The role of human drug self-administration procedures in the development of medications

Abstract

The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest -that is, drug taking. The present paper 1) reviews the most commonly used human self-administration procedures, 2) discusses the concordance of subjective reports and selfadministration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and 3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including "abuse deterrent" formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of selfadministration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting.

Evaluation of the “Pipeline” for Development of Medications for Cocaine Use Disorder: A Review of Translational Preclinical, Human Laboratory, and Clinical Trial Research

“…Although subjective ratings can be rapidly and easily assess abuse potential and the efficacy of potential interventions (Griffiths et al, 2003), these methods have been criticized as an indirect measure of drug taking (Katz, 1990) and for significant variability across subjects due to variations in interpretation across time and individuals (Kelly et al, 2003). Perhaps the most important criticism is that subjective ratings can produce false positives when used to screen putative pharmacotherapies (Comer et al, 2008;Haney and Spealman, 2008). The use of multiple subjective ratings items, with most studies including 10 to 20 individual subjective ratings, also complicates interpretation because different effects may be observed across questions or responses to these items may covary (Bolin et al, 2013;Strickland et al, 2014).…”

“…These procedures were largely developed to study the behavioral pharmacology of abused drugs, particularly to predict the abuse potential of new compounds. Whether these behavioral measures demonstrate predictive validity regarding efficacy in treating cocaine use disorders has been a topic of debate, although self-administration measures appear to be the best screening tool (Mello and Negus, 1996;Comer et al, 2008;Haney and Spealman, 2008).…”

Controversies in translational research: drug self-administration

“…Although there are examples in which medications, such as amantadine, bromocriptine, and phenytoin, failed to decrease cocaine intoxication in the laboratory Preston et al 1992;Sofuoglu et al 1999) and also failed to decrease cocaine use in clinical trials de Lima et al 2002;Gorelick and Wilkins 2006), overall, cocaine's subjective effects appear to be more sensitive to modulation by medications, resulting in a high rate of false positives when this is the primary outcome measured (see also Comer et al 2008a). A vast array of compounds including gabapentin, desipramine, pergolide, risperidone, ecopipam, selegeline, venlafaxine, and naltrexone, for example, have been shown to decrease ratings of a cocaine intoxication or cocaineelicited craving in the laboratory (Hart et al 2004(Hart et al , 2007aFischman et al 1990;Haney et al 1998;Romach et al 1999;Newton et al 1999;Foltin et al 2003;Sofuoglu et al 2003), yet none of these compounds decreased cocaine use in controlled clinical trials (Bisaga et al 2006;Campbell et al 2003;Malcolm et al 2000;Grabowski et al 2000;Elkashef et al 2006;Ciraulo et al 2005;Grassi et al 2007).…”

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…The support of operant responding in drug self-administration assays is often viewed as the most significant abuse-related effect amenable to preclinical study. Importantly, candidate medications can be evaluated for the degree to which they reduce self-administration of a target drug of abuse, such as cocaine (Mello and Negus, 1996;Comer et al, 2008;Haney and Spealman, 2008). That said, as with all relevant animal preclinical models, the outcomes are affected by the species, strain, and experimental history of the subjects employed in self-administration studies, and thus, interpretations must be made in the context of available knowledge from multiple in vivo assays.…”