INTRODUCTION: Musculoskeletal conditions are a significant health challenge and second leading cause of disability worldwide. Diclofenac sodium topical gel 1% (DSG1%) provides effective relief of arthritis pain. While clinical studies show that DSG1% is safe and well-tolerated, long-term safety and tolerability in real-world settings are limited. This study aimed to profile users and prescribers of DSG1% and to evaluate its safety and tolerability over a screening period of 8.5 years with an average follow-up of nearly 1 year. The focus was on patients with risk factors and comorbidities, especially those taking concomitant medication in addition to topical nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: This retrospective, longitudinal cohort study used the US Department of Defense (DoD) electronic health records (EHR) database. The database included 521,593 individuals with ≥ 1 prescription for DSG1% for either indicated or non-indicated conditions with mean (standard deviation
SD) follow-up of 348.4 (562.4) days. The primary outcome measure assessed the incidence of predefined events of interest (EOIs), including gastrointestinal, hepatic, renal diseases, cardiovascular events, hypertension, skin reaction, misuse, abuse, and death (all-cause mortality). RESULTS: The average age of subjects was 56.7 years (SD = 18.1), with women comprising 60.4% of population. During study-period, 74.2% of subjects experienced no adverse EOIs after initiating treatment with DSG1%. Among the remaining 25.8%, average time to first EOI was 244.0 (SD = 368.6) days. Notably, the frequency of reported EOIs increased with age. Additionally, subjects with conditions such as rheumatoid arthritis, systemic lupus erythematosus, or diabetes had a higher incidence of cardiovascular EOIs. CONCLUSIONS: The study results indicate that DSG demonstrated a favorable safety profile, particularly for patients with comorbidities and high-risk factors and when used with other medications. Despite an older population and high baseline risk factors (93%), only 26% DSG1% users experienced a predefined EOI, observed on average 244.0 (368.6) days from index date. These findings confirm the long-term tolerability of topical DSG1% for musculoskeletal disorders.