Abstract Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Acute pancreatitis (AP) is a common gastrointestinal condition that carries a significant financial and physical burden for patients due to the painful presentation and frequent need for hospitalization. Treatment varies in the type and route of analgesic used. Unmanaged pain can lead to worsening health outcomes and prolonged admissions. Further research is needed to understand current practices for managing AP. Methods This study was a retrospective, exploratory, single-center cohort study. Patients admitted to an internal medicine unit with AP from September 1, 2020, to December 31, 2021, were included. Our primary outcome was the change in pain scores during the first 24-hours after administration of the first pain-relieving medication. Secondary outcomes included change in pain scores within the first 12-hours, time to oral tolerance, characterization of analgesic orders, comparison of median pain scores by home analgesic usage, and specific inpatient opioid use. Results One hundred sixty-nine patients were screened, and 94 were included in the study. Forty-four patients were assigned to the multimodal cohort and 50 patients to the opioid-only cohort. Changes in pain scores per unit of time, assessed by a mixed-effects model, within the first 24 hours were –0.080 (SE, 0.018) in the multimodal cohort and –0.090 (SE, 0.014) in the opioid-only cohort (P = 0.780). Morphine milligram equivalents (MME) administered in the multimodal and opioid-only cohorts were 24.50 (interquartile range [IQR], 51.75) and 52.5 (IQR, 68.5) (P = 0.001), respectively. Conclusion There was no significant difference in the change in pain scores between patients receiving multimodal therapy and those receiving opioids only. Significantly fewer MME were administered in the multimodal group, suggesting that multimodal therapy can be opioid-sparing in AP.