The evolving epidemiology of opioid use disorder: polysubstance use, drug supply transformation, and policy implications.

BACKGROUND: Synthetic Opioids and the rising polysubstance use have caused a substantial change in the epidemiology of opioid use disorder (OUD) in the United States. Current overdose patterns may no longer be adequately explained by traditional opioid-driven theories. METHODS: A structured review was conducted using PRISMA-informed methods. Literature published between 2010 and 2026 was identified through PubMed, Scopus, and Google Scholar using terms related to OUD, fentanyl, polysubstance use, and treatment strategies. Eligible sources included peer-reviewed studies and government reports addressing epidemiology, risk factors, and interventions. RESULTS: A polysubstance-driven milieu marked by fentanyl monopoly, stimulant co-use, and new adulterants like xylazine and nitazenes has resulted from the opioid crisis's evolution through several phases. A regional evaluation of South Florida shows how current drug market trends and past prescribing practices converge to increase the risk of overdose. Structural inequities, like unstable finances and limited access to therapy, continue to affect OUD outcomes. Systemic barriers also make evidence-based treatments less effective. CONCLUSION: Opioid use disorder needs to be recognized within a wider context of polysubstance risk rather than seen as a solely opioid issue. Successful strategies demand comprehensive policy responses, enhanced harm reduction measures, and flexible surveillance systems that can adapt to rapid shifts in drug availability and usage trends.