The current opioid crisis is a far-reaching drug and public health policy issue affecting several geographical regions. Since its appearance, endeavours have been undertaken both at the national and international level to develop integrated policy responses to address the crisis. Yet, despite some progress, the crisis continues both to expand geographically and to deepen in complexity with the emergence of a new generation of new psychoactive substances (NPS) with opioid effects, including substances belonging to chemical structural classes which were not significantly present on illicit drug markets previously. This evolution in chemical structural groups signals the potential development of similar new substances which may exacerbate the already significant challenges faced by public health and drug control systems. Additionally, the onset of the COVID-19 pandemic in late 2019 and early 2020 may further complicate and reshape existing trends in the crisis.