Anti-nerve growth factor in pain management: current evidence

Abstract

There continues to be an unmet need for safe and effective pain medications. Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) dominate the clinical landscape despite limited effectiveness and considerable side-effect profiles. Although significant advancements have identified myriad potential pain targets over the past several decades, the majority of new pain pharmacotherapies have failed to come to market. The discovery of nerve growth factor (NGF) and its interaction with tropomyosin receptor kinase A (trkA) have been well characterized as important mediators of pain initiation and maintenance, and pharmacotherapies targeting this pathway have the potential to be considered promising methods in the treatment of a variety of nociceptive and neuropathic pain conditions. Several methodologic approaches, including sequestration of free NGF, prevention of NGF binding and trkA activation, and inhibition of trkA function, have been investigated in the development of new pharmacotherapies. Among these, NGF-sequestering antibodies have exhibited the most promise in clinical trials. However, in 2010, reports of rapid joint destruction leading to joint replacement prompted the US Food and Drug Administration (FDA) to place a hold on all clinical trials involving anti-NGF antibodies. Although the FDA has since lifted this hold and a number of new trials are under way, the long-term efficacy and safety profile of anti-NGF antibodies are yet to be established.

Keywords: drug discovery; fasinumab; fulranumab; neuropathic pain; nociceptive pain; tanezumab.

Figure 1

Schematic diagram of the NGF mechanisms involved in the initiation and maintenance of pain. Note: Drawing courtesy of Caitlin Hottinger. Abbreviations: 5-HT, 5-hydroxytryptamine; ASIC3, acid-sensing ion channel 3; BDNF, brain-derived neurotrophic factor; BR₂, bradykinin receptor 2; Ca_v, voltage-gated calcium channel; CGRP, calcitonin gene-related peptide; CGRP-R, calcitonin gene-related peptide receptor; DRG, dorsal root ganglia; IL-1, interleukin 1; K, delayed-rectifier potassium channel; Na_v, voltage-gated sodium channel; NGF, nerve growth factor; NK-1, neurokinin 1 receptor; p75, neurotrophin receptor; SP, substance P; TNF-α, tumor necrosis factor alpha; trkA, tropomyosin receptor kinase A; trkB, tropomyosin receptor kinase B; TRPV1, transient receptor potential cation channel subfamily V member 1 receptor.