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.

Chronic pain syndrome is a heterogeneous group of diseases characterized by several pathological mechanisms. One in five adults in Europe may experience chronic pain. In addition to the individual burden, chronic pain has a significant societal impact because of work and school absences, loss of work, early retirement, and high social and healthcare costs. Several anti-inflammatory treatments are available for patients with inflammatory or autoimmune diseases to control their symptoms, including pain. However, patients with degenerative chronic pain conditions, some with 10-fold or more elevated incidence relative to these manageable diseases, have few long-term pharmacological treatment options, limited mainly to non-steroidal anti-inflammatory drugs or opioids. For this review, we performed multiple PubMed searches using keywords such as "pain," "neurogenic inflammation," "NGF," "substance P," "nociception," "BDNF," "inflammation," "CGRP," "osteoarthritis," and "migraine." Many treatments, most with limited scientific evidence of efficacy, are available for the management of chronic pain through a trial-and-error approach. Although basic science and pre-clinical pain research have elucidated many biomolecular mechanisms of pain and identified promising novel targets, little of this work has translated into better clinical management of these conditions. This state-of-the-art review summarizes concepts of chronic pain syndromes and describes potential novel treatment strategies.