Anti-Nerve Growth Factor for Pain: Jun 2016

Anti-nerve growth factor in pain management: current evidence – free full-text 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. It’s great that they found NGF to be an important mediator of pain initiation, but what else might it be an important mediator of? 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. And then… 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. I’d be much more reassured if they explained exactly why the FDA lifted the hold. This is mentioned much later in the study under the heading of “Safety”. Introduction

Chronic pain is a disease unto itself, a state in which the protective role of pain transmission becomes deranged and pathologic. According to a 2010 analysis, chronic pain affects ~100 million Americans at an estimated annual cost of US$560–US$635 billion. Despite their limited effectiveness for many chronic pain conditions and considerable side-effect profile, opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) continue to dominate clinical practice It is largely believed that mechanism-based treatments, rather than disease- or diagnosis-based treatments, hold the key to the development of new successful therapies. Shortcomings in the pharmacologic management of pain are thought to be attributed to a failure to target underlying mechanisms of chronic pain. It is within this context that nerve growth factor (NGF) and its related molecular targets represent a completely novel therapy mode, with potentially broad clinical applications for both nociceptive and neuropathic pain conditions. NGF Background

NGF was initially discovered in the 1950s as a tumor tissue-produced soluble factor that promotes the growth and differentiation of sensory and sympathetic ganglia . NGF was the first growth factor to be identified and its discovery represented a landmark achievement in developmental neurobiology. The illumination of NGF’s critical role in neuronal development eventually led to the creation of the “neurotrophic factor hypothesis” and the classical neurotrophic model in which NGF is synthesized and released by target tissues during embryonic development, promoting the growth, differentiation, and survival of neurons in a dose-dependent manner. Subsequent studies have broadened our understanding of this process and the role that neurotrophic factors play in the mammalian nervous system. Rationale: NGF and Pain

NGF levels are elevated in preclinical models of both inflammation and peripheral nerve injury. Clinically, NGF concentration is increased in chronic pain conditions such as interstitial cystitis, prostatitis, arthritis, pancreatitis, chronic headaches, cancer pain, diabetic neuropathy, and noncancer pain, suggesting that NGF-mediated signaling is an ongoing and active process in chronic nociceptive and neuropathic pain states. A number of studies involving direct intradermal injection of NGF in rodents and humans have demonstrated a clear functional role for NGF in both activation and sensitization of nociceptors. Mechanism of action in nociceptive pain

Nociceptive pain occurs through the activation of nociceptors located in peripheral tissues in response to noxious stimuli. A noxious stimulus is any stimulus (eg, chemical, thermal, or mechanical) that either damages or threatens to cause damage to normal tissues. NGF is produced and released by peripheral tissues following noxious stimuli (eg, injury and inflammation) secondary to the production of inflammatory cytokines , such as interleukin-1 and tumor necrosis factor-alpha. NGF binds to trkA receptors on multiple targets , with multiple modulating effects on pain signaling NGF binds to trkA that is selectively expressed on the peripheral terminals of A-delta and peptidergic unmyelinated C-fibers. The NGF–trkA complex is then internalized and transported retrogradely to DRG cell bodies , modulating and/or increasing the expression of a variety of cell surface receptors involved in nociception, including bradykinin receptors,

acid-sensing ion channels (ASIC) 2/3,

voltage-gated sodium channels,

voltage-gated calcium channels,

delayed rectifier potassium channels,

putative mechanotransducers, as well as

transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor-mediated currents ( Figure 1 )

the increase in TRPV1 signaling and the increased activity of other channels result in peripheral sensitization and pain hypersensitivity. NGF–trkA signaling also leads to transcriptional changes that result in the increased expression of the pronociceptive neurotransmitters substance P (SP),

calcitonin gene-related peptide (CGRP), and

BDNF,

thereby leading to central sensitization ( Figure 1 ) Figure 1 Schematic diagram of the NGF mechanisms involved in the initiation and maintenance of pain Abbreviations: 5-HT, 5-hydroxytryptamine; ASIC3, acid-sensing ion channel 3; BDNF, brain-derived neurotrophic factor; BR2, bradykinin receptor 2; Cav, 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; Nav, 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. An additional effect of NGF on pain processing occurs through its binding of trkA receptors located on mast cells. This process is proinflammatory and elicits the release of inflammatory mediators such as histamine, serotonin or 5-hydroxytryptamine (5-HT), protons, as well as NGF itself, resulting in a positive feedback loop So mast cells are also involved in pain signal processing, making the mast cell disorders that are more common with EDS folks even more damaging. Thus, not only does NGF signaling increase the expression of peripheral nociceptive receptors and centrally located pronociceptive neurotransmitters, but it also sensitizes adjacent nociceptive neurons in response to inflammation. Mechanism of action in neuropathic pain

Neuropathic pain results from damage to the neurons of the somatosensory system , secondary to either direct injury or disease-related dysfunction, and results in the generation of ectopic discharges that occur independently of somatic stimuli. So this would be pain entirely separate and independent of activity. I realize how lucky I am that my pain is usually directly linked to a physical activity that is mostly under my control. As mentioned previously, NGF levels are generally increased in chronic neuropathic conditions such as diabetic neuropathy and cancer pain, in particular, invasive nerve cancers But the relationship between NGF signaling and neuropathic pain states is complex , and in some patients with diabetic neuropathy, NGF levels are actually decreased. In preclinical studies, NGF has demonstrated a trophic and neuroprotective action on peptidergic small-diameter DRG cells after nerve injury, and a number of clinical studies have been conducted investigating the negative correlation between NGF levels and peripheral neuropathy by examining the administration of subcutaneous injections of recombinant NGF It is noteworthy to mention that all clinical studies have reported significant dose-dependent hyperalgesia at the site of NGF injection NGF administration has also shown the ability to induce nerve sprouting of trk-A-positive nociceptive as well as sympathetic nerve fibers, while NGF blockade by systemic injection of neutralizing antibodies in models of neuropathic pain appears to prevent allodynia and hyperalgesia. Mechanistically, NGF sequestration has demonstrated inhibition of neuroma formation and a decrease in ectopic discharges. In models of bone cancer, where neuroma formation and reorganization of sensory and sympathetic fibers is prominent, the administration of an NGF- sequestering antibody prevents this pathologic reorganization and inhibits the development of cancer pain. Pharmacotherapy

A number of approaches have been developed to target the NGF pathway and its effect on pain initiation and maintenance. The majority of these efforts have centered on the NGF–trkA pathway and focus on three methodologic approaches: 1) sequestration of free NGF;
2) prevention of NGF binding and activation of trkA; and
3) inhibition of trkA function. Approach 1: NGF-sequestering agents

Antibodies possess significant advantages compared to small molecules due to generally higher specificity and reduced off-target effects, culminating in quicker clinical development and faster US Food and Drug Administration (FDA) approval Preclinical studies pretreatment with systemic anti-NGF antibody have shown successfully reduced acute thermal and mechanical hypersensitivity. This preventative effect is also observed in models of visceral inflammation anti-NGF antibody administration has demonstrated the ability to reverse colonic hypersensitivity models of autoimmune arthritis have demonstrated analgesia equivalent to indomethacin despite continued joint destruction and inflammation. Anti-NGF administration has also resulted in significant analgesic effects in the treatment of hypersensitivity associated with chronic injury models of bone cancer and closed femur fracture, effectively […]

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