![]() Sites along the peripheral and central nervous systems where pathophysiologic changes may contribute to the mechanisms of neuropathic pain. 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. Moreover, only 11% of new drugs for pain advanced from Phase 2 to Phase 3 trials, and drug development for pain swung from cultivating new molecular entities to primarily reformulating old drugs. Not including reformulations, the proportion of new drugs for pain treatment entering phase 1 clinical trials (relative to all new drugs) declined between 2000–20–2015. Anticonvulsants, such as gabapentin and pregabalin, and antidepressants, such as nortriptyline and duloxetine, remain the first-line drugs for the treatment of NP. Regrettably, advances in clinical therapies for NP have not paralleled the significant advances in basic science. A myriad of associated functional, structural, and molecular changes in neurons, glial cells, and other non-neuronal cells (e.g., macrophages) from the periphery to the brain have been characterized in several preclinical models ( Figure 1, for review see references. Since the initial neurophysiologic evidence, nearly four 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. Therefore, developing new treatments for NP with minimal CNS-related adverse effects is a high research priority. 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. 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, cognitive dysfunction), addiction, and abuse. The burning, stinging, shooting, dysesthetic sensations associated with NP can be excruciating, markedly detract from quality of life, and lead to depression and even suicide. It is estimated that approximately 7–10% of the population and 25–30% of individuals with chronic pain suffer from NP. Neuropathic pain (NP) results from injury to or disease of the somatosensory system. In future drug development efforts, therapies directed at peripheral mechanisms may offer potential advantages over current CNS-penetrating drugs, including minimal adverse effects. We summarize work from our group and others that identifies potential peripheral drug targets, including peripheral opioid receptors, involved in the modulation of NP. Hyperexcitability of peripheral neurons may represent a “low-hanging target” in the development of safe therapies for a subset of patients with NP. Several potential peripheral “pain generator” sites have been identified, and defining their role in NP states of different etiologies is important for targeted therapy. ![]() We consider the relative importance of peripheral and central mechanisms and present several lines of clinical and preclinical evidence supporting the tenet that spontaneous and ectopic activity in primary afferent neurons plays a critical role in NP. ![]() Therefore, identifying key targets involved in the initiation and maintenance of NP in the periphery, with guidance from meticulous clinical evidence, merits renewed focus. Most drugs currently used for the treatment of NP bind to receptors that are widely expressed in the peripheral and central nervous systems, and hence are frequently associated with adverse effects. Disappointingly, advances in clinical therapies for NP have not paralleled the substantial advances in basic science. Preclinical and clinical studies have considerably advanced our understanding of the myriad peripheral and central changes in neuronal and non-neuronal cells associated with persistent pain states. Neuropathic pain (NP) resulting from injury or disease of the somatosensory system is a common, debilitating chronic disorder that significantly undermines quality of life. ![]()
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