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 self-administration 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 self-administration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting.

Figure 1

Effects of a long-acting naltrexone formulation on the effects of heroin. For both panels, open symbols represent data collected during the baseline period and closed symbols represent data collected after administration of depot naltrexone. Error bars represent ± 1 standard error of the mean (S.E.M.). Asterisks indicate week difference from baseline at P < 0.01. Top panel (A). Self-administration of heroin as a function of dose (0 to 25 mg) and study week. Data points represent mean breakpoint for heroin. Maximum score = 2800. There was a significant main effect of Study Week (P < 0.0005) and a significant Week by Heroin Dose interaction (P < 0.005). Bottom panel (B). Mean peak VAS ratings of “Good drug effect” after administration of heroin (0 to 25 mg) as a function of dose and study week. Data points represent mean peak ratings. Maximum rating = 100 mm. [Figure reproduced from Sullivan, et al., 2006].

Figure 2

Effects of different maintenance doses of methadone on the effects of heroin. Left panel. Mean total number of injections during the self-administration sessions. There were significant main effects of Methadone Dose and Heroin Dose, as well as an interaction between Methadone and Heroin Dose (P < 0.05). Right panel. Mean change from baseline visual analog rating of “How strong is the drug effect?” There was a significant main effect of Methadone Dose (P < 0.05) and a Methadone Dose by Heroin Dose interaction (P < 0.05). [Figure reproduced from Donny, et al., 2005].