The benzodiazepines crisis : the ramifications of an over-used drug class

When properly prescribed, benzodiazepines and related “Z” drugs, are usually safe and effective. However, some patients experience lack of efficacy, severe adverse effects, and/or protracted withdrawal symptoms. Unfortunately, there is no reliable way to predict outcome prior to treatment. Use has dramatically expanded, to the point where some experts suggest a disconnect with actual medical need. With increased and longer prescribing there has been a corresponding increase in the “down-side” of these drugs. Benzodiazepines, as all drugs, produce some degree of normal physiologic tolerance and physical dependence. But for some patients withdrawal can result in a bewildering array of symptoms, that can persist for protracted time periods, difficult to understand and live with. Although there is currently no clear mechanistic explanation, some potentials include alterations of receptor number, promoters of receptor protein synthesis or degradation, absorption, distribution, metabolism, and elimination, GABA~A~-receptor function or subtype-distribution, or involvement of peripheral benzodiazepine binding/receptor sites. This book attempts to bring benzodiazepine use under a more rational paradigm and reduce the incidence of side-effects and drug–drug interactions (DDI). It is the first devoted to take on this responsibility. Use, overuse/misuse, side-effects, DDI, physiology, and withdrawal are reviewed by expert clinicians and basic scientists in-depth. The book challenges the medical community to take seriously the use of this class of drug and to ameliorate prescribing behavior. The case is made for limiting initiation and duration (2–4 weeks) of use, and careful, supported discontinuation. We laud and suggest increased research into this class of drug and it’s “down-side.” When properly prescribed, benzodiazepines and related “Z” drugs, are usually safe and effective. However, some patients experience lack of efficacy, severe adverse effects, and/or protracted withdrawal symptoms. Unfortunately, there is no reliable way to predict outcome prior to treatment. Use has dramatically expanded, to the point where some experts suggest a disconnect with actual medical need. With increased and longer prescribing there has been a corresponding increase in the “down-side” of these drugs. Benzodiazepines, as all drugs, produce some degree of normal physiologic tolerance and physical dependence. But for some patients withdrawal can result in a bewildering array of symptoms, that can persist for protracted time periods, difficult to understand and live with. Although there is currently no clear mechanistic explanation, some potentials include alterations of receptor number, promoters of receptor protein synthesis or degradation, absorption, distribution, metabolism, and elimination, GABA A -receptor function or subtype-distribution, or involvement of peripheral benzodiazepine binding/receptor sites. This book attempts to bring benzodiazepine use under a more rational paradigm and reduce the incidence of side-effects and drug-drug interactions (DDI). It is the first devoted to take on this responsibility. Use, overuse/misuse, side-effects, DDI, physiology, and withdrawal are reviewed by expert clinicians and basic scientists in-depth. The book challenges the medical community to take seriously the use of this class of drug and to ameliorate prescribing behavior. The case is made for limiting initiation and duration (2-4 weeks) of use, and careful, supported discontinuation. We laud and suggest increased research into this class of drug and it’s “down-side.” Dedication 6 Epigraph 7 Contents 8 Overview 10 Foreword: Addiction • A. J. Reid Finlayson 12 Foreword: Pain • Lynn Webster 14 Foreword: Patient Advocacy • Bernie Silvernail 18 Foreword: Patient • Carrie Silvernail 20 Preface • John F. Peppin, Joseph V. Pergolizzi Jr., Robert B. Raffa, and Steven L. Wright 29 Preface • John F. Peppin, Joseph V. Pergolizzi Jr., Robert B. Raffa, and Steven L. Wright 24 Contributors 26 Benzodiazepines: A Chronology 28 1. Introduction: The Origins and Rise of Benzodiazepines • Michael M. Miller and John F. Peppin 32 2. The Evolution of Benzodiazepine Receptor Agonists: Developments in Pharmacology and Toxicology • Jamie L. Hansen and Timothy J. Atkinson 37 3. Benzodiazepine Therapy: The Good, the Bad, and the Ugly • Jeffrey Guina, Brian Merrill, and Jo Ann LeQuang 48 4. Use of Benzodiazepines and Z- Drugs in the Geriatric Population • Jan M. Kitzen 72 5. The Central Benzodiazepine Receptor • Michael H. Ossipov 99 6. Benzodiazepine Receptors in the Periphery • Robert B. Raffa 112 7. Drug Withdrawal: A Modern Motivational View and Neurobiological Substrates • George F. Koob 128 8. Benzodiazepine Withdrawal: Clinical Aspects • Steven L. Wright 148 9. Benzodiazepines and Pain Management • John F. Peppin and Steven L. Wright 180 10. The Regulatory History of Benzodiazepines in the Age of the Dark Web and Other Threats • John J. Coleman 191 11. Benzodiazepines Today and Tomorrow: What We Know and Don’t Know About Them • John J. Coleman 224 12. In Search of Benzodiazepine Guidelines • Jo Ann LeQuang 247 Conclusion • John F. Peppin, Joseph V. Pergolizzi Jr., Robert B. Raffa, and Steven L. Wright 268 Disclosure Agreements 270 Index 272 Developed decades ago to treat a legitimate medical need, benzodiazepines promisingly displaced less-effective and less-safe drugs, though prescribing has since exceeded their intended use and outpaced the available data. The current situation is characterized by excessive prescribing and extended utilization beyond good therapeutic practice. Evidence indicates that prolonged use of benzodiazepines causes a wide range of adverse reactions, and withdrawal can be particularly challenging. Misused, abused, diverted, and counterfeited, benzodiazepines have serious potential for substance use disorder, and are among the leading causes of drug-related overdose deaths. The Benzodiazepines Crisis sounds the alarm against the overuse of benzodiazepines, presenting an updated, evidence-based overview of this class of drugs and their negative consequences. Bringing together years of research, clinical expertise, and scientific evidence, this book aims to address a perceived lag between evidence and action in order to call for rational and dramatically reduced usage of benzodiazepines. Introduction : Anxiety, Insomnia, and Benzodiazepines / Michael M. Miller John Peppin -- The Evolution of Benzodiazepines and the 'Z' Drugs / Jamie L. Hansen and Timothy J. Atkinson -- Uses, Efficacy, and Adverse Effects of Benzodiazepines / Brian Merrill and Jeffrey Guina -- Problems with Benzodiazepine Use in the Elderly / Jan Kitzen -- Benzodiazepine Receptors in the Brain / Michael H. Ossipov -- Benzodiazepine Receptors in the Periphery / Robert B. Raffa -- Benzodiazepine Withdrawal : Neurobiologic Aspects / George F. Koob -- Benzodiazepine Withdrawal : Clinical Aspects / Steven Wright -- Benzodiazepines and Pain / John F. Peppin and Steven Wright -- Benzodiazepines Abuse / John J. Coleman -- History of the Regulatory Control of Benzodiazepines / John J. Coleman -- Guidelines and Guidances / Jo Ann LeQuang -- The Benzodiazepine Legacy Patient / Jeffrey Guina and Brian Merrill -- Perspective / John Peppin This book is a much-needed compilation and examination of the risks and benefits of the long-term use of benzodiazepine drugs. Named to elicit thoughts of equilibrium, peaceful valleys, rest, relaxation and halcyon days, benzodiazepine minor tranquilizers provide safer sedation than the barbiturates that were in general use 60 years ago.Although these drugs are approved for use in seizure disorders, generalized anxiety, and panic disorders, benzodiazepines are no longer considered first- line treatment. The benzodiazepine class of sedating drugs carries significant risks that involve depression, dependence, addiction, amnesia, and overdose death, especially when combined with other agents that affect the central nervous system. Benzodiazepines are useful in emergency settings and operating theaters and to avert the consequences of withdrawal from alcohol and sedating drugs. "Benzodiazepines were developed to treat legitimate medical needs. However, unbridled success and prescribing beyond their intended duration of use and the available data has led to excessive prescribing, extended utilization beyond good therapeutic practice, and unintended adverse effects and substance use disorder. This book is the first to bring to light and discuss the largely unrecognized and enigmatic problem of an exceedingly prolonged withdrawal syndrome from benzodiazepines that can persist for months or years in susceptible patients, and the medical need for better evidence-based prescribing of benzodiazepines, and a call for the recognition and better treatment of the prolonged withdrawal syndrome"-- Provided by publisher