Abuse liability testing: safety versus drug control requirements

Since many psychoactive compounds are necessary to maintain the health and general welfare of the population at large, international controls were established to maintain an adequate and uninterrupted supply of these compounds to meet legitimate medical needs while simultaneously reducing their diversion and abuse. To that end, the community of nations joined together in 1961 and signed “The Single Convention on Narcotic Drugs, and later an additional agreement entitled, “The Convention on Psychotropic Substances” in 1971. These two international agreements were to establish suitable controls over the manufacture, distribution, transfer and use of certain psychoactive substances. In 1988 a third international treaty was signed entitled, “The United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances”. It was the intent of the co-signers of these treaties to ensure the availability of legitimate, safe, and effective pharmaceutical psychoactive substances to manufacturers, distributors, dispensers and researchers while making every effort to prevent drug diversion and abuse.

The diversion of legitimate pharmaceutical products from the distribution system and the use of legitimately prescribed pharmaceutical products outside the scope or direction of medical practice has supported a widespread pattern of “prescription drug abuse.” The persistent use of drugs in a manner that is inconsistent with or unrelated to acceptable medical practice, is a growing epidemic in industrialized societies in the face of insufficient supplies of these same pharmaceutical products in developing nations. Inappropriate prescribing practices, direct-to-consumer advertisements, aggressive marketing strategies, as well as insufficient labeling may all represent contributing influences on the rate of growth of prescription drug abuse in the world today.

The distinction between physiological and psychological dependence is difficult to make in clinical practice, and the role that either of these play in the continued patterns of misuse is difficult to measure. It is clear that withdrawal and tolerance are neither required nor sufficient for a positive diagnosis of dependence syndrome under the ICD-10 diagnostic guidelines. The defining property of “dependence” and “drug abuse” is that they are not mutually inclusive – they do not invariably occur together, and the methods by which they are assessed differ. Determinations of dependence potential, based primarily on the demonstration of tolerance and withdrawal signs, do not necessarily predict a drug’s liability or potential for the generation and maintenance of self-administration outside the scope of medical or legitimate use. There are compounds (e.g. beta blockers, corticosteroids or SSRIs) which produce tolerance and/or an abstinence syndrome after the abrupt cessation of treatment but which do not initiate, maintain, or re-instate drug-seeking or drug self-administration.

A convenient perspective for such evaluation focuses on the changes or events preceding the repeated drug taking on the one hand, and those following it, on the other. Operationally, assessment of the biochemical, physiological, and behavioral changes which follow a chronic pattern of drug intake provides an effective means to address the drug’s dependence potential. Conversely, measures of antecedent drug-seeking and drug discriminating behaviors which occur prior to or during the early stages of development of habitual use can reliably be used as an index of the drug’s abuse liability.

The criteria set forth by international drug control policy are based on the fundamental principle of “similarity.” It is the main criterion for control under the 1961 Convention. The principle of similarity described in the 1971 Convention applies only in situations when the new chemical entity does not produce a state of dependence. In the absence of a finding that a new chemical entity produces dependence, similarity takes on importance; otherwise it is secondary (WHO, 2004; EB115/12). Under the 1961 drug control guidelines it is of primary importance to decide whether the new chemical entity has “morphine-like, cocaine-like, or cannabis-like effects”. But the question is, “how do you do this in the preclinical arena”?

The methodological and operational basis for development of laboratory procedures for the pharmacological assessment within the framework of the pharmaceutical industry has been provided by the systematic analyses of two major stimulus properties of drugs: 1) the reinforcing properties that are operationally defined using self-administration methodologies, and, 2) the discriminative or subjective properties of drugs that are operationally defined using operant drug discrimination procedures. The demonstration of “similarity” to known exemplars of drugs already under international and national control is operationally defined using these behavioral assays.

The problem for the pharmaceutical industry is that the contributions of these distinguishable processes in the potential for abuse of new chemical entities can vary with different classes of drugs as a function of dose, environmental and behavioral contingencies, as well as drug and experimental history. More importantly, the experimental methods used to assess dependence potential and abuse liability of a new chemical entity are quite distinct. To add additional problems there appears to be competing interests within health agencies focused on safety and regulatory agencies focused on drug control with respect to how the preclinical analysis is to be conducted.

A fact to always keep in mind is that drug control policy is based on characteristics of the drug substance, while drug safety evaluations may be linked to a very narrow dose range of that substance. While fulfilling the needs for the health care agency with respect to drug safety, your study package may not adequately address the needs of the drug control agency in its assessment for scheduling.

In consideration of the above, it is the goal of the Contract Research Organization to provide GLP-compliant and validated core assessment batteries that will adequately address both abuse liability and dependence potential of new chemical entities that will pass the regulatory litmus test required for both drug control and drug safety evaluation required as part of the submission of a New Drug Application.

About Dr David Gauvin

David is the Director of Neurobehavioral Sciences and a Senior Principal Study Director at MPI Research. He received his PhD in Behavioral Pharmacology from Wayne State University and has focused on drug abuse liability research for much of his career. Formerly a Drug Science Officer with the DEA, Dr. Gauvin’s expertise was utilized in federal drug scheduling decisions.