The opioid epidemic has been extensively documented in the United States and Canada, but fewer data are available for Europe. To describe the trends in opioid use-volume of prescriptions, dosage and number of patients treated-in a Spanish population with more than 4.2 million inhabitants aged 18 years and older. Population-based cross-sectional analysis of opioid prescription in adults (≥18 years) from January 1, 2010 to December 31, 2018 in the region of Valencia, Spain. Outcomes were estimated on an annual basis: number of prescriptions, prescription rate per 100 inhabitants, dosage per capita (morphine mg equivalents, MME/c) and volume of patients treated (overall and by drug). Over the study period, 2,107,756 unique patients were prescribed more than 35 million total treatments. The yearly number of treatments doubled, and total MME/c showed almost a threefold increase. Fentanyl MME/c more than tripled, accounting for 34.4% of the total MME/c in 2018. Oxycodone MME/c showed a 10-fold increase, while tapentadol, launched in 2011, showed the highest growth rates. The annual number of patients receiving at least one opioid prescription more than doubled, from 335,379 in 2010 to 722,838 in 2018. Even if proportions still seem far from epidemic, urgent research is warranted on the observed patterns of use, their appropriateness and their association with health and safety outcomes, especially for high-use and high-strength drugs.