Drug Abuse Liability Assessment
Amid the ongoing opioid crisis gripping the country, what can pharmaceutical companies do to prevent new medications from being abused?
Drug and alcohol abuse are complex problems with staggering economic and societal costs. The National Institute on Drug Abuse (NIDA, 2017) reports that tobacco, alcohol, and drug abuse costs Americans approximately $740 billion. Amid America’s ongoing opioid crisis, one may wonder what role pharmaceutical companies play in helping to prevent or reduce the likelihood that new medications will be abused.
In drug development, there are often two strategies that are undertaken: 1) to develop an effective medication demonstrating significant benefits that outweigh potential risks to the patient, or 2) develop medications to effectively block the unexpected (side) effects of the drug that may motivate the patient to abuse the drug. The experiments required for drug approval that support either of these two strategies are referred to as drug abuse liability (DAL) studies. To aid in DAL assessments, the US Food and Drug Administration recently published a guidance document (Assessment of Abuse Potential of Drugs, 2017) for researchers developing animal experiments designed to predict the DAL of new medications before the drug is administered to human patients. For obvious ethical reasons, all drug development programs conduct safety studies with animals. But how does animal data translate to predict whether humans are likely to abuse a drug?
In the nonclinical arena, DAL studies are conducted with both rats and large animals. In general, the rat is considered the most preferred species for DAL assessment. The concordance between nonclinical DAL data and actual human abuse is strong. Using animals, we model (drug-taking behaviors) human drug abuse in controlled laboratory settings. We are able to measure how much of a given drug dose an animal will voluntarily take and how hard they are willing to work for a given drug dose.
The self-administration model involves training an animal to press a lever, initially for food, and then eventually for a given dose of a known abused drug (e.g., cocaine or morphine). Under the first strategy, in which a Sponsor is specifically concerned with a test article’s DAL, once animals are consistently taking the known drug of abuse (positive comparator), they are given the test article and their behavior is then compared to baseline conditions under which they were exposed to the positive comparator. If animals continue to press a lever for a given drug, it may indicate that the test article serves to motivate the animal to continue to work for more, and that the test article may have the potential for abuse once on the market.
Under the second strategy, in which the goal is to block the rewarding feelings that, for example, a pain medication may produce, we can measure the amount of a drug that is taken before and during treatment with the test article. Changes in the amount of drug taken in combination with the new drug can indicate that the medication may have a positive clinical effect with regard to decreasing or blocking its pleasurable effects, while still reducing patient pain.
With few exceptions, most drugs that maintain animal responses will also be abused or have rewarding effects in humans. Using animal models in lieu of DAL studies in humans helps to meet our high ethical standards and maintain our commitment to reduce animal use during drug development. Amidst the current climate and worldwide patterns of drug abuse, it is our responsibility to ensure that new drugs entering the market are safe and effective, but more importantly that the drug does not pose substantial risks of addiction or dependence in legitimate patients taking the drug under the care of their physician.