LAUSR

Neuropathic pain (NP) results from injury to or disease of the somatosensory system. It is estimated that approximately 7% to 10%of the population and 25% to 30%of individuals with chronic pain suffer fromNP. The burning, stinging, shooting, and dysesthetic sensations associated with NP can be excruciating, markedly detract from quality of life, and lead to depression and even suicide. Most drugs currently in use for NP bind to receptors that are widely expressed throughout the central nervous system (CNS) and hence are frequently associated with dose-limiting adverse effects (sedation, dizziness, and cognitive dysfunction), addiction, and abuse. The limited efficacy of the NP drugs may have also contributed, in part, to the increased use of opioids for treating this chronic pain disorder. Therefore, developing new treatments for NP with minimal CNS-related adverse effects is a high research priority. Since the initial neurophysiologic evidence, nearly 4 decades ago, for an increase in excitability of CNS neurons after peripheral tissue injury in an animal model, much has been learned about the peripheral and central changes associated with persistent pain states, particularly NP. A myriad of associated functional, structural, and molecular changes in neurons, glial cells, and other non-neuronal cells (eg, macrophages) from the periphery to the brain have been characterized in several preclinical models (Fig. 1, for review see refs. 9,16,26,65,77). Regrettably, advances in clinical therapies for NP have not paralleled the significant advances in basic science. Anticonvulsants, such as gabapentin and pregabalin, and antidepressants, such as nortriptyline and duloxetine, remain the first-line drugs for the treatment of NP. Not including reformulations, the proportion of new drugs for pain treatment entering phase 1 clinical trials (relative to all new drugs) declined between 2000 to 2002 and 2013 to 2015. Moreover, only 11% of new drugs for pain advanced from phase 2 to phase 3 trials, and drug development for pain swung from cultivating newmolecular entities to primarily reformulating old drugs. Bridging this ongoing gap between advances in mechanistic research and the discovery of safe and effective novel clinical therapies, the “valley of death” in drug development may warrant a renewed focus on identifying key targets involved in the initiation and maintenance of NP with guidance from meticulous accrual of clinical evidence. Human and preclinical studies in the latter part of the last century shed considerable light on the mechanisms that contribute to peripheral and central sensitization after acute tissue injuries, such as a burn and surgical wound. Fortunately, in most cases, the increased sensitivity of peripheral and central neurons that develop after such injuries is short-lived. Considerable advances have also been made in the treatment of patients with acute pain. However, the management of certain chronic pain conditions, particularly NP, remains a challenge.