ReviewThe role of human drug self-administration procedures in the development of medications
Introduction
Recent epidemiological data reveal that opioid and cocaine dependence is an important area of public health concern (SAMHSA, 2007; World Health Report, 2005). For example, the number of current (past month) users of heroin in the U.S. more than doubled from 136,000 individuals in 2005 to 338,000 individuals in 2006. Please note that these values were obtained only from those individuals residing in households and therefore are likely to be lower than the true incidence of current heroin users. Of equal or greater concern is the increasing number of users of prescription pain relievers for non-medical reasons (Comer and Ashworth, in press, Zacny et al., 2003). An estimated 5.2 million people were currently using prescription pain relievers for non-medical purposes in 2006, which was an increase from 4.7 million users in 2005, and 2.6 million users in 1999. Incidence rates for new initiation of illicit drug use also appear to be the highest for prescription pain relievers compared to all illicit drugs, including marijuana, with approximately 2.2 million new initiates among individuals aged 12 and older in 2006 (SAMHSA, 2007). Correspondingly, data from the Drug Abuse Warning Network (DAWN, 2005) reveal that there were a total of 108 million emergency department visits, approximately 1.4 million of which were associated with drug misuse or abuse. Of these, heroin was involved in approximately 11% of visits and non-medical use of prescription opioids was involved in approximately 33% of visits. With regard to drug-related deaths, in 91% of the geographical areas studied, more drug misuse deaths involved an opioid than any other drug. Although the rates of past month cocaine use remained relatively stable in the U.S. between 2002 and 2006 (SAMHSA, 2007), cocaine was involved in close to one in three drug misuse/abuse emergency department visits (31%; DAWN, 2005). Worldwide, approximately 16 million people abuse opiates and 14 million people use cocaine (World Drug Report, 2005). Thus, it is clear that the treatment of opioid and cocaine dependence continues to be an area requiring a great deal of attention.
In addition to prevention efforts, drug dependence can be reduced either by developing new medications with limited abuse liability or by developing new more effective pharmacotherapies. Assessment of the abuse liability of new compounds is an important component in the drug development process. The likelihood of abuse is initially assessed by examination of the chemical structure of the new compound compared to known drugs of abuse, the in vitro receptor pharmacology of the compound, and the results of behavioral studies conducted in laboratory animals. The latter studies often employ drug discrimination and drug self-administration paradigms in order to determine the likelihood of abuse (Ator and Griffiths, 2003). The next major component in the assessment of the abuse liability of a new medication is studies conducted in human research volunteers who are experienced with the effects of the drugs in the same pharmacological class as the test compound and who have used the drugs for non-medical purposes. The choice of this subject population is predicated on the belief that it is this group that will most likely misuse the new medication and that they are known to be sensitive to the euphoric effects of that drug class. The standard procedure in such studies is to measure subjective ratings of drug “liking” and other self-report ratings of positive effects produced by a test compound compared to a drug with known abuse liability. Typically, placebo and several doses of the test compound and of the comparator drug are administered to volunteers residing on an inpatient hospital unit. Studies are typically conducted in a well-controlled environment in order to prevent unsanctioned drug use and control other extraneous variables. In these studies, the adverse effects of the potential medication also are examined, such as subjective ratings of negative effects, impairments in cognitive task performance, or changes in physiological functioning, such as decreases in respiration or increases in blood pressure. Details of the methods used to conduct these studies have been published recently in several excellent reviews (Balster and Bigelow, 2003, Griffiths et al., 2003, McColl and Sellers, 2006, Preston and Walsh, 1998).
These same methods have been applied to the evaluation of putative pharmacotherapies for substance abuse disorders in order to determine whether the potential treatment agent can modify the abuse liability profile of the targeted drug of abuse. In this case, subjective effect measures are typically used to characterize the profile of action of the drug of abuse over a range of doses, both in the presence and absence (ideally, under placebo-controlled conditions) of the putative treatment agent. Although the data obtained from subjective effects batteries in both abuse liability studies and drug-interaction studies for medications development can be quite rich and yield critical qualitative and quantitative information, they can sometimes be difficult to interpret. For example, some drugs produce increases in both positive and negative subjective effects, and the balance of these effects may determine whether the drug will be abused (Foltin and Fischman, 1991). However, the determination of the point at which the positive effects outweigh the negative effects can be difficult to assess. The overall profile of subjective responses for a pharmacologically well-characterized compound can be compared to known drugs of abuse within that same pharmacological class in order to assess its abuse liability (Preston and Jasinski, 1991), but the abuse liability of a pharmacologically novel compound can be more difficult to assess in the absence of knowing the most suitable comparator. In an effort to deter abuse, different formulations of new and existing medications are being developed. Some examples of these new formulations include agonist–antagonist combinations, modifications of the physical properties of tablets to hinder tampering, or the addition of aversive agents, such as capsaicin or niacin. Standard approaches to abuse liability testing of such “abuse-deterrent” formulations (ADFs) may not be applicable in some cases, as described below.
The purpose of the present paper is first to summarize briefly the self-administration procedures that are commonly used in human laboratory research. While measurements of subjective effects are also critical to a comprehensive evaluation of the abuse liability of medications, the utility of these measurements and the specific questionnaires most commonly used have been reviewed recently and so will not be repeated here (Balster and Bigelow, 2003, Comer and Zacny, 2005, Griffiths et al., 2003, McColl and Sellers, 2006, Preston and Walsh, 1998). By contrast, a detailed review of the role of human drug self-administration procedures in abuse liability testing and its predictive validity in terms of clinical trial outcomes has not been made in recent years (although see Haney and Spealman, in press, Panlilio and Goldberg, 2007 for comparisons of animal and human self-administration studies). We will then discuss the importance of examining drug self-administration in the development of medications for treating substance abuse and assessing the abuse liability of novel compounds for other medical uses, including those formulations specifically designed to reduce abuse and diversion.
Section snippets
Self-administration procedures
By traditional definition, a drug “serves as a reinforcer” if the behavior leading to its consumption increases in probability over time (e.g., Foltin and Fischman, 1991, Skinner, 1966). For example, individuals tend to expend more effort accumulating money and locating a specific drug dealer if the drug sold by that dealer is considered to be of good quality than if it is considered to be of poor quality. The measurement of the increased behavior leading to drug consumption is the key feature
Drug self-administration and medications development for drug dependence
The potential utility of self-administration procedures in human laboratory research has been examined in the context of the development and evaluation of pharmacotherapies for the treatment of various substance dependence disorders (e.g., O’Brien and Gardner, 2005, Rukstalis et al., 2005, Stoops et al., 2007). These studies are germane to abuse liability testing because they have been commonly employed to detect the ability of the putative pharmacotherapy (typically as a pretreatment) to
Direct assessments of the reinforcing effects of test compounds
In addition to medications development for treating substance dependence, another use of the self-administration procedure has been to evaluate the abuse liability of the treatment agents themselves. When the receptor pharmacology of the compound is known, as is the case for many opioids, the use of the self-administration paradigm is relatively straightforward as long as attention is paid to certain experimental details. Because buprenorphine, a partial mu opioid agonist, is one of the best
Assessing abuse-deterrent formulations
In response to the increased awareness of prescription medication tampering (Cone, 2006), industry and academic scientists have begun to develop an array of novel abuse-deterrent formulations designed to make the manipulation of modified-release formulations more difficult for abusers and, thus, less attractive (Table 2). Most of these technologies either (1) add one or more aversive agents, (2) add an antagonist, (3) make pills difficult to crush, (4) make extraction difficult, (5) use
Conclusions
As reviewed above, drug self-administration paradigms have been used for decades to examine the abuse liability of psychoactive drugs in infrahuman and, to a lesser extent, human studies. There is generally good concordance between those drugs that are self-administered in laboratory settings and those that are abused in the natural environment. Similarly, medications effective at reducing drug self-administration in the laboratory generally reduce drug use in clinical settings. The opioid
Conflict of interest
SDC serves as a consultant to Johnson & Johnson Pharmaceutical Research and Development, L.L.P., King Pharmaceuticals, Schering-Plough Corporation, Cephalon, Inc. and Grunenthal GmbH. In addition, she received funding from Grunenthal GmbH and from Schering-Plough Corporation to conduct investigator-initiated trials on prescription opioid abuse liability. CEJ is a member of CRS Associates, LLC, that has contracts related to abuse liability from Reckitt Benckiser, Merck Pharmaceuticals, Takeda,
Acknowledgements
The authors would like to thank Dr. Nathaniel Katz for organizing a series of conferences at the Tufts Health Care Institute on the issue of opioid risk management, which served as the impetus for this paper. A portion of this review was presented as part of a symposium at the 2006 68th Annual Scientific Meeting of the College on Problems of Drug Dependence (SLW).We gratefully acknowledge the support of the National Institute on Drug Abuse (DA09236 and DA16759 (SDC); DA06234 (RWF); DA01678,
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