Abstract Background/Aims Prescription opioids for non-cancer pain in the UK have increased over the past two decades, alongside associated harms. There is an increasing recognition that policies to address opioid prescribing need to be tailored according to individual patient needs with specific indications and disease systems. This study aimed to evaluate clinical indications associated with new opioid initiation in non-cancer pain using UK large-scale data. Methods National primary care electronic health records from 01/01/2006 to 31/20/2021 were used from the Clinical Research Practice Datalink. Codelists for opioid-related conditions based on literature and experts in pain management, primary care, rheumatology, and pharmacy were applied to a one-year period before first opioid prescription for surgical indications (given the acute nature) and five-years prior for chronic conditions. Descriptive statistics were used for data analysis, accounting for overlapping indications. Results A total of 3,031,950 new opioid users were identified. Opioids were initiated more commonly in women (60.7%), people in age groups: 45-64 (40.0%) and ≥65 years (37.0%). Nine systems associated with opioid-initiation were identified. The most common were musculoskeletal (74.0%), respiratory (53.1%), infections (25.7%), trauma/injury (16.1%), neurology (16.0%), gastrointestinal (4.2%) within five years prior to the opioid prescription date and post-surgical within one-year prior (3.8%). Musculoskeletal conditions most frequently associated with opioid use were osteoarthritis (n = 1,536,338, 50.7%), low back pain (1,094,163, 36.1%), other non-inflammatory musculoskeletal conditions 344,3412 (11.4%), rheumatoid arthritis 63,365 (2.1%) and fibromyalgia 56,038 (1.9%). Post-surgical indications were associated with 3.8% of all prescriptions, with orthopaedic surgeries being the most common: 42.1% of all post-surgical indications, including total knee replacements (n = 31,944; 27.6%) and total hip replacements (n = 17,863; 14.5%). Conclusion This is the first study in the UK evaluating large scale national data to assess indications associated with opioid initiation. Almost three quarters of the new prescriptions of opioids for non-cancer pain were in people with a diagnosis of a musculoskeletal condition. Orthopaedic surgeries contributed to a third of all post-surgical indications. These findings could help inform prioritisation of targeted interventions in opioid de-prescribing, clinical vigilance, and policy development to support non-pharmacological interventions in patients with musculoskeletal conditions. Disclosure M. Lyon: None. C. Ramirez Medina: None. E. Davies: None. M. Jani: None.