Reinforcing Effects of Opioid/Benzodiazepine Mixtures

Abuse of prescription opioids had reached epidemic levels and is responsible for increasing emergency department visits and overdose deaths. Most prescription opioid deaths involve at least one other drug, often a benzodiazepine (BZD). Up to 70% of opioid abusers also use BZDs, reportedly to enhance opioid-induced feelings of euphoria. Coabuse of opioids and BZDs increases the risk of physical dependence and overdose, and studies in humans suggest that BZD enhancement of abuse-related effects of opioids occurs in dependent, and not in nondependent, individuals. Despite its prevalence and many anecdotal reports of the problem, few studies have systematically examined coabuse of opioids and BZDs, and little is known about the reinforcing effects of mixtures and how they compare to those of either drug alone in nondependent, dependent or withdrawn subjects. Because of this paucity of data, it is not clear how to best treat coabusers. Proposed studies address this major gap in our knowledge about opioid/BZD mixtures by establishing a model of coabuse in monkeys. A choice procedure will be used because it appears to be more sensitive to the reinforcing effects of drug mixtures than single-response, self-administration procedures, and it provides a measure of preference that is relatively independent of response rate, an important feature when studying dependence and withdrawal. Aim 1 establishes choice (self administration) between opioid/BZD mixtures (heroin/midazolam) and heroin alone and compares preference for the mixture in monkeys who are physically dependent on a combination of an opioid (morphine) and a BZD (lorazepam) to those who are not dependent. This Aim tests the hypothesis that heroin/midazolam mixtures are preferred over the same doses of heroin alone in codependent, but not in nondependent, monkeys. Aim 2 examines preference for opioid/BZD mixtures in withdrawn monkeys and compares choice of the mixture to the emergence of other signs of withdrawal. This Aim tests the hypothesis that withdrawal from combined treatment with an opioid and a BZD increases the reinforcing effects of opioid/BZD mixtures, which covary with the emergence of other withdrawal signs. Despite overwhelming epidemiological evidence in drug abusers indicating preference for an opioid/BZD mixture, studies in nonhumans have not replicated these effects perhaps because the procedures are not sensitive to the reinforcing effects of mixtures or the physiological condition of subjects (i.e., nondependent) do not model the typical condition of coabusers. Because systematic studies on drug mixtures are neither safe nor ethical in humans, proposed studies use nonhuman primates and procedures that are well established in this laboratory to model the pharmacological conditions (i.e., opioid/BZD codependence) that are common in coabusers, thereby determining how codependence on and withdrawal from opioids and BZDs impact choice of opioid/BZD mixtures and providing a platform that will be used to investigate other factors that might contribute to coabuse and to assess current and new therapeutic approaches for this important public health problem. PUBLIC HEALTH RELEVANCE: Abuse of prescription opioids has risen dramatically, resulting in a concomitant increase in overdose deaths with most prescription opioid deaths involving at least one other drug, often a benzodiazepine (BZD). This increase is highly unexpected, based on results obtained with this drug combination in the small number of controlled studies that have been conducted to date, and indicates that currently available laboratory procedures, usually conducted in nondependent subjects, do not adequately model the condition of opioid/BZD coabusers, who are often physically dependent. Proposed studies test the hypothesis that opioid/BZD mixtures are preferred in codependent, but not in nondependent, individuals and, if confirmed, would address the lack of understanding of opioid/BZD coabuse, indicate that dependent subjects provide the appropriate preclinical model to study opioid/BZD coabuse, and provide a foundation for developing better treatments.