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Ostheoarthritis (OA) is an irreversible disease, which affects the population worldwide, predominantly those over 60 years of age. The treatments available comprehend conservative and surgical treatment. The complications related to disease and side effects of these interventions can impact directly on patient’s quality of life, with impairment of work capacity and daily activities. Nowadays the standard therapy for OA is exercise and adjunctive medication, as needed. Important to note that opioids should be avoided in this population, limiting the theurapetical arsenal in the management of pain. Duloxetine is an effective treatment for chronic pain as it acts on central pain sensitization, neuropathic pain and also improves associated depressive or anxiety symptoms. We considered that the synergistic effect of Duloxetine and exercise on pain and mood symptoms may offer a better control as compared to current standard treatment of patients with OA. Therefore, this 12-week multicentre double blind randomized trial will evaluate the improvement in WOMAC score (frequently used in OA to assess pain and functional limitation) of patients with knee OA treated with Duloxetine + exercise vs Placebo + exercise. Secondary outcomes include impact in quality of life (i.e. EQ-5D-5L - mobility, self-care, usual activities, pain/discomfort, anxiety/depression), frequency of use a rescue drug for pain and occurrence of major depression (DSM-V).