Principles of initial experimental drug abuse liability assessment in humans

https://doi.org/10.1016/S0376-8716(03)00098-XGet rights and content

Abstract

This paper describes 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. Such a trial is most appropriate for predicting the likelihood of abuse by drug abusers and, in turn, the extent of drug diversion and illicit street sales if the novel compound became available in the community. The dose–effect abuse liability trial typically involves a double-blind complete crossover design in 10–14 subjects with histories of polydrug abuse in a controlled clinical pharmacology laboratory setting. Drug conditions usually involve placebo, three doses of the novel compound and three doses of an appropriate reference compound of known abuse liability. In each session, the time-course of effects of a single drug dose are evaluated. Intervals between experimental sessions are typically 1 to several days. The importance of testing high supra-therapeutic doses of the novel drug for the validity of the trial is emphasized, and the use of a dose run-up pilot study for selecting maximal doses and matching doses between the novel and comparison compound is explained. The rationale and description of outcome measures is discussed, including measures that reflect likelihood of abuse (e.g. drug vs. money choice and subject ratings of liking, good effects, estimated monetary street value), secondary measures that should be considered in interpreting likelihood of abuse (e.g. drug identification, subject-rated side effects and mood changes), and additional concurrent measures to establish equivalence of the novel and comparison compound (e.g. behavioral performance, observer-rated assessments, physiological measures).

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)

  • G.J. Baylon et al.

    Comparative abuse liability of intravenously administered remifentanil and fentanyl

    J. Clin. Psychopharmacol.

    (2000)
  • G.E. Bigelow

    Human drug abuse liability assessment: opioids and analgesics

    Br. J. Addict.

    (1991)
  • U. Busto et al.

    Pharmacologic effects and abuse liability of bretazenil, diazepam, and alprazolam in humans

    Clin. Pharmacol. Ther.

    (1994)
  • U. Busto et al.

    Identifying appropriate subjects for abuse liability studies using prestudy pharmacological testing

    Can. J. Clin. Pharmacol.

    (1999)
  • Camı́, J., Bigelow, G.E., Griffiths, R.R., Drummond, D.C. (Eds.), 1991a. Barcelona meeting on clinical testing of drug...
  • Camı́, J., Bigelow, G.E., Griffiths, R.R., Drummond, D.C. (Eds.), 1991b. Special issue: clinical testing of drug abuse...
  • L.D. Chait et al.

    Effects of caffeine on cigarette smoking and subjective response

    Clin. Pharmacol. Ther.

    (1983)
  • H. de Wit et al.

    Preference for ethanol and diazepam in light and moderate social drinkers: a within-subjects study

    Psychopharmacology

    (1994)
  • S.M. Evans et al.

    Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability

    J. Pharmacol. Exp. Ther.

    (1990)
  • S.M. Evans et al.

    Abuse liability assessment of anxiolytics/hypnotics: rationale and laboratory lore

    Br. J. Addict.

    (1991)
  • S.M. Evans et al.

    Tandospirone and alprazolam: comparison of behavioral effects and abuse liability in humans

    J. Pharmacol. Exp. Ther.

    (1994)
  • S.M. Evans et al.

    Preference for diazepam, but not buspirone in moderate drinkers

    Psychopharmacology

    (1996)
  • Fischman, M.W., Mello, N.K., 1989. Testing for abuse liability of drugs in humans, National Institute on Drug Abuse...
  • R.W. Foltin et al.

    Methods for the assessment of abuse liability of psychomotor stimulants and anorectic agents in humans

    Br. J. Addict.

    (1991)
  • Food and Drug Administration, 1999. Guidelines for research involving the abuse liability assessment of new drugs, Food...
  • H.F. Fraser et al.

    The assessment of the abuse potentiality of sedative/hypnotics (depressants) (methods used in animal and man)

  • B.E. Garrett et al.

    Physical dependence increases the relative reinforcing effects of caffeine verses placebo

    Psychopharmacology

    (1998)
  • R.R. Griffiths et al.

    Benzodiazepine self-administration in humans and laboratory animals—implications for problems of long-term use and abuse

    Psychopharmacology

    (1997)
  • R.R. Griffiths et al.

    Multiple-choice procedure: an efficient approach for investigating drug reinforcement in humans

    Behav. Pharmacol.

    (1993)
  • R.R. Griffiths et al.

    Validation of the multiple-choice procedure for investigating drug reinforcement in humans

    Exp. Clin. Psychopharmacol.

    (1996)
  • C.A. Haertzen

    Development of scales based on patterns of drug effects, using the Addiction Research Center Inventory (ARCI)

    Physiological Reports

    (1966)
  • L.A. Haunert et al.

    Relationship between the multiple-choice procedure, drug choice and subjective ratings

    Drug Alcohol Depend.

    (2002)
  • J.L. Hill et al.

    Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers

    Psychopharmacology

    (2000)
  • Cited by (173)

    View all citing articles on Scopus

    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.

    View full text