Challenges in the development of novel treatment strategies for neuropathic pain

Abstract

Summary:Neuropathic pain might best be considered as a collection of various pain states with a common feature, that being symptoms suggestive of dysfunction of peripheral nerves. The development of therapeutic options for the treatment of neuropathic pain is complicated significantly by several factors. Neuropathic pain may arise from widely diverse etiologies such as physical trauma, disease, infection, or chemotherapy. Symptoms indicative of neuropathic pain may also arise in individuals with no evidence of any type of nerve trauma (idiopathic). Although neuropathic pain is a substantial health care issue, it is relatively uncommon and only occurs in a small fraction (Ͻ10%) of individuals with these initiating factors. Moreover, the efficacy of treatment protocols, even against the same type of symptoms, differ depending on the underlying initiating cause of the neuropathy. Although these observations strongly suggest that there are predisposing factors that may impart susceptibility to the development of neuropathic pain, no common predisposing factors or genetic markers have been satisfactorily identified. Because of these vagaries, treatment of neuropathic pain has been based on trial and error. However, recent progress in the understanding of neurophysiologic changes that accompany peripheral nerve dysfunction indicate that regulation of ion channels that maintain membrane potentials or generate action potentials may provide an important therapeutic approach. Neuropathic pain is accompanied by increased activity of peripheral nociceptors, which is produced in part by changes in levels of specific calcium and sodium channels. The identification of sodium and/or calcium channels subtypes that are expressed almost exclusively on nocicpetors may provide a way of regulating the activity of exaggerated nociceptor function without altering other sensory modalities. Thus, the selective targeting of ion channels may represent a viable therapeutic target for the management of the neuropathic pain state, regardless of etiology.

Growth Factors and Neuropathic Pain

“…Thus, different causes and physiologic mechanisms may exist among different patients, but would manifest as the same symptoms of neuropathic pain. The management of neuropathic pain is a significant unmet medical need because this pain is resistant to many therapeutic interventions, and pain relief obtained, even with opioids, is far from satisfactory [2]. Targeting the neurotrophic factors that promote nerve regeneration and repair or blocking the activity of the neurotrophic factors that may promote pain represent novel avenues for the modification of neuropathic pain [3,4].…”

Structure–activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

“…Neuropathic pain is an abnormal pain that can result from nerve injuries and current treatment with opioids are problematic due to the side-effects associated with doses necessary to achieve sufficient pain relief in patients [36,51]. While mechanisms of neuropathic pain are still being elucidated, emerging studies indicate the involvement of neuroplasticity in which significant increased expression of neuromodulators and neurotransmitters in the central nervous system such as cholecystokinin (CCK) occurs [17,46,47,49,50].…”

Antihyperalgesic effects of loperamide in a model of rat neuropathic pain are mediated by peripheral δ-opioid receptors

“…Damage to nervous system sometimes causes a chronic pain state referred to as neuropathic pain which is characterized most often by spontaneous burning pain and sometimes by allodynia (pain evoked by nonpainful stimuli), and hyperalgesia (an increased response to painful stimuli) [9]. Presently available therapeutic approaches are not sufficient for treatment of these symptoms due to the side-effects associated with currently available therapies [10].…”