The American Academy of Orthopaedic Surgeons has recommended the use of tramadol for the management of pain for patients with knee osteoarthritis, and the American College of Rheumatology guideline also conditionally recommends tramadol as first-line therapy for patients with knee osteoarthritis (along with non-steroidal anti-inflammatory drugs). But just how safe is this approach?? Researchers from the UK have recently examined the association of tramadol use with all-cause mortality in this context amongst people aged 50 years and older. 88 902 patients were included in the analysis (mean age 70.1 +/-9.5, 61.2% women). During the 1-year follow-up, 278 deaths (23.5/1000 person-years) occurred amongst those treated with tramadol and 164 (13.8/1000 person-years) occurred in the naproxen cohort: hazard ratio [HR], 1.71 [95% CI, 1.41-2.07]). Mortality was higher for tramadol compared with diclofenac, celecoxib and etoricoxib, but no statistically significant difference in all-cause mortality was observed between tramadol and codeine. The authors caution with regard to confounding by indication, and suggest further research to determine if the association between tramadol use and higher all-cause mortality is causal.