Drug Abuse and Drug Dependence

Much of the recent renewed interest in the topic of drug abuse liability and dependence assessment within the pharmaceutical industry, as highlighted within such forums as the Safety Pharmacology Society and other key scientific/industry meetings, is related to the issuance of the latest in a line of regulatory guidance documents (EMEA/CHMP) addressing the scope of the issue and key requirements for appropriately defining safety relative to these problematic phenomena.

Relative to their commonplace nature, there is an intuitive sense of the meaning conveyed by the words “abuse liability”, and “drug dependence”.  Despite (or possibly in fact due to) their common use in the vernacular, there is invariably confusion surrounding the differential use of definitions in discussing these entities.  This article is intended as a guide to understanding some of the key distinctions between the subjective and reinforcing properties of drugs that tend to promote their acute administration (i.e., abuse), and those events that reflect the pattern of neuro-adaptation that may also play a role in maintaining drug taking by its own unique mechanisms (i.e., dependence syndromes).

The international community has long recognized the danger involved in the manufacture, distribution, and use of certain psychoactive substances for nonscientific and/or nonmedical purposes.  To that end, the community of nations joined together in 1971 and signed a treaty entitled, “The Convention on Psychotropic Substances” to establish suitable controls over the manufacture, distribution, transfer and use of certain psychoactive substances.  In the United States, the obligation to the Psychotropic Convention formed the framework for the Comprehensive Drug Abuse and Control Act, also known as the Controlled Substances Act.  It was the intent of the U.S. Congress and the co-signers of the treaty, to insure 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.

A distinction is generally made between substance use, substance abuse, and substance dependence.  Substance abuse is generally characterized by a pattern of “pathological” use or the impairment in social or occupational functioning that is related to the use of the substance for an extended period of time.  Under the Controlled Substances Act, the definition of an “addict” is any individual who habitually uses any [narcotic] drug so as to endanger the public morals, health, safety, or welfare, or who is so far addicted to the use of [narcotic] drugs as to have the lost the power of self-control with reference to his addiction.

The difficulty in discussing drug abuse, in general, can be highlighted by the use of the word “dependence”.  Dependence has at least two connotations: 1) dependence, or more precisely “physical dependence” is used with specific reference to the chemical and biological effects which follow repeated exposure to a drug resulting in tolerance and an abstinence syndrome when the drug is withdrawn; and  2) in the more general vernacular, “dependence” is often used interchangeably with “abuse”, referring to a range of complex behaviors characterized as “loss of voluntary control over drug taking” or “compulsive drug use”.

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 for self-administration outside the scope of legitimate use.  There are compounds (e.g. beta blockers [propranol] or corticosteroids) which produce tolerance and an abstinence syndrome after the abrupt cessation of chronic treatment but which do not initiate, maintain, or re-instate drug-seeking or drug self-administration.  Conversely, six decades of research has clearly shown that drug seeking or drug self-administration can be initiated and maintained in both animal and human subjects by doses of drug that demonstrate no appreciable degree of tolerance or withdrawal upon abrupt cessation of administration.

The contiguity between the physiological and behavioral consequences of drug intake provides for a convenient operational basis to define and characterize the range of a new chemical entity’s functional properties and for differentiating between its dependence potential and abuse liability. 

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 the repeated 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 habitual use are reliable indicators of the drug’s abuse liability.  Conveniently, due to decades of research since the 1960’s, reliable behavioral pharmacology methodologies have been developed by a host of scientists, and the refinement of their pioneering techniques currently represents the state-of-the-art in delineating these complex biobehavioral phenomena.

It would seem intuitive that physiological dependence and drug abuse are, of course, commonplace.  Changes in drug-seeking or drug-taking most often will be found as an outcome of both the initial (acute) effects of a drug, and to the tolerance and withdrawal effects which follow more repeated drug exposures.  On the other hand, the withdrawal or physiological dependence syndromes produced following repeated drug exposures certainly can initiate drug-seeking and drug-taking behaviors motivated by the need to alleviate the full expression of physiological withdrawal symptoms. 

The problem for the pharmaceutical industry is that the relative contributions of these distinguishable processes in determining the potential for abuse of new chemical entities can vary with different classes of drugs as a function of dose, environmental contingencies, as well as the unique drug and experimental history of the patient.  Importantly, the experimental methods used to assess dependence potential and abuse liability of a new chemical entity are quite distinct.  In consideration these factors, it is clear that scientifically validated and GLP-compliant core assessment batteries are required that will adequately address both abuse liability and dependence potential of new chemical entities towards passing the regulatory litmus test required to submit the New Drug Application.