With a celebrity death in 2023 attributed to a combination of prescription medications (along with medical comorbidities), the media put a magnifying glass on what is considered appropriate use or combinations of pain medications. On top of that, as recreational marijuana becomes more ubiquitous, the issue of managing people with pain using other substances will become the norm. Additionally, patients commonly consume alcohol and have pain requiring treatment. Rational polypharmacy, use of several medications that work in different ways, is a common approach in managing pain. However there can be deleterious effects to the use of several medications used in combination inappropriately or if there are non-prescribed substances involved as well. Providers need guidance on what to do, what not to do, and how to mitigate risk in patients. The goal of this presentation is to improve critical thinking skills, clinical knowledge, practice behavior, and practice outcomes by increasing knowledge around MOA for drug and substance interactions with common pain medications which will ideally reduce inappropriate prescribing of medications given potential drug interactions, including illicit substances and alcohol.