Background/Objectives: This study evaluated the appropriateness of transmucosal immediate-release fentanyl (TIRF) prescriptions in a Madrid emergency room during 2019 and 2022, following a 2018 warning about off-label use. Methods: TIRF prescription in the emergency room search yielded 993 patients in 2019 and 1499 in 2022, of which 140 were randomized for the study, 70 in 2019, and 70 in 2022. Dose appropriateness and indication for TIRF were analyzed according to established criteria. Results: Despite a high prevalence of cancer diagnoses (77.9%, 109/140), only 32.9% (46/140) of patients met the appropriateness criteria pre-hospitalization. This improved to 42.5% (51/120) at discharge, but the change was not statistically significant overall. However, focusing on surviving patients reveals a significant improvement in appropriateness, increasing from 30.83% (37/120) to 42.50% (p = 0.002). This improvement was particularly pronounced in 2022 (p = 0.0269), but not in 2019 (p = 0.0771). Interestingly, appropriateness in patients with prior TIRF prescriptions remained relatively stable from pre-hospitalization (46.75%) to discharge (48.78%). A concerningly high proportion of patients with cancer diagnoses (68.75%) received low-dose opioid therapy (<60 MME) at discharge, and 36.8% of patients over 80 years old were co-prescribed benzodiazepines, contradicting prescribing guidelines. Conclusions: This study found inappropriate TIRF prescriptions were common in an emergency room setting, often due to low pre-hospital opioid doses. While hospitalization improved TIRF appropriateness in survivors, especially in 2022, concerning prescribing practices persisted. This emphasizes the need for better education and interventions to ensure safe and effective TIRF use.