Intravenous vs. Oral Trazodone in the Management of Withdrawal Symptoms in Psychiatric Inpatients: A Naturalistic Study

Background: Trazodone, a serotonin antagonist and reuptake inhibitor (SARI), is widely used off-label in psychiatric settings for agitation, insomnia, and substance withdrawal. Although the oral formulation is common, intravenous (IV) trazodone may offer superior efficacy in acute care. Methods: In this naturalistic observational study, we compared oral versus IV trazodone in 100 psychiatric inpatients with Substance Use Disorders (SUD) admitted to the SPDC of Pavia between January and October 2024. Fifty patients received oral trazodone (up to 300 mg/day), and 50 received IV trazodone (50 mg TID) for at least five days. Efficacy was assessed with the CIWA-Ar and a visual analogue scale for craving. Tolerability was evaluated using the UKU Side Effect Rating Scale. Results: IV trazodone resulted in a greater reduction in CIWA-Ar scores (mean Δ: 14.8 vs. 9.2; p < 0.001) and higher rates of clinically significant improvement (86% vs. 62%; p = 0.012). Fewer adverse events were observed in the IV group, including sedation and orthostatic hypotension. Conclusions: IV trazodone demonstrated superior efficacy and tolerability compared to the oral formulation in the short-term management of withdrawal symptoms, supporting its potential use in high-intensity psychiatric settings.