Chronic low-intensity inflammation is emerging as a potential key mechanism in diseases that were previously considered degenerative, such as tendinopathies, osteoarthritis and intervertebral disc disease. This new approach recognises the role of structures such as the subchondral bone in knee osteoarthritis and the vertebral endplate in disc disease. In this sterile inflammatory context, plasma rich in growth factors (PRGF) a specific type of platelet-rich plasma (PRP) without leucocytes and activated with calcium chloride, has emerged as a promising therapy that exhibits reparative, anti-inflammatory, immunomodulatory, analgesic and antifibrotic properties yet with varied clinical outcomes due to specific patient's physiopathology, product variability and different protocols of application. Its action is based on the regenerative potential of several proteins stemmed from platelets, plasma biomolecules, as well as the fibrin matrix, which acts as a dynamic biological system. Several in vitro and in vivo studies associate the analgesic effect of PRPs with the inhibition of the NF-kappaB pathway in damaged cells, and the presence of endocannabinoids, which reduce nociceptor excitability, with anti-apoptotic and trophic effects at the tissue level. However, variability in PRP preparation and application methods, as well as patient-specific factors, makes it difficult to compare the large heterogeneous clinical outcomes stemmed from the myriad PRP preparation methods and the varied modalities for their application. This review is focused on analysing the latest clinical evidence on PRGF in the treatment of chronic low-intensity inflammation of musculoskeletal disorders, its role in reducing chronic pain, and the limitations of this type of biological therapy.