ABUSE LIABILITY OF THERAPEUTIC DRUGS: TESTING IN ANIMALS

Determining the probability that a new drug will be abused is an important step in reducing the overall abuse of therapeutic drugs. Since the likelihood that a drug will be abused by a patient must be carefully weighed against the benefit provided by the drug, it is important that research outline any and all reinforcing effects a drug may have which could lead to subsequent abuse. Prediction of the likelihood of abuse has historically been based upon human experiments and observation. This method, however, is increasingly being replaced with experimentation on animals.

Research conducted since the early 1960s has shown that animals such as monkeys and rats will, with very few exceptions, repeatedly self-administer the same drugs that human beings are likely to abuse. Moreover, test animals do not self-administer drugs that human beings do not abuse.

Research based on animal testing is conducted in a slightly different manner and often requires laboratory procedures not needed for research based on human test subjects. Provisions must be made to allow the animal a means by which to self-administer the drug. Since animals frequently are not physically able to administer a drug in the same way a human would, alternate methods are employed. Animals may be taught to push levers or do similar actions in order to get a dose of a drug. The results of these drug self-administration studies in animals play a critical role in the prediction of the likelihood of abuse of new drugs in human beings.

The liability that a drug will be abused is often evaluated by what has been termed a "substitution procedure." Such research begins with the administration of a known drug, which is then substituted with a new drug under investigation. The first phase in the substitution procedure is designed to establish a baseline of how much effort an animal is willing to make to obtain a drug dose in general. Each day an animal is allowed to give itself a drug of known potential for abuse. The researcher notes how frequently the animal takes a dose and how much effort it is willing to make to get a dose of the drug. The researcher can make a lever harder to push, make the animal push it repeatedly, or make the animal follow a complicated set of actions to get a dose. This provides a baseline against which to compare the effects of the new drug which will be studied.

For example, a monkey may give itself cocaine or codeine via intravenous injections during sessions that last several hours. When session-to-session intake of the known drug is stable (that is, stays about the same, thus showing the dosage which is sufficient to satisfy the animal and reduce its drive to obtain more), the liquid in which it was dissolved is substituted for the baseline drug for several consecutive sessions. Since this liquid is usually neutral, with no positive or negative effects, the animal gives itself fewer and fewer injections until it hardly bothers pushing the lever at all. The animal is briefly returned to baseline conditions, followed by a substitution period during which a dose of the test drug is made available. This continues for at least as many sessions as were required for the animal to stop bothering with pushing the lever for the neutral liquid. This process is repeated with different concentrations of the new drug until the experimenter has tested a range of possible doses of the new medicine.

The rates at which the animal gives itself the test drug, neutral liquid, and known addictive drug are then compared. A new drug that the animal prefers to the neutral liquid is considered to be a substance that reinforces the desire for itself (a "positive reinforcer") and would thus be predicted to have abuse liability.

Such substitution procedures provide information which indicates whether or not a drug is liable to be abused, but do not allow a comparative estimate as to whether or not a new drug is more addictive or less addictive than other known drugs. These procedures measure how frequently the animal gives itself a dose, a measure that reflects both the direct effects of the drug and the effects of the drug's reinforcement of the desire for itself. Another method must be used to measure the reinforcing effect of a drug separately from its other effects. To compare drugs, it is useful to know how big the maximum reinforcing effect is—termed its reinforcing efficacy. Several procedures have been developed to measure reinforcing efficacy. Most either allow an animal to choose between the new drug and another drug or non-drug reinforcer (choice procedures), or they measure how hard an animal will work to obtain an injection (progressive-ratio procedures).

In choice procedures, the measure of reinforcing efficacy is how often the new drug is chosen in preference to the other drug (or non-drug). In progressive-ratio procedures, the number of times the animal must push the lever in order to get a drug injection is increased until the animal no longer bothers to push the lever. At some point the animal determines that it is not worth the extra effort to get another dose. This point is called the break point and is a measure of the reinforcing efficacy of the drug.

The fact that animals given a choice between different strengths of the same drug show a propensity to choose the higher dose most often is evidence that these procedures provide a valid measure of reinforcing efficacy. In addition, break points are higher in progressive-ratio experiments involving higher stable doses and lower for experiments involving lower doses. Results of both the choice and the progressive-ratio procedures in animal research are consistent with what is known about abuse of drugs in human beings—that is, drugs such as cocaine, a highly preferred drug in choice studies, maintain higher break points in progressive-ratio studies than other drugs, and are frequently abused.

These experiments show how animals discriminate among drugs, and the extent to which they prefer certain drugs over other drugs. The results may be used to predict potential subjective effects in human beings. Since subjective effects play a major role in drug abuse, such experiments are an important tool used in the evaluation of the likelihood of abuse in new drugs. A new drug with subjective effects similar to those of a known, addictive, and often abused drug is likely to be abused itself. Additionally, drug-discrimination experiments not only identify the potential for abuse but also provide important information which allows researchers to classify new drugs based on their predicted subjective effects, something that drug self-administration experiments cannot do. Thus, drug discrimination provides additional information relevant to the comparison between the new drug and drugs that we already know are addictive and frequently abused. For example, a monkey shows a similar discrimination pattern using a new drug as it has shown previously using a known drug such as cocaine. This new drug is likely to be abused and to have subjective effects similar to those produced by cocaine.

CONCLUSION

Researchers have improved methods for predicting the likelihood that a new drug will be abused. Using animals in substitution, choice, and progressive-ratio procedures has greatly enhanced researchers' understanding of factors involved in determining the liability that a new drug or chemical compound will be abused. Current research techniques allow the evaluation of likely preference and the reinforcing efficacy of a new compound based on experiments with animals such as monkeys and rats. This information is then used to reliably predict whether a drug is likely to be abused and to which known drugs it is likely to be similar, both in terms of how addictive it is and what its subjective effects will be. Such information is clearly valuable in deciding how much to restrict a new drug and is a critical tool in the effort to reduce the abuse of therapeutic drugs.

(See also: Abuse Liability of Drugs: Testing in Humans ; Controlled Substances Act of 1970 ; Reinforcement ; Research: Animal Model )

BIBLIOGRAPHY

Brady, J. V., & S. E. Lukas (1984). Testing drugs for physical dependence potential and abuse liability. NIDA Research Monograph no. 52. Washington, D.C.: U.S. Government Printing Office.

Thompson, T., & K. R. Unra (Eds.) (1977). Predicting dependence liability of stimulant and depressant drugs, Baltimore: University Park Press.

William Woolverton

Revised by James T. McDonough, Jr.