The etiology of pain in osteoarthritis is multifactoral and includes mechanical and inflammatory processes. to clearly define the role of intra-articular HA injections in the treatment of osteoarthritis. Keywords: hyaluronans knee pain osteoarthritis Introduction Osteoarthritis (OA) is the most common form of arthritis. It has been reported that 40% of people over the age of 80 will have at least one joint involved and 27 million people in the United States have clinical OA.1 2 OA is a slowly evolving process characterized by joint pain stiffness and loss of range of motion. Excess weight bearing usually worsens the pain and it is improved with rest. OA results from a complex conversation of biomechanical biochemical and genetic factors and is characterized by degradation of cartilage and hypertrophy of bone. The etiology of OA remains unknown; however significant risk factors have been recognized with OA PF-3644022 development.1 3 These include joint trauma hypermobility mal-alignment and genetic abnormalities. On physical examination patients usually have a swollen joint with warmness palpable osteophytes crepitus with movement tenderness and reduced range of motion. The treatment of OA includes non-pharmacological interventions such as individual education physical therapy excess weight loss and low-impact exercises.4-7 Pharmacological treatment options include acetaminophen non-steroidal anti-inflammatory drugs (NSAIDs) topical NSAIDs glucosamine and/or chondrotin sulfate and intra-articular (IA) corticosteroids. Opioid and non-narcotic analgesics may be prescribed in refractory pain patients. IA hyaluronans (HAs) have recently been used PF-3644022 for the treatment of painful knee joints with OA.8 Surgical intervention should be considered only after pharmacological and non-pharmacological treatment have failed.3 The purpose of this review is to address the role of IA HAs treatment for pain in OA of the knee. Pain mechanism in OA The etiology of pain in the joint with OA is complex but a brief summary of the pathophysiology of pain production is helpful to understand the role of HAs in its treatment.1 Studies have identified the three major types of pain. Acute pain is directly associated with the activation of peripheral nerve receptors. Chronic pain is associated with an ongoing inflammation of peripheral tissues.9 When there is a significant chronic pain damage occurs to the pain pathways either peripherally or centrally which results in the third type of pain neuropathic.10 Synovial joints are innervated by nerves that originate in primary sensory neurons located in the dorsal root ganglion.11 The tissues of synovial joints that are innervated by nerve endings are the capsule ligaments synovial membrane and subchondral bone. Hyaline cartilage does not have nerve endings. The nerves of the synovial joint are sensitive to the detection of both noxious and non-noxious stimuli. Activation of the nerve endings can begin with any mechanical chemical or thermal process. The pathophysiology PF-3644022 of OA involves the release of a large number of inflammatory mediators and these directly act on the nerve endings and reduce their threshold to pain recognition.11 The result is an enhanced discharge of PF-3644022 nerve impulses that are perceived as a painful stimuli. IA HAs have been shown to have a pain-reduction effect through a PLA2G12A number of mechanisms which will be discussed later. Hyaluronans Hyaluronan or hyaluronic acid (HA) is a complex glycosaminoglycan composed of repeated disaccharide units to form a linear polymer. It is widely present in mammalian tissues and has the highest concentration in synovial fluid. Its function in the diarthrodial joint is both mechanical and metabolic. HA provides important viscoelasticity and lubricating properties to synovial fluid thereby reducing articular cartilage wear.10 Further HA molecules restrict large plasma protein from entering into the synovial fluid while facilitating the passage of small molecules into the joint for maintenance of nutrition.12 The synthesis of HA in OA is disrupted by increased levels of pro-inflammatory cytokines free radicals and proteinases resulting in an HA with a significantly reduced molecular weight more molecular polydisaccharides and a reduction in synovial fluid viscoelasticity.12 This abnormal hyaluronic acid increases the potential for articular cartilage wear and accelerates progression of the disease. The progression of OA results from the disruption of the.