BackgroundThe misuse of opioid medications among adolescents is a serious problem in the United States. Serious games (SGs) are a novel way to promote the safe and responsible management of opioid medications among adolescents, thereby reducing the number of adolescent opioid misuse cases reported annually.ObjectiveThis study aimed to examine the effect of the SG MedSMART: Adventures in PharmaCity on adolescents’ opioid safety knowledge, awareness, behavioral intent, and self-efficacy.MethodsA nationally representative sample of adolescents aged 12 to 18 years were recruited online through Qualtrics panels from October to November 2020. Data collection consisted of a pregame survey, 30 minutes of gameplay, and a postgame survey. The pregame and postgame surveys included 66 items examining the participants’ baseline opioid knowledge, safety, use, and demographic information. The postgame survey had 25 additional questions regarding the MedSMART game. Gameplay scenarios included 5 levels intended to mimic adolescents’ daily life while educating the players about appropriate opioid storage and disposable practices, negative consequences of sharing opioid medications, and the use of Narcan. Survey questions were divided into 10 categories to represent key concepts and were summarized into concept scores. Differences in concept scores were described by overall mean (SD) when stratified by gender, race, school, grade, and age. Differences of change in concept score were analyzed using the Kruskal-Wallis and correlation tests.ResultsA total of 117 responses were analyzed. The results showed significant improvement on all concept scores except for Narcan knowledge (mean change -0.04, SD 0.29; P=.60) and safe storage (mean change 0.03, SD 0.20; P=.09). Female participants had greater improvement than males for safe disposal (female mean 0.12, SD 0.25 vs male mean 0.04, SD 0.17; P=.05). Male participants had higher improvement than female participants for misuse behavior (female mean 0.05, SD 0.28 vs male mean 0.14, SD 0.27; P=.04). Perceived knowledge for participants who had non-White or Hispanic racial backgrounds had higher improvement than for non-Hispanic White participants (non-White mean 1.10, SD 1.06 vs White mean 0.75, SD 0.91; P=.03). Older grades were associated with greater improvement in opioid knowledge (correlation coefficient -0.23, 95% CI -0.40 to -0.05; P=.01). There were 28 (23.9%) participants who played all 5 levels of the game and had better improvement in opioid use self-efficacy.ConclusionsOur findings suggest MedSMART: Adventures in PharmaCity can be used as an effective tool to educate adolescents on the safe and responsible use of prescribed opioid medications. Future testing of the effectiveness of this SG should involve a randomized controlled trial. Additionally, the feasibility of implementing and disseminating MedSMART: Adventures in PharmaCity in schools and health care settings such as adolescent health or primary care clinics, emergency departments, and pharmacies should be investigated.