Principles of initial experimental drug abuse liability assessment in humans
Introduction
The purpose of this paper is to describe the rationale and procedures for conducting what is considered by many to be the current “gold standard” for initial abuse liability testing of a novel compound: the classic acute dose–effect comparison study in volunteers with histories of drug abuse. The historical development of these methods for abuse liability testing has been discussed previously (Jasinski, 1977; Jaffe and Jaffe, 1989), and there are two excellent monographs that provide a detailed presentation of various strategies for drug abuse liability assessment in humans (Fischman and Mello, 1989, Camı́ et al., 1991b). Also, focused reviews have addressed abuse liability assessment of specific drug classes: stimulants and anorectics (Foltin and Fischman, 1991a, Foltin and Fischman, 1991b), anxiolytics and hypnotics (Roache and Griffiths, 1989, Evans et al., 1991, de Wit and Griffiths, 1991), opioids and analgesics (Jasinski, 1977, Bigelow, 1991), NMDA antagonists and neuroprotectants (Klein et al., 1999).
Table 1 presents the primary features of an acute dose–effect comparison abuse liability trial. Typically, such a trial compares the profile of acute effects of a range of doses of the novel compound to those of placebo and a range of doses of a reference compound of known positive abuse liability on an array of outcome measures related to or reflective of abuse liability. Most of the features listed in the table have been explicitly or implicitly endorsed in reviews on abuse liability assessment of various drug classes (Roache and Griffiths, 1989, Jasinski and Henningfield, 1989, Evans et al., 1991, Bigelow, 1991, Klein et al., 1999), in a 1990 consensus statement about abuse liability testing from an international group of experts (Camı́ et al., 1991a), as well as in draft guidelines on abuse liability assessment distributed by the Food and Drug Administration (FDA, 1998). This paper involves a synthesis and updating of these previous discussions, providing background and rationale as appropriate.
Before discussing specific features of the acute dose–effect abuse liability trial, it is important to clarify what such a trial can and cannot be expected to accomplish. A dose–effect abuse liability trial with a novel unmarketed compound is most appropriate for predicting the likelihood of abuse by recreational drug abusers and, in turn, the extent of drug diversion and illicit street sales if the novel compound became widely available to the drug abuse community. It is less clear whether these same procedures and data would predict the likelihood of overuse or misuse in patient populations exposed to the drug therapeutically, though many believe these same methods have predictive applicability both to drug abusers and to therapeutically exposed patients. Experimental methods in patient populations have not been developed and validated for predicting the risk of overuse or misuse of medically prescribed drugs in patient populations, with the possible exception of recent studies of nicotine replacement products in cigarette smokers (Schuh et al., 1997, West et al., 2000, Houtsmuller et al., 2002).
Section snippets
Typical trial design characteristics
The great majority of dose–effect abuse liability evaluations have used similar experimental designs. Typically, a double-blind within-subject or complete crossover design is used in which all subjects are tested with all drug conditions, although there have been occasional studies that used between group designs (e.g. Preston et al., 1987, Funderburk et al., 1988) and incomplete crossover designs (Jaffe et al., 1983). The drug conditions typically involve placebo, three doses of the novel
Controlled clinical pharmacology laboratory setting
Drug abuse liability evaluations should be conducted in controlled laboratory settings which permit careful assessment of outcome measures in the context of appropriate medical support and prevention of other drug use. For studies with subjects with histories of drug abuse, it is particularly important that volunteers be closely monitored for use of other drugs. Ideally, and most often, such studies are conducted on a closed residential drug abuse pharmacology research unit which provides a
Selection of an appropriate subject population
Drug abuse liability evaluations are best conducted in subjects with extensive histories of polydrug abuse, including abuse of drugs from the same pharmacological class as the novel compound, if possible. There are several reasons for this. First, subjects with histories of polydrug abuse can use their prior drug abuse experiences with a variety of drugs and drug classes as a context from which to provide meaningful ratings of the drug experiences in the laboratory. Examples of measures that
Double-blind, placebo-controlled drug administration
Standard clinical pharmacology methods require that the subject and the staff who interact with the subject must remain uninformed about which specific drug conditions administered on a given session. In addition, a “no-effect” control in the form of placebo is standard in abuse liability evaluations as a further protection from expectancy or accidental bias influences. Because expectancy can play such an important role in any measures of subjective effects, it is also desirable to keep
Selection of appropriate positive control comparison drug(s)
A well-established principle of any biological assay is that the unknown sample must be compared with a standard compound tested under identical assay conditions. Use of a pharmacologically inactive negative control condition alone (i.e. placebo) does not verify the sensitivity of the assay. The biobehavioral assay of abuse liability assessment involves comparing the novel compound to a standard compound of known abuse liability (i.e. a positive control). The positive control should have
Selection of an appropriate range of doses of the positive control comparison drug
Ideally, three or four dose levels of the positive control compound are included, spanning a 3–8 fold range of doses, and producing effects ranging from little to moderate or high. Within the study, the positive control compound should demonstrate dose-related statistically significant increases on the primary measures of abuse liability. Failure to demonstrate significant increases with the positive control drug invalidates the assay. One purpose of testing a range of doses is to determine the
Selection of an appropriate range of doses of the novel compound, including high supratherapeutic doses
It is essential to the validity of an abuse liability trial that a sufficiently high supratherapeutic dose of the novel compound be tested. The principal purpose of the initial abuse liability evaluation is to determine whether the compound is likely to lead to public health and social problems because of its abuse by drug abusers. With any new drug, it must be assumed that drug abusers will inevitably sample high doses and the effects of these doses will determine whether or not the drug
Selection of appropriate outcome measures
Three types of outcome measures should be considered in dose–effect abuse liability trials: 1. measures most directly related to predicting the likelihood of abuse (e.g. ratings of liking, disposition to take the drug again, street value and drug vs. money choice behavior); 2. measures that should be considered when interpreting likelihood of abuse (e.g. drug identification, subject-rated side effects and mood changes); and 3. other concurrent measures of drug effect (e.g. subject-rated
Limitations and future directions
This paper outlines the features of the current “gold standard” for initial abuse liability assessment of a novel drug—the classic acute dose–effect comparison study. Because research in abuse liability assessment will continue to develop and refine these methods, and because novel pharmacological agents or dosage forms often present special considerations, none of the features outlined in Table 1 and discussed in the preceding sections should be considered as an inflexible mandate. Rather, the
Conclusions
The present paper describes the rationale and procedures for conducting the classic acute dose–effect comparison abuse liability assessment study in volunteers with histories of drug abuse. Such a trial is appropriate for predicting the likelihood of abuse by drug abusers and represents a crucial initial step in assessing the abuse risk of marketing a novel compound. In addition to predicting the likelihood of abuse, such a study may also provide an assessment of some of the adverse
Acknowledgments
Preparation of this review was supported by the College on Problems of Drug Dependence and, in part, by National Institute on Drug Abuse grants R01 DA03889, R01 DA03890, R01 DA04133, K05 DA00050, and P50 DA05273.
References (67)
- et al.
Response patterns of the Spanish version of the 49-item short form of the Addiction Research Center Inventory after the use of sedatives, stimulants, and opioids
Drug Alcohol Depend.
(1999) - et al.
Principles of drug abuse liability assessment in laboratory animals
Drug Alcohol Depend.
(2003) - et al.
Testing the abuse liability of anxiolytics and hypnotic drugs in humans
Drug Alcohol Depend.
(1991) - et al.
Individual differences in the reinforcing and subjective effects of amphetamine and diazepam
Drug Alcohol Depend.
(1986) - et al.
Reinforcing and subjective effects of diazepam in nondrug-abusing volunteers
Pharmacol. Biochem. Behav.
(1989) - et al.
Assessment of abuse liability of stimulant drugs in humans: a methodological survey
Drug Alcohol Depend.
(1991) - et al.
Relative abuse liability of lorazepam and diazepam: an evaluation in “recreational” drug users
Drug Alcohol Depend.
(1988) - et al.
Flavor improvement does not increase abuse liability of nicotine chewing gum
Pharmacol. Biochem. Behav.
(2002) - et al.
Flunitrazepam and triazolam: a comparison of behavioral effects and abuse liability
Drug Alcohol Depend.
(1998) - et al.
Effect of intravenous injection speed on responses to cocaine and hydromorphone in humans
Psychopharmacology
(2001)
Comparative abuse liability of intravenously administered remifentanil and fentanyl
J. Clin. Psychopharmacol.
Human drug abuse liability assessment: opioids and analgesics
Br. J. Addict.
Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans
Clin. Pharmacol. Ther.
Identifying appropriate subjects for abuse liability studies using prestudy pharmacological testing
Can. J. Clin. Pharmacol.
Effects of caffeine on cigarette smoking and subjective response
Clin. Pharmacol. Ther.
Preference for ethanol and diazepam in light and moderate social drinkers: a within-subjects study
Psychopharmacology
Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability
J. Pharmacol. Exp. Ther.
Abuse liability assessment of anxiolytics/hypnotics: rationale and laboratory lore
Br. J. Addict.
Tandospirone and alprazolam: comparison of behavioral effects and abuse liability in humans
J. Pharmacol. Exp. Ther.
Preference for diazepam, but not buspirone in moderate drinkers
Psychopharmacology
Methods for the assessment of abuse liability of psychomotor stimulants and anorectic agents in humans
Br. J. Addict.
The assessment of the abuse potentiality of sedative/hypnotics (depressants) (methods used in animal and man)
Physical dependence increases the relative reinforcing effects of caffeine verses placebo
Psychopharmacology
Benzodiazepine self-administration in humans and laboratory animals—implications for problems of long-term use and abuse
Psychopharmacology
Multiple-choice procedure: an efficient approach for investigating drug reinforcement in humans
Behav. Pharmacol.
Validation of the multiple-choice procedure for investigating drug reinforcement in humans
Exp. Clin. Psychopharmacol.
Development of scales based on patterns of drug effects, using the Addiction Research Center Inventory (ARCI)
Physiological Reports
Relationship between the multiple-choice procedure, drug choice and subjective ratings
Drug Alcohol Depend.
Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers
Psychopharmacology
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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.