Challenges of neuropathic pain: focus on diabetic neuropathy

Daniela C Rosenberger, Vivian Blechschmidt, Hans Timmerman, André Wolff, Rolf-Detlef Treede, Daniela C Rosenberger, Vivian Blechschmidt, Hans Timmerman, André Wolff, Rolf-Detlef Treede

Abstract

Neuropathic pain is a frequent condition caused by a lesion or disease of the central or peripheral somatosensory nervous system. A frequent cause of peripheral neuropathic pain is diabetic neuropathy. Its complex pathophysiology is not yet fully elucidated, which contributes to underassessment and undertreatment. A mechanism-based treatment of painful diabetic neuropathy is challenging but phenotype-based stratification might be a way to develop individualized therapeutic concepts. Our goal is to review current knowledge of the pathophysiology of peripheral neuropathic pain, particularly painful diabetic neuropathy. We discuss state-of-the-art clinical assessment, validity of diagnostic and screening tools, and recommendations for the management of diabetic neuropathic pain including approaches towards personalized pain management. We also propose a research agenda for translational research including patient stratification for clinical trials and improved preclinical models in relation to current knowledge of underlying mechanisms.

Keywords: Neuroinflammation; Painful diabetic neuropathy; Personalized pain management; Quantitative sensory testing; Spinal sensitization; Stratification in clinical trials.

Conflict of interest statement

R.D.T. reports grants from DFG, non-financial support from Astellas Pharma GmbH (Munich, Germany), during the conduct of the study; grants from Bayer, DFG, EU, personal fees from Astellas, Bayer, Decision Resources, Grünenthal, GSK, Hydra, and Pfizer, all outside the submitted work. The other authors report no conflicts of interest in this work.

Figures

Fig. 1
Fig. 1
Selection of peripheral and central mechanisms contributing to neuropathic pain. AMPA-R/NMDA-R ionotropic glutamate receptors, AP action potential, ATP adenosine triphosphate, BDNF brain-derived neurotrophic factor, CCL2/FKN chemokines, CCR2/CX3CR1 chemokine receptors, CGRP calcitonin gene-related peptide, GABA gamma-aminobutyric acid, Gly Glycin, FKN fractalkine (CX3CL1), IL-1β interleukin 1β, IL-6 interleukin 6, KCC2 chloride potassium symporter, MMP matrix metalloproteinase, NK1-R neurokinin 1 receptor, NO nitric oxide, p-p38 MAPK phosphorylated p38 mitogen-activated protein kinase, PG prostaglandins, SP substance P, TNFα tumor necrosis factor-alpha, TNF-R tumor necrosis factor receptor, trkB tyrosine kinase B, TRPV1 transient receptor potential vanilloid 1, VGSC voltage-gated sodium channel
Fig. 2
Fig. 2
Selection of structural and functional alterations in diabetic neuropathy. AGE advanced glycation end products, ROS reactive oxygen species
Fig. 3
Fig. 3
Pathophysiology of painless and painful diabetic neuropathy: diabetes mellitus leads to several pathological changes in neuronal, immune and vascular cells that can lead to structural and functional alterations of the nervous system that can result in diabetic neuropathy (see Fig. 2). Several factors contribute to the development of neuropathic pain in diabetic neuropathy. AGE advanced glycation end products, HIF-1α hypoxia-induced factor 1α, PKC protein kinase C, TRPA1 transient receptor potential ankyrin 1, VGSC voltage-gated sodium channel, vWF von Willebrand factor

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