In addition, drugs with a demonstrated low GI risk profile may be of benefit, such as coxibs and nabumetone. In recent years, the widespread use of oral NSAIDs has been called into question due to the appearance of significant upper gastrointestinal (GI) complications and cardiovascular (CV) adverse events (AEs). Recommendation has been made by some that naproxen may be the preferred agent in patients at high CV risk because of its lower risk of CV events. Among patients who fail to respond adequay to sequential ESCEO algorithm Step 1 and Step 2 treatments, the short-term use of weak opioids, such as tramadol, for severely symptomatic OA patients is recommended. Non-steroidal anti-inflammatory drugs (NSAIDs) are at the cornerstone of treatment for osteoarthritis (OA). Among non-selective NSAIDs, ibuprofen and naproxen seem preferable to diclofenac, the latter being associated with higher CV risk. The identification of patients with significant CV and/or GI risk is critical, and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm provides guidance on appropriate treatments for OA patients with elevated risk. Low dose celecoxib (200 mg/day) is also associated with a lower risk of CV events compared with other coxibs. Although studies exploring the efficacy of tramadol in OA are limited, there is good evidence that tramadol works if prescribed properly. Furthermore, slow upwards titration of tramadol SR is recommended to improve tolerability and minimize treatment discontinuations. Nevertheless, if properly prescribed oral NSAIDs can provide an effective and safe treatment for OA in real-life situations. The sustained-release (SR) formulation of tramadol is preferred as it avoids the peak plasma concentrations reached with immediate-release tramadol, and is believed to reduce the incidence of AEs. However, NSAIDs are non-homogeneous, and there are noticeable differences between them in AE risk for GI and CV events.