The management of patients on chronic methadone therapy for opioid use disorder presents unique pharmacological and psychosocial challenges in hospital settings. This case series discusses complexities such as methadone's variable pharmacokinetics, alternatives to oral methadone and conversion ratios. Additionally, it outlines the nuances around the psychosocial considerations of methadone therapy and addressing addiction-related behaviors without compromising patient dignity. The review calls for individualized care plans with uninterrupted opioid agonist therapy to meet the baseline opioid requirements and pro-active pain management plans. Enhanced clinician education and better real-world data to guide methadone management is important to improve outcomes for this vulnerable patient cohort.