Principles of drug abuse liability assessment in laboratory animals
Introduction
Abuse liability assessment in laboratory animals is an important component of drug development and evaluation of a psychoactive drug for governmental controls. Studies in laboratory animals have unique advantages over studies in humans. They can be done earlier in an evaluative process, across a greater dose range, and for a more extended duration than in patients or research volunteers.
At early phases of drug development, abuse liability assessment in laboratory animals can contribute to strategic decisions on how and whether to proceed with a new series of centrally acting compounds. If a goal is that the candidate compound be as efficacious as existing medications but less subject to legal controls on prescribing, then an abuse liability assessment early in drug development can be critical. A comprehensive abuse liability evaluation also contributes to the pharmacological characterization of the compound. For example, such data can show whether a novel molecular mechanism of action results in a novel behavioral profile in comparison to other compounds with the same intended use.
The Food and Drug Administration (FDA), which reviews data relevant to the abuse liability of new centrally acting drugs, expressed the view that ‘the integration of specialized preclinical and clinical abuse liability studies with data [on] safety and efficacy provides the best predictor of the abuse potential of a new drug that has not been marketed anywhere in the world.’ (‘Guidelines for Research Involving the Abuse Liability Assessment of New Drugs’, Draft 12-2-98, FDA Center for Drug Evaluation and Research; Division of Anesthetic, Critical Care and Addiction Drug Products; cf. 1990 Guidelines in Balster and Bigelow, 2003, this volume).
Similarly the Drug Enforcement Administration (DEA) must evaluate whether compounds that begin appearing in drug abuse trafficking and emergency room overdose cases should be subject to new or increased legal control. Data from abuse liability evaluations are needed to inform final scheduling under the Controlled Substances Act. Due to the nature of some compounds of concern, preclinical studies may be the only ones ethically or practically feasible for such decision making (e.g. chemical analogs of phencyclidine, PCP, Lukas et al., 1984).
Beyond governmental requirements, however, a compelling reason to obtain a comprehensive abuse liability assessment in the process of new drug development is to be able to supply practitioners and patients with information they need for appropriate use. Some caveats accompany use of virtually any efficacious psychoactive drug. The Valium scare of the 70s, which led to Congressional hearings on the benzodiazepines, provides dramatic testimony to the unfortunate consequences of failure to obtain and disseminate data on the abuse liability and physical dependence potential of a clinically useful drug (Use and misuse of benzodiazepines, 1979). The belief of physicians and patients that these drugs were completely ‘safe’ in this regard led to sometimes cavalier prescribing and use practices, which culminated in lurid popular accounts of physical and psychological dependence (Gordon, 1979). Such an outcome, which reverberates to the present day in restrictive laws and litigious former patients, likely could have been avoided if physicians and patients had been made fully aware of the possibility of a withdrawal syndrome upon discontinuation and the liability of these compounds for abuse. In fact, limited data on physical dependence with the first clinically available benzodiazepine, chlordiazepoxide (Librium) had been published (Hollister et al., 1961), but the implications had not been fully pursued. Current attention to full characterization of candidate medications in the course of drug development is key to preventing such unfortunate episodes.
Section snippets
Behavioral methods for abuse liability evaluation in animals
The FDA Guidelines cited above set forth the definition of abuse liability that is most relevant for the purposes of the present paper: “The term ‘abuse liability’ refers to the likelihood that a drug with anabolic, psychoactive or central nervous system (CNS) effects will sustain patterns of non-medical self-administration (SA) that result in disruptive or undesirable consequences”. (p. 3). The FDA document pointed out that there is no single test or assessment procedure likely to offer a
Cross-cutting methodological considerations
A primary intent of the present paper is to emphasize methodological considerations that must be made to be able to draw well-founded conclusions about a test drug's reinforcing, discriminative, and physical-dependence-producing effects. Regardless of the specifics of procedures used, certain overarching methodological considerations apply to any study that is intended to contribute to an abuse liability assessment.
Background
A key component of preclinical abuse liability assessment is to determine whether the compound will be self-administered. The goal is to assess the ability of the drug to serve as a reinforcer, which is operationally defined as determining whether drug delivery maintains behavior at a meaningfully higher rate than does the control (usually vehicle delivery). The model originally was developed by use of intravenous drug delivery through chronically indwelling catheters in rats and monkeys (
Background
In drug discrimination procedures, animals are trained to respond differentially depending on the nature of the drug pretreatment. The goal is to train the animal to use the drug effect as a cue (technically termed a discriminative stimulus) as to which response to make to obtain some commodity (or, in some procedures, to avoid an aversive stimulus). The drug discrimination procedure has been characterized as providing information analogous to a human testing situation in which people who are
Background and overview
Physical dependence is manifested as time-limited biochemical, physiological, and behavioral disruptions upon termination of a regimen of chronic drug administration. When any chronically administered drug no longer is given, some sort of ‘discontinuation’ or ‘withdrawal’ syndrome is not uncommon; this applies to peripherally as well as centrally acting drugs. The phenomenon often has been called an ‘abstinence’ syndrome in the case of psychoactive drugs in humans. The basis for any such
Final comments
Obtaining profiles of the reinforcing, discriminative, and physical-dependence-producing effects of newly developed, centrally acting compounds in laboratory animals is essential for regulatory compliance and can be particularly useful in the drug development process. Drug SA, drug discrimination, and physical dependence assessment procedures each uniquely supply information that forms the core of an abuse liability assessment, but no one of them is definitive as to the level of legal control
Acknowledgments
Preparation of this manuscript was supported by the Committee on Problems of Drug Dependence and by National Institute on Drug Abuse grants RO1 DA04133, RO1 DA01147, RO1 DA03889, and RO1 DA03890.
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Based on a background paper prepared for the October 28–29, 2002 College on Problems of Drug Dependence-sponsored meeting on Assessing the Abuse Liability of CNS Drugs held in Bethesda, MD.