Review
Polydrug abuse: A review of opioid and benzodiazepine combination use

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Abstract

This paper reviews studies examining the pharmacological interactions and epidemiology of the combined use of opioids and benzodiazepines (BZDs). A search of English language publications from 1970 to 2012 was conducted using PubMed and PsycINFO®. Our search found approximately 200 articles appropriate for inclusion in this paper. While numerous reports indicate that the co-abuse of opioids and BZDs is ubiquitous around the world, the reasons for the co-abuse of these medications are not entirely clear. Though the possibility remains that opioid abusers are using BZDs therapeutically to self-medicate anxiety, mania or insomnia, the data reviewed in this paper suggest that BZD use is primarily recreational. For example, co-users report seeking BZD prescriptions for the purpose of enhancing opioid intoxication or “high,” and use doses that exceed the therapeutic range. Since there are few clinical studies investigating the pharmacological interaction and abuse liability of their combined use, this hypothesis has not been extensively evaluated in clinical settings. As such, our analysis encourages further systematic investigation of BZD abuse among opioid abusers. The co-abuse of BZDs and opioids is substantial and has negative consequences for general health, overdose lethality, and treatment outcome. Physicians should address this important and underappreciated problem with more cautious prescribing practices, and increased vigilance for abusive patterns of use.

Introduction

Benzodiazepines and opioids are among the most frequently abused psychoactive drug classes in the world (Grytten, 1998, Joranson et al., 2000, Substance Abuse and Mental Health, 2008). Not surprisingly, the concomitant use of these two classes of drug has received the attention of researchers and physicians since the 1970s (KIeber and Gold, 1978). The goal of this review is to gain a better understanding of the motivations for, and consequences of their co-use. Using PubMed and PsycINFO we searched for English language articles on this topic published between 1970 and 2012. Various combinations of the following search terms were used: opioid, benzodiazepine, heroin, methadone, polydrug abuse, concomitant use, co-administration, prescription opioid, midazolam, valium, diazepam, alprazolam, flunitrazepam, pharmacological interactions, and epidemiology. With this method, we identified over 5000 publications. After the removal of duplicates, titles and/or abstracts were reviewed by the authors for relevance. Data from approximately 200 articles was included in this manuscript. This review and synthesis of that literature focuses on clinical studies investigating pharmacological interactions between opioids and BZDs and the epidemiology of their co-abuse. Clinical research is the focus of this paper. At times however, preclinical data are used to supplement these finding and support the authors’ supposition concerning the motivation and risks that underlie the combined use of opioids and BZDs.

This review begins with a brief overview of the abuse of each drug alone, followed by a review of clinical literature investigating how opioid and BZD drugs interact pharmacologically. Finally, we review reports relating to the prevalence and consequences of BZD and opioid co-abuse. It is our hope that this review will lead to a better understanding of: how these drugs interact pharmacologically, which populations are abusing these two drugs and why, the prevalence of their co-abuse, and the clinical implications of this behavior.

Section snippets

A brief overview of opioid abuse

The opioid class of drugs includes natural opiates (e.g., morphine, codeine, salvia divinorum), semi-synthetic opioids (e.g., heroin, oxycodone, hydromorphone, hydrocodone, salvanorin A), and synthetic opioids (e.g., methadone, buprenorphine, and fentanyl; National Institutes on Drug Abuse/U.S. Dept of Health and Human Services, 2009). Opioids have multiple actions: they alter body temperature, cause sedation, depress respiration, induce eating, decrease gastrointestinal transit, affect urinary

A brief overview on benzodiazepine abuse

Benzodiazepines are among the most frequently prescribed psychotropic drugs in the world (Coach, 1990). These drugs, whose core chemical structure is the fusion of a benzene and diazepine ring, act as positive allosteric modulators of the GABAA receptor complex. Benzodiazepines act to enhance the effects of GABA by increasing chloride (Cl) flux and rate of channel opening. These drugs are a commonly used and effective treatment for anxiety disorders, and adjunctive treatment in several

Pharmacological interactions between opioids and benzodiazepines

A number of studies have attempted to elucidate the mechanisms underlying opioid and BZD co-abuse by examining how these two types of drugs interact with one another. Preclinical research has shown that opioids and BZDs exert significant modulatory effects upon one another (Duka et al., 1980, LaBuda and Fuchs, 2001, Lopez et al., 1990, Moroni et al., 1978, Poisnel et al., 2009, Rocha et al., 1993, Sasaki et al., 2002, Soria et al., 1991, Tien et al., 2007). One possible mechanism to explain

The co-abuse of benzodiazepines and opioids in humans

Research suggests that the abuse liability of BZDs may only be notable in certain clinical populations, specifically, recreational users of other drugs of abuse and detoxified alcoholics (Cole and Chiarello, 1990). Furthermore, the abuse of BZDs among patients maintained on opioid agonists such as methadone, and more recently, buprenorphine has been consistently reported in the literature (Barnas et al., 1992, Brands et al., 2008, KIeber and Gold, 1978). The prevalence of BZD use among

Complications of benzodiazepine and opioid co-abuse

Because BZD and opioid polydrug use appears to be common, it is important to investigate potential adverse events that may result. Polysubstance abuse has been found to be a significant predictor of drug overdose (Kerr et al., 2005). Data indicate that 62–72% of patients being treated for overdose had consumed more than one class of drug (Backmund et al., 1999, Darke et al., 1996). This percentage is even higher (71–98%) when only fatal overdoses are assessed (Cook et al., 1998, Grass and

Conclusions

Abundant evidence documents the significant co-use of BZDs and opioids. Opioids have considerable therapeutic utility yet their euphoric effects make them among the most commonly abused drugs in the world. In comparison to opioids, BZDs are believed to act as euphoriants in very limited settings and when administered alone, have less abuse liability. Drug users appear to have discovered that BZDs are able to enhance the positive subjective effects of opioids. As such, individuals may be

Role of funding source

Financial support for the preparation of this manuscript was provided by the U.S. National Institute on Drug Abuse (DA030446-01A, DA09236, DA016759, DA022222, and DA031022). However, NIDA had no role in the decision to submit or write this report.

Contributors

Dr. Jones constructed sections describing the basic pharmacology of opioids and benzodiazepines, their physiological interactions and prevalence of their co-use around the world. Dr. Mogali described the abuse of these two drugs in human populations, along with its clinical implications and dangers. Dr. Comer wrote sections describing the significance and impact of this research and synthesized the various sections into one cohesive manuscript. All authors have approved the final manuscript.

Conflict of interest

Only the authors listed are responsible for the content and preparation of this manuscript. The authors declare that over the past 3 years SDC, JDJ, and SM have all received compensation (in the form of partial salary support) from investigator-initiated studies supported by Reckitt-Benckiser Pharmaceuticals, Schering-Plough Corporation, Johnson & Johnson Pharmaceutical Research & Development, Endo Pharmaceuticals, and MediciNova. In addition, SDC has served as a consultant to the following

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