Expecting medication misuse: a proactive approach to drug discovery to prevent fatal overdose

Misuse of central nervous system (CNS) depressants (alprazolam, fentanyl, etc.) is a major cause of fatal overdose, with a high prevalence of deaths involving polydrug interactions from the victim's own prescriptions. Thus, there is an urgent need to improve the safety of CNS depressants to prevent fatalities. Pharmacological pursuits aiming to prevent harm through the design of non-addictive alternatives have either failed before clinical trials or produced mediocre treatment alternatives. Therefore, we propose a new perspective for medicinal chemists: rather than aiming to prevent misuse, we must design new central nervous system (CNS) depressants under the expectation of misuse. By shifting the design focus to partial modulators rather than full agonists, we can develop novel chemical entities (NCEs) that intrinsically minimize physical harm caused by misuse without sacrificing therapeutic efficacy. In this perspective, we provide an overview of the two most widely misused classes of medications (opioid and GABA_A receptor modulators) in relation to pharmacodynamic properties and clinical outcomes. We then suggest a drug discovery pathway focused on physiological parameters. It is our opinion that this approach would dramatically decrease the lethality of overdose and improve outcomes of treatments for pain, anxiety, and withdrawal from alcohol, benzodiazepines, and opioids.