determine the appropriate role of BZRAs in the course of pain management, and how prescribers might address these challenges.