OBJECTIVES: Treating post-surgical patients with opioid and non-opioid medications simultaneously can be an effective way to treat pain, minimize opioid-associated side-effects, and reduce hospital length of stay (LOS). The objective of this exercise was to develop a budget impact model to evaluate the economic impact of increased use of multi-modal analgesia following orthopedic or abdominal/pelvic surgery in the hospital setting. METHODS: A total of 50,648 unique patient encounters from a 2009-2012 US electronic health record database were evaluated.  Patients were segmented into 280 cohorts based on surgical procedure (40 unique orthopedic and abdominal/pelvic procedures) and NSAID risk factors (7 unique risk groups). Median LOS was calculated for each cohort and compared based on analgesia received (opioid-only vs. multi-modal). Findings were adjusted to fit the general case of a 250-bed hospital with an 80% occupancy rate and performing 3,400 total orthopedic and abdominal/pelvic surgeries/year. Median per-day hospital stay costs of $400 and $460 per orthopedic and abdominal/pelvic procedure, respectively, were applied. RESULTS:  Current proportions of patients receiving multi-modal, opioid-only, and non-opioid-only therapy were 29.9%, 63.0%, and 7.1%, respectively. Multi-modal therapy was associated with reduced LOS for 45.2% of cohorts, no change in LOS for 41.7% of cohorts, and increased LOS for 13.1% of cohorts.  Increasing the proportion of patients receiving multi-modal therapy resulted in cost savings. Shifting 20% of patients from opioid-only to multi-modal therapy resulted in estimated annual savings of $71,526, while shifting 40% of patients in this manner reduced costs by $141,317. Conversely, shifting all patients treated with multi-modal therapy to opioid-only therapy increased annual costs by $105,204. CONCLUSIONS: The model supports the hypothesis that multi-modal therapy is associated with reduced LOS and reduced health care costs. While currently-available NSAIDs may present their own side-effect risks, NSAIDs with improved safety may further reduce costs, assuming similar efficacy and LOS effects.