Opioid use, opioid misuse, and long-term opioid therapy (LTOT) have captured the nation’s attention, raising questions regarding pain management and concerns about who is most at risk for the use of nonmedical prescribed opioids (NMPOs). In 2015, opioid overdoses accounted for 33 091 US deaths.1 During this same year, more than 276 000 adolescents were current NMPO users, placing these adolescents at serious health risk.2 Physicians therefore face the challenge of trying to calculate the varying risks of patients transitioning into the use of NMPOs while addressing the pain of patients. A primary concern is to prevent adolescents from transitioning from supervised medical use of opioids into use of NMPOs. Preventing this transition is critical because nearly 80% of adolescents who reported using heroin indicated their NMPO use preceded their heroin use.3 The question arises of which adolescents are at greatest risk of initiating this dangerous transition during this critical period of development, which can have long-term health consequences. Important foundational research is being conducted to better understand these complex and fragile trajectories of risk and protective factors associated with opioid involvement.