The evolution of nerve growth factor inhibition in clinical medicine

Nerve growth factor (NGF) is a neurotrophin that activates nociceptive neurons to transmit pain signals from the peripheral to the central nervous system and that exerts its effects on neurons by signalling through tyrosine kinase receptors. Antibodies that inhibit the function of NGF and small molecule inhibitors of NGF receptors have been developed and tested in clinical studies to evaluate the efficacy of NGF inhibition as a form of analgesia in chronic pain states including osteoarthritis and chronic low back pain. Clinical studies in individuals with painful knee and hip osteoarthritis have revealed that NGF inhibitors substantially reduce joint pain and improve function compared with NSAIDs for a duration of up to 8 weeks. However, the higher tested doses of NGF inhibitors also increased the risk of rapidly progressive osteoarthritis in a small percentage of those treated. This Review recaps the biology of NGF and the studies that have been performed to evaluate the efficacy of NGF inhibition for chronic musculoskeletal pain states. The adverse events associated with NGF inhibition and the current state of knowledge about the mechanisms involved in rapidly progressive osteoarthritis are also discussed and future studies proposed to improve understanding of this rare but serious adverse event. Nerve growth factor has been investigated as a therapeutic target for osteoarthritis and chronic low back pain, yet worries over adverse effects have stalled drug development. This Review provides an update on the current status of nerve growth factor inhibitors. Key pointsChronic pain from osteoarthritis (OA) is highly prevalent, and effective non-opioid medications are few.Nerve growth factor (NGF) is an important neurotrophin that activates nociceptive neurons to transmit pain signals from the peripheral to the central nervous system.Treatment with anti-NGF antibodies inhibits joint pain and improves function in individuals with moderate to severe knee and hip OA.NGF inhibition is associated with rapidly progressive large joint OA; many theories exist as to why but the exact mechanisms involved remain unknown.Anti-NGF antibody treatments, if approved, should reduce pain and improve quality of life for individuals with knee and hip OA; however, safety monitoring programmes will be necessary.

Automated summary

NGF is an important neurotrophin involved in pain signal transmission, and inhibitors have shown efficacy in reducing joint pain in osteoarthritis patients, but higher doses may increase the risk of rapidly progressive osteoarthritis. Ongoing studies aim to better understand the mechanisms involved in this adverse event.