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The DSM-5-TR diagnostic criteria for Prescription Opioid-Use Disorder (POUD) have undergone significant changes when using opioids medically supervised. However, there is a lack of research supporting these changes. This prospective study aimed to analyze the influence of tolerance, withdrawal symptoms, and craving on the severity of POUD in chronic pain population on long-term opioid therapy. Initial individual interviews and follow-ups at 6 and 12 months were conducted on 62 patients to assess tolerance, withdrawal symptoms, craving, and POUD severity. Information on sociodemographic, clinical, and psychological variables was also collected. Unadjusted and covariate-adjusted multinomial repeated measures mixed models were run. Results showed that, compared to not having POUD, tolerance was the sole variable that significantly predicted mild disorder, while interdose withdrawal symptoms, craving, depressive symptoms, and younger age predicted moderate-severe POUD. The effect of time was also significant in predicting moderate-severe POUD, increasing rates at 6- and 12-month follow-ups compared to initial assessment. These findings highlight that maintaining opioid therapy over time is associated with an increased likelihood of having a more severe disorder. Furthermore, although tolerance and withdrawal symptoms have been removed from POUD diagnosis, their assessment and early management remain critical even during supervised opioid treatment for chronic pain., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)