Addiction Potential of Abused Drugs and Drug Classes

Barry Stimmel

• Publisher: Routledge
• Year: 2013
• ISBN:
  9781317839477
• Edition: 1
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

Increase your awareness of the relative addiction liabilities of various drugs and drug classes that are commonly abused. A timely and masterful new book, Addiction Potential of Abused Drugs and Drug Classes clarifies, in contemporary terminology, the state of addiction liability of cocaine, opiates, alcohol, sedative-hypnotics, nicotine, anxiolytics, marijuana, inhalants and anesthetics, and PCP and hallucinogens--the nine drugs that are most abused today. Authorities combine their research expertise with the available scientific literature to evaluate those factors which contribute to the addictive qualities of drugs. Specific chapters highlight the positive and negative reinforcement qualities that make drugs rewarding, focus on the two major subtypes of alcoholics, and cover the neuroanatomical and neurochemical bases of psychological dependence, the greatest contributing factor to drug addiction. An essential new resource for scientists, clinicians, and administrators, Addiction Potential of Abused Drugs and Drug Classes also highlights those areas where more work is needed in order to understand how individual drugs affect the processes of dependence, tolerance, and addiction, so that adequate treatment of these disorders can be discovered. The book was written for teachers and researchers in the chemical dependency field, to provide an up-to-date review of the literature. In addition, physicians, nurses, and pharmacists will find the book to be valuable as an update on the relative addiction strengths of abused drugs. Finally, treatment counselors and professionals with some knowledge of physiology and pharmacology will be interested in the book because of its relevance to the clinical treatment of chemically-dependent patients.

Addiction Potential of Benzodiazepines and Non-Benzodiazepine Anxiolytics

John D. Roache, PhD

John D. Roache is affiliated with the Department of Psychiatry and Behavioral Sciences and Department of Pharmacology, University of Texas Medical School at Houston, and the Substance Abuse Research Group, University of Texas Mental Sciences Institute. Correspondence may be addressed to the author at the University of Texas Mental Sciences Institute, Substance Abuse Research, Room 342, 1300 Moursund Avenue, Houston, TX 77030.

SUMMARY. This paper reviews the addiction potential of all benzodiazepines currently available in the U.S.A. as well as several non-benzodiazepine anxiolytic drugs. Addiction potential was assessed by separately considering the potential for these drugs to produce three different phenomena of addiction; namely, physical dependence, psychological dependence and deleterious consequences. This review focuses on human studies conducted with research volunteers outside the therapeutic context and also on clinical studies conducted with patients receiving treatment in the therapeutic context. It is concluded that benzodiazepines have a reduced addiction potential in comparison to the predecessor barbiturates. Conclusions regarding the relative addiction potential of several non-benzodiazepine anxiolytics are difficult due to a paucity of data; however limited evidence suggests a reduced addiction potential for several of these compounds. Within the benzodiazepine class, qualitative differences in addiction potential between individual drugs are not well established.

INTRODUCTION

In reviewing the addiction potential of benzodiazepines (BZ’s) and non-BZ anxiolytics, one must retain as a caveat that recurring cycles have appeared throughout the historical development of different CNS depressants.¹ Since the early use of bromide salts in the nineteenth century, the introduction of each successive generation of psychosedative has been heralded as a major innovation resulting in improved efficacy with reduced side effects. Each of the drugs successively developed, including paraldehyde, chloral hydrate, barbiturates, meprobamate and the BZ’s, probably represent improvements in efficacy and/or safety; however, the potential for abuse and addiction has been recognized belatedly in each case. The barbiturates fell into disfavor in the late 1950’s as their potential for abuse and physical dependence was recognized. The BZ’s have now replaced the barbiturates for the treatment of anxiety disorders. Compared to the barbiturates, BZ’s are considered safer and more effective with fewer side effects. However, BZ’s were once thought to not cause addiction. Now, more than 25 years following the introduction of chlordiazepoxide, we have finally begun to recognize the addiction potential of the BZ’s.

DEFINITIONS OF ADDICTION POTENTIAL

Although the term addiction has long been considered by the lay public to refer to an intense devotion to a bad habit or a regular over-reliance upon a drug, the medical and scientific communities have had a much less clear view of the meaning of addiction. Early clinical researchers attempted to operationalize the term to describe the state of chronic intoxication to opioids or barbiturates which was associated with mostly physiological signs observed upon cessation of drug treatment. With this definition, drugs which did not produce fairly profound physiological withdrawal signs (e.g., cocaine) were unfortunately considered by some as non-addicting. In order to standardize definitions and allow for compulsive drug taking which occurs in the absence of strong physiological withdrawal signs, the World Health Organization abandoned the term addiction in favor of the term “drug dependence” which was defined as: “A state, psychic and sometimes also physical, which results from the interaction between a living organism and a drug, which is characterized by behavioral and other responses that always include compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects and sometimes to avoid the discomfort of its absence. Tolerance may be present.” This definition of drug dependence commonly is subdivided into the categories of “physical dependence” to describe the state evidenced by withdrawal symptoms observed in the chronic user upon drug abstinence and “psychological dependence” to refer to the psychic drive or emotional state evidenced by the intense reliance upon and compulsive use of the substance. Whereas scientists can operationally define drug dependence, drug abuse and drug addiction are socially defined terms which refer to socially unacceptable forms of drug use or drug dependence, respectively. While variables influencing social attitudes are not always clear, Western society generally would define drug dependence as addiction when regular drug self-ingestion occurs in a pattern which is detrimental or interferes with social function.² The medical community and the lay public need information on each of the components involved in the definition of an addictive substance in order to make informed decisions and judgments regarding the use and control of these substances. Therefore, this paper will provide information on the addiction potential of BZ’s and other anxiolytics by separately assessing their potential for physical dependence, psychological dependence and deleterious consequences or socially detrimental effects. It should be noted that the Diagnostic and Statistical Manual (DSM III-R) of the American Psychiatric Association incorporates the concept of social impairment within the definition of substance dependence. However, it may be worthwhile to maintain a distinction between the terms addiction and dependence because physical dependence could develop without producing socially injurious effects and psychological dependence may occur in such a way that society would not consider it harmful (e.g., regular caffeine use).² Finally, consistent with the distinctions made in DSM III-R, substance abuse is distinguished from dependence (or addiction) in that abuse refers to a harmful pattern of drug self-ingestion which is not so extreme as to be considered drug dependence.

ANXIOLYTICS TO BE DISCUSSED

As the term “anxiolytic” suggests, this paper should address those agents which are effective in the treatment of anxiety disorders. Historically, a variety of CNS depressants including bromide salts, paraldehyde, choral hydrate, meprobamate and barbiturates have been used to sedate or tranquilize the emotionally aroused patient. With the ubiquitous use of BZ’s in the last 25 years, these drugs have largely replaced other types of pharmacotherapy and have become almost synonymous with the term anxiolytic. This term has been used to distinguish the presumably anxio-selective actions of BZ minor tranquilizers from the major tranquilizer phenothiazine or buterophenone neuroleptics. Other than the BZ’s, several types of drugs have been used to treat anxiety including neuroleptics, antidepressants, antihistamines and adrenergic blockers; however, with few exceptions, BZ anxiolytics are considered superior in efficacy.³ Several recent developments in pharmacopsychiatry have begun to shake the previously unchallenged position of BZ’s in the treatment of anxiety disorders. In one development, Panic Disorder was redefined as a distinct diagnostic disorder which is responsive to tricyclic and monoamine oxidase inhibitor antidepressants. This, coupled with the recent use of imipramine in anxiety disorders and BZ’s in affective and panic disorders,³ has muddled the distinctions between the drug classes used to treat anxiety and depression. Finally, the introduction of buspirone as a novel anxiolytic has challenged theories regarding the biological basis of anxiety and presumably has ushered in a new generation of anxiolytic agents which are structurally unrelated to the BZ’s and do not act through BZ receptors.^3,4

Since their introduction in the early 1960’s, BZ’s increasingly have replaced the barbiturates for various psychotherapeutic purposes; barbiturates are no longer used for anxiolytic indications. Perhaps it is not surprising that the majority of BZ prescriptions are written by non-psychiatric physicians for the symptomatic treatment of a variety of illnesses manifesting anxiety and insomnia.⁵ BZ’s have been among the most widely prescribed drugs in the world and diazepam has been the most frequently prescribed BZ. Worldwide, BZ use reached a peak in the mid 1970’s when concerns regarding an over-medicated society caused a re-evaluation of prescribing practices^5,6; prescription rates for BZ’s and other sedatives generally have been declining ever since. During the same period, there was an increasing recognition of BZ addiction occurring within the therapeutic context. Due to concerns regarding BZ overuse and addiction, there is now an interest in the use of non-BZ compounds and also in the development of new anxiolytics with reduced addiction potential.

In this paper, the addiction potential of BZ’s and other non-BZ anxiolytics will be assessed mostly through an examination of studies conducted in human research volunteers and patients receiving treatment in the therapeutic context. Most of these data will refer to BZ’s in general and diazepam in particular since these have been the most widely used and studied drugs. However, due to an interest in the use of non-BZ’s or some of the newer BZ anxiolytics, data regarding each of the individual drugs listed in Table 1 will be introduced where possible. The thirteen BZ’s currently approved for use in the U.S. are categorized according to their pharmacokinetic elimination profiles: six BZ’s produce active N-desalkyl metabolites which are slowly-eliminated, three of which (chlordiazepoxide, diazepam and flurazepam) are active parent compounds and three (clorazepate, halazepam and prazepam) are inactive pro-drugs which are converted to the active metabolites; five BZ’s (alprazolam, clonazepam, lorazepam, oxazepam, and temazepam) have intermediate elimination profiles; and two BZ’s (midazolam and triazolam) have very rapid elimination profiles. The non-BZ compounds which are available for use as anxiolytics³ are also listed in Table 1. Of these, the beta-blockers (e.g., propranolol) have not proved useful although there has been a renewed interest in the use of antidepressants (e.g., doxepin and imipramine). The remaining non-BZ anxiolytics (buspirone, chlormezanone, hydroxyzine and meprobamate) are atypical in that they work through undefined mechanisms and have not been utilized or studied as widely as the BZ’s. Meprobamate dates back to the pre-BZ era of the late 1950’s but continues to be used today. Hydroxyzine has antihistaminic and sedative effects and is used for patients who should not receive BZ’s. Chlormezanone has not been widely used in recent years and the newly developed drug, buspirone, has been utilized increasingly for anxiolytic therapy.

TABLE 1: Benzodiazepines and non-benzodiazepine compounds available for use as anxiolytics in the United States.

BENZODIAZEPINES APPROVED BY U.S. FDA	PRIMARY INDICATION
Slowly-Eliminated Desalkvl Metabolites
Chlordiazepoxide (LIBRIUM)	Anxiolytic
Diazepam (VALIUM)	Anxiolytic
Flurazepam (DALMANE)	Hypnotic
Prodrugs for N-Desalkvl Metabolites
Clorazepate (TRANXENE)	Anxiolytic
Halazepam (PAXIPAM)	Anxiolytic
Prazepam (CENTRAX)	Anxiolytic
Intermediate Elimination Profile
Alprazolam (XANAX)	Anxiolytic
Clonazepam (CLONOPIN)	Anti-convulsant
Lorazepam (ATIVAN)	Anxiolytic
Oxazepam (SERAX)	Anxiolytic
Temazepam (RESTORIL)	Hypnotic
Rapid Elimination Profile
Midazolam (VERSED)	Pre-Anesthetic
Tri...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• EDITORIAL: Drug Dependence: Defining the Issues
• Addictiveness of Central Stimulants
• The Opioids: Abuse Liability and Treatments for Dependence
• Alcohol: Mechanisms of Addiction and Reinforcement
• Abuse Liability of Barbiturates and Other Sedative-Hypnotics
• An Analysis of the Addiction Liability of Nicotine
• Addiction Potential of Benzodiazepines and Non-Benzodiazepine Anxiolytics
• Cannabis Dependence and Tolerance Production
• Relative Addiction Potential of Major Centrally-Active Drugs and Drug Classes–Inhalants and Anesthetics
• PCP and Hallucinogens
• SELECTIVE GUIDE TO CURRENT REFERENCE SOURCES ON TOPICS DISCUSSED IN THIS ISSUE