Diabetic neuropathy

Abstract

The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Patterns of nerve injury in diabetic neuropathy.
Fig. 2: The peripheral nervous system and alterations in diabetic neuropathy.
Fig. 3: Diabetic neuropathy pathogenesis.
Fig. 4: Central and peripheral mechanisms contributing to neuropathic pain in diabetic neuropathy.
Fig. 5: NCS and biopsy study in diabetic neuropathy.
Fig. 6: Treatment of painful diabetic neuropathy.

References

  1. 1.

    International Diabetes Federation. IDF Diabetes Atlas - 8th edition: key messages. IDF https://diabetesatlas.org/key-messages.html (2019).

  2. 2.

    Tabish, S. A. Is diabetes becoming the biggest epidemic of the twenty-first century? Int. J. Health Sci. (Qassim) 1, V–VIII (2007).

  3. 3.

    World Health Organization. Diabetes. WHO https://www.who.int/news-room/fact-sheets/detail/diabetes (2018).

  4. 4.

    Wang, L. et al. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA 317, 2515–2523 (2017).

  5. 5.

    Anjana, R. M. et al. Prevalence of diabetes and prediabetes in 15 states of India: results from the ICMR-INDIAB population-based cross-sectional study. Lancet Diabetes Endocrinol. 5, 585–596 (2017).

  6. 6.

    Centers for Disease Control and Prevention. Prediabetes: your chance to prevent type 2 diabetes. CDC https://www.cdc.gov/diabetes/basics/prediabetes.html (updated 21 Jun 2018).

  7. 7.

    Callaghan, B. C., Price, R. S., Chen, K. S. & Feldman, E. L. The importance of rare subtypes in diagnosis and treatment of peripheral neuropathy: a review. JAMA Neurol. 72, 1510–1518 (2015).

  8. 8.

    Boyle, J. P., Thompson, T. J., Gregg, E. W., Barker, L. E. & Williamson, D. F. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul. Health Metr. 8, 29 (2010).

  9. 9.

    Pop-Busui, R. et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care 40, 136–154 (2017). This article contains the most recent recommendations from the ADA for the prevention, screening, diagnosis, management and treatment of diabetic neuropathy, as well as recommended research and clinical trial neuropathy end points.

  10. 10.

    Gordois, A., Scuffham, P., Shearer, A., Oglesby, A. & Tobian, J. A. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 26, 1790–1795 (2003).

  11. 11.

    Italian General Practitioner Study Group (IGPSG). Chronic symmetric symptomatic polyneuropathy in the elderly: a field screening investigation in two Italian regions. I. Prevalence and general characteristics of the sample. Neurology 45, 1832–1836 (1995).

  12. 12.

    Bharucha, N. E., Bharucha, A. E. & Bharucha, E. P. Prevalence of peripheral neuropathy in the Parsi community of Bombay. Neurology 41, 1315–1317 (1991).

  13. 13.

    Callaghan, B. C. et al. Role of neurologists and diagnostic tests on the management of distal symmetric polyneuropathy. JAMA Neurol. 71, 1143–1149 (2014).

  14. 14.

    Visser, N. A., Notermans, N. C., Linssen, R. S., van den Berg, L. H. & Vrancken, A. F. Incidence of polyneuropathy in Utrecht, the Netherlands. Neurology 84, 259–264 (2015).

  15. 15.

    Ang, L., Jaiswal, M., Martin, C. & Pop-Busui, R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr. Diab. Rep. 14, 528–0528 (2014).

  16. 16.

    Martin, C. L., Albers, J. W. & Pop-Busui, R. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 37, 31–38 (2014).

  17. 17.

    Pop-Busui, R. et al. Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort. Diabetes Care 36, 3208–3215 (2013).

  18. 18.

    Franklin, G. M., Kahn, L. B., Baxter, J., Marshall, J. A. & Hamman, R. F. Sensory neuropathy in non-insulin-dependent diabetes mellitus. The San Luis Valley Diabetes study. Am. J. Epidemiol. 131, 633–643 (1990).

  19. 19.

    Partanen, J. et al. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 333, 89–94 (1995).

  20. 20.

    Dyck, P. J. et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 43, 817–824 (1993).

  21. 21.

    Boulton, A. J., Knight, G., Drury, J. & Ward, J. D. The prevalence of symptomatic, diabetic neuropathy in an insulin-treated population. Diabetes Care 8, 125–128 (1985).

  22. 22.

    Tesfaye, S. et al. Vascular risk factors and diabetic neuropathy. N. Engl. J. Med. 352, 341–350 (2005).

  23. 23.

    Andersen, S. T. et al. Risk factors for incident diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes followed for 13 years: ADDITION-Denmark. Diabetes Care 41, 1068–1075 (2018).

  24. 24.

    Callaghan, B. C. et al. Diabetes and obesity are the main metabolic drivers of peripheral neuropathy. Ann. Clin. Transl Neurol. 5, 397–405 (2018).

  25. 25.

    Callaghan, B. C. et al. Metabolic syndrome components are associated with symptomatic polyneuropathy independent of glycemic status. Diabetes Care 39, 801–807 (2016). This study demonstrates a link between the number of metabolic syndrome components and neuropathy prevalence that is independent of glycaemic status.

  26. 26.

    Callaghan, B. C. et al. Association between metabolic syndrome components and polyneuropathy in an obese population. JAMA Neurol. 73, 1468–1476 (2016).

  27. 27.

    Hanewinckel, R. et al. Metabolic syndrome is related to polyneuropathy and impaired peripheral nerve function: a prospective population-based cohort study. J. Neurol. Neurosurg. Psychiatry 87, 1336–1342 (2016).

  28. 28.

    Lu, B. et al. Determination of peripheral neuropathy prevalence and associated factors in Chinese subjects with diabetes and pre-diabetes - ShangHai Diabetic neuRopathy Epidemiology and Molecular Genetics Study (SH-DREAMS). PLOS ONE 8, e61053 (2013).

  29. 29.

    Tesfaye, S. & Selvarajah, D. The Eurodiab study: what has this taught us about diabetic peripheral neuropathy? Curr. Diab. Rep. 9, 432–434 (2009).

  30. 30.

    Callaghan, B. C., Price, R. S. & Feldman, E. L. Distal symmetric polyneuropathy: a review. JAMA 314, 2172–2181 (2015).

  31. 31.

    Prabodha, L. B. L., Sirisena, N. D. & Dissanayake, V. H. W. Susceptible and prognostic genetic factors associated with diabetic peripheral neuropathy: a comprehensive literature review. Int. J. Endocrinol. 2018, 8641942 (2018).

  32. 32.

    Politi, C. et al. Recent advances in exploring the genetic susceptibility to diabetic neuropathy. Diabetes Res. Clin. Pract. 120, 198–208 (2016).

  33. 33.

    Dunnigan, S. K. et al. Conduction slowing in diabetic sensorimotor polyneuropathy. Diabetes Care 36, 3684–3690 (2013).

  34. 34.

    Gumy, L. F., Bampton, E. T. & Tolkovsky, A. M. Hyperglycaemia inhibits Schwann cell proliferation and migration and restricts regeneration of axons and Schwann cells from adult murine DRG. Mol. Cell Neurosci. 37, 298–311 (2008).

  35. 35.

    Mizisin, A. P., Shelton, G. D., Wagner, S., Rusbridge, C. & Powell, H. C. Myelin splitting, Schwann cell injury and demyelination in feline diabetic neuropathy. Acta Neuropathol. 95, 171–174 (1998).

  36. 36.

    Pan, S. & Chan, J. R. Regulation and dysregulation of axon infrastructure by myelinating glia. J. Cell Biol. 216, 3903–3916 (2017).

  37. 37.

    Feldman, E. L., Nave, K. A., Jensen, T. S. & Bennett, D. L. H. New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. Neuron 93, 1296–1313 (2017). This article provides a detailed review of advances in our understanding of the pathways underlying peripheral nerve injury and pain in diabetic neuropathy, including systems biology insights and ideas related to bioenergetic crosstalk and the axon–Schwann cell relationship.

  38. 38.

    Court, F. A., Hendriks, W. T., MacGillavry, H. D., Alvarez, J. & van Minnen, J. Schwann cell to axon transfer of ribosomes: toward a novel understanding of the role of glia in the nervous system. J. Neurosci. 28, 11024–11029 (2008).

  39. 39.

    Willis, D. E. & Twiss, J. L. The evolving roles of axonally synthesized proteins in regeneration. Curr. Opin. Neurobiol. 16, 111–118 (2006).

  40. 40.

    Cashman, C. R. & Hoke, A. Mechanisms of distal axonal degeneration in peripheral neuropathies. Neurosci. Lett. 596, 33–50 (2015).

  41. 41.

    Scott, J. N., Clark, A. W. & Zochodne, D. W. Neurofilament and tubulin gene expression in progressive experimental diabetes: failure of synthesis and export by sensory neurons. Brain 122, 2109–2118 (1999).

  42. 42.

    Lupachyk, S., Watcho, P., Stavniichuk, R., Shevalye, H. & Obrosova, I. G. Endoplasmic reticulum stress plays a key role in the pathogenesis of diabetic peripheral neuropathy. Diabetes 62, 944–952 (2013).

  43. 43.

    Ma, J., Pan, P., Anyika, M., Blagg, B. S. & Dobrowsky, R. T. Modulating molecular chaperones improves mitochondrial bioenergetics and decreases the inflammatory transcriptome in diabetic sensory neurons. ACS Chem. Neurosci. 6, 1637–1648 (2015).

  44. 44.

    Urban, M. J. et al. Modulating molecular chaperones improves sensory fiber recovery and mitochondrial function in diabetic peripheral neuropathy. Exp. Neurol. 235, 388–396 (2012).

  45. 45.

    Ilnytska, O. et al. Poly(ADP-ribose) polymerase inhibition alleviates experimental diabetic sensory neuropathy. Diabetes 55, 1686–1694 (2006).

  46. 46.

    Lupachyk, S., Shevalye, H., Maksimchyk, Y., Drel, V. R. & Obrosova, I. G. PARP inhibition alleviates diabetes-induced systemic oxidative stress and neural tissue 4-hydroxynonenal adduct accumulation: correlation with peripheral nerve function. Free Radic. Biol. Med. 50, 1400–1409 (2011).

  47. 47.

    Cheng, C. et al. Evidence for epigenetic regulation of gene expression and function in chronic experimental diabetic neuropathy. J. Neuropathol. Exp. Neurol. 74, 804–817 (2015).

  48. 48.

    Toth, C., Brussee, V. & Zochodne, D. W. Remote neurotrophic support of epidermal nerve fibres in experimental diabetes. Diabetologia 49, 1081–1088 (2006).

  49. 49.

    Fernyhough, P., Diemel, L. T., Brewster, W. J. & Tomlinson, D. R. Altered neurotrophin mRNA levels in peripheral nerve and skeletal muscle of experimentally diabetic rats. J. Neurochem. 64, 1231–1237 (1995).

  50. 50.

    Fernyhough, P., Diemel, L. T. & Tomlinson, D. R. Target tissue production and axonal transport of neurotrophin-3 are reduced in streptozotocin-diabetic rats. Diabetologia 41, 300–306 (1998).

  51. 51.

    Delcroix, J. D., Michael, G. J., Priestley, J. V., Tomlinson, D. R. & Fernyhough, P. Effect of nerve growth factor treatment on p75NTR gene expression in lumbar dorsal root ganglia of streptozocin-induced diabetic rats. Diabetes 47, 1779–1785 (1998).

  52. 52.

    Hur, J. et al. The metabolic syndrome and microvascular complications in a murine model of type 2 diabetes. Diabetes 64, 3294–3304 (2015).

  53. 53.

    Hur, J. et al. Transcriptional networks of murine diabetic peripheral neuropathy and nephropathy: common and distinct gene expression patterns. Diabetologia 59, 1297–1306 (2016).

  54. 54.

    McGregor, B. A. et al. Conserved transcriptional signatures in human and murine diabetic peripheral neuropathy. Sci. Rep. 8, 17678 (2018).

  55. 55.

    Kobayashi, M. et al. Diabetic polyneuropathy, sensory neurons, nuclear structure and spliceosome alterations: a role for CWC22. Dis. Model. Mech. 10, 215–224 (2017).

  56. 56.

    Zochodne, D. W. & Ho, L. T. The influence of sulindac on experimental streptozotocin-induced diabetic neuropathy. Can. J. Neurol. Sci. 21, 194–202 (1994).

  57. 57.

    Viader, A. et al. Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron 77, 886–898 (2013).

  58. 58.

    Vincent, A. M., Callaghan, B. C., Smith, A. L. & Feldman, E. L. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat. Rev. Neurol. 7, 573–583 (2011).

  59. 59.

    Vincent, A. M., Kato, K., McLean, L. L., Soules, M. E. & Feldman, E. L. Sensory neurons and schwann cells respond to oxidative stress by increasing antioxidant defense mechanisms. Antioxid. Redox Signal 11, 425–438 (2009).

  60. 60.

    Russell, J. W. et al. Oxidative injury and neuropathy in diabetes and impaired glucose tolerance. Neurobiol. Dis. 30, 420–429 (2008).

  61. 61.

    Vincent, A. M., Edwards, J. L., Sadidi, M. & Feldman, E. L. The antioxidant response as a drug target in diabetic neuropathy. Curr. Drug Targets 9, 94–100 (2008).

  62. 62.

    Vincent, A. M., Calabek, B., Roberts, L. & Feldman, E. L. Biology of diabetic neuropathy. Handb. Clin. Neurol. 115, 591–606 (2013).

  63. 63.

    Vincent, A. M., Russell, J. W., Low, P. & Feldman, E. L. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr. Rev. 25, 612–628 (2004).

  64. 64.

    Fernyhough, P. Mitochondrial dysfunction in diabetic neuropathy: a series of unfortunate metabolic events. Curr. Diab. Rep. 15, 89 (2015).

  65. 65.

    Fernyhough, P. & McGavock, J. Mechanisms of disease: mitochondrial dysfunction in sensory neuropathy and other complications in diabetes. Handb. Clin. Neurol. 126, 353–377 (2014).

  66. 66.

    Chowdhury, S. K., Smith, D. R. & Fernyhough, P. The role of aberrant mitochondrial bioenergetics in diabetic neuropathy. Neurobiol. Dis. 51, 56–65 (2013).

  67. 67.

    Rumora, A. E. et al. Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons. FASEB J. 32, 195–207 (2018).

  68. 68.

    Singh, V. P., Bali, A., Singh, N. & Jaggi, A. S. Advanced glycation end products and diabetic complications. Korean J. Physiol. Pharmacol. 18, 1–14 (2014).

  69. 69.

    Padilla, A., Descorbeth, M., Almeyda, A. L., Payne, K. & De Leon, M. Hyperglycemia magnifies Schwann cell dysfunction and cell death triggered by PA-induced lipotoxicity. Brain Res. 1370, 64–79 (2011).

  70. 70.

    Legrand-Poels, S. et al. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochem. Pharmacol. 92, 131–141 (2014).

  71. 71.

    Jang, E. R. & Lee, C. S. 7-Ketocholesterol induces apoptosis in differentiated PC12 cells via reactive oxygen species-dependent activation of NF-kappaB and Akt pathways. Neurochem. Int. 58, 52–59 (2011).

  72. 72.

    Vincent, A. M. et al. Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1. Diabetes 58, 2376–2385 (2009).

  73. 73.

    Nowicki, M. et al. Oxidized low-density lipoprotein (oxLDL)-induced cell death in dorsal root ganglion cell cultures depends not on the lectin-like oxLDL receptor-1 but on the toll-like receptor-4. J. Neurosci. Res. 88, 403–412 (2010).

  74. 74.

    Vincent, A. M. et al. Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress. Endocrinology 148, 548–558 (2007).

  75. 75.

    Keller, J. N., Hanni, K.B. & Markesbery, W. R. Oxidized low-density lipoprotein induces neuronal death: implications for calcium, reactive oxygen species, and caspases. J. Neurochem. 72, 2601–2609 (1999).

  76. 76.

    Cotter, M. A. & Cameron, N. E. Effect of the NAD(P)H oxidase inhibitor, apocynin, on peripheral nerve perfusion and function in diabetic rats. Life Sci. 73, 1813–1824 (2003).

  77. 77.

    Kim, H., Kim, J. J. & Yoon, Y. S. Emerging therapy for diabetic neuropathy: cell therapy targeting vessels and nerves. Endocr. Metab. Immune Disord. Drug Targets 12, 168–178 (2012).

  78. 78.

    Thrainsdottir, S. et al. Endoneurial capillary abnormalities presage deterioration of glucose tolerance and accompany peripheral neuropathy in man. Diabetes 52, 2615–2622 (2003).

  79. 79.

    Nowicki, M., Kosacka, J., Serke, H., Bluher, M. & Spanel-Borowski, K. Altered sciatic nerve fiber morphology and endoneural microvessels in mouse models relevant for obesity, peripheral diabetic polyneuropathy, and the metabolic syndrome. J. Neurosci. Res. 90, 122–131 (2012).

  80. 80.

    Coppey, L. J. et al. Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity, and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 50, 1927–1937 (2001).

  81. 81.

    Schratzberger, P. et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J. Clin. Invest. 107, 1083–1092 (2001).

  82. 82.

    Frazier, W. A., Angeletti, R. H. & Bradshaw, R. A. Nerve growth factor and insulin. Science 176, 482–488 (1972).

  83. 83.

    Fernyhough, P., Willars, G. B., Lindsay, R. M. & Tomlinson, D. R. Insulin and insulin-like growth factor I enhance regeneration in cultured adult rat sensory neurones. Brain Res. 607, 117–124 (1993).

  84. 84.

    Brussee, V., Cunningham, F. A. & Zochodne, D. W. Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes 53, 1824–1830 (2004).

  85. 85.

    Sugimoto, K., Murakawa, Y., Zhang, W., Xu, G. & Sima, A. A. Insulin receptor in rat peripheral nerve: its localization and alternatively spliced isoforms. Diabetes Metab. Res. Rev. 16, 354–363 (2000).

  86. 86.

    Guo, G., Kan, M., Martinez, J. A. & Zochodne, D. W. Local insulin and the rapid regrowth of diabetic epidermal axons. Neurobiol. Dis. 43, 414–421 (2011).

  87. 87.

    Singhal, A., Cheng, C., Sun, H. & Zochodne, D. W. Near nerve local insulin prevents conduction slowing in experimental diabetes. Brain Res. 763, 209–214 (1997).

  88. 88.

    Kim, B., McLean, L. L., Philip, S. S. & Feldman, E. L. Hyperinsulinemia induces insulin resistance in dorsal root ganglion neurons. Endocrinology 152, 3638–3647 (2011).

  89. 89.

    Singh, B. et al. Resistance to trophic neurite outgrowth of sensory neurons exposed to insulin. J. Neurochem. 121, 263–276 (2012).

  90. 90.

    Grote, C. W. et al. Peripheral nervous system insulin resistance in ob/ob mice. Acta Neuropathol. Commun. 1, 15 (2013).

  91. 91.

    Grote, C. W., Morris, J. K., Ryals, J. M., Geiger, P. C. & Wright, D. E. Insulin receptor substrate 2 expression and involvement in neuronal insulin resistance in diabetic neuropathy. Exp. Diabetes Res. 2011, 212571 (2011).

  92. 92.

    Abbott, C. A., Malik, R. A., van Ross, E. R., Kulkarni, J. & Boulton, A. J. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care 34, 2220–2224 (2011).

  93. 93.

    von Hehn, C. A., Baron, R. & Woolf, C. J. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 73, 638–652 (2012).

  94. 94.

    Hebert, H. L., Veluchamy, A., Torrance, N. & Smith, B. H. Risk factors for neuropathic pain in diabetes mellitus. Pain 158, 560–568 (2017).

  95. 95.

    Raputova, J. et al. Sensory phenotype and risk factors for painful diabetic neuropathy: a cross-sectional observational study. Pain 158, 2340–2353 (2017).

  96. 96.

    Themistocleous, A. C. et al. The Pain in Neuropathy Study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy. Pain 157, 1132–1145 (2016).

  97. 97.

    Suzuki, Y., Sato, J., Kawanishi, M. & Mizumura, K. Lowered response threshold and increased responsiveness to mechanical stimulation of cutaneous nociceptive fibers in streptozotocin-diabetic rat skin in vitro — correlates of mechanical allodynia and hyperalgesia observed in the early stage of diabetes. Neurosci. Res. 43, 171–178 (2002).

  98. 98.

    Garcia-Perez, E. et al. Behavioural, morphological and electrophysiological assessment of the effects of type 2 diabetes mellitus on large and small nerve fibres in Zucker diabetic fatty, Zucker lean and Wistar rats. Eur. J. Pain 22, 1457–1472 (2018).

  99. 99.

    Orstavik, K. et al. Abnormal function of C-fibers in patients with diabetic neuropathy. J. Neurosci. 26, 11287–11294 (2006).

  100. 100.

    Haroutounian, S. et al. Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain 155, 1272–1279 (2014).

  101. 101.

    Bennett, D. L. & Woods, C. G. Painful and painless channelopathies. Lancet Neurol. 13, 587–599 (2014). This review presents insights into pain mechanisms, diagnosis and treatment that have emanated from studies of heritable pain disorders.

  102. 102.

    Dubin, A. E. & Patapoutian, A. Nociceptors: the sensors of the pain pathway. J. Clin. Invest. 120, 3760–3772 (2010).

  103. 103.

    Blair, N. T. & Bean, B. P. Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J. Neurosci. 22, 10277–10290 (2002).

  104. 104.

    Sun, W. et al. Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats. Brain 135, 359–375 (2012).

  105. 105.

    Bierhaus, A. et al. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat. Med. 18, 926–933 (2012).

  106. 106.

    Hansen, C. S. et al. The role of serum methylglyoxal on diabetic peripheral and cardiovascular autonomic neuropathy: the ADDITION Denmark study. Diabet. Med. 32, 778–785 (2015).

  107. 107.

    Andersson, D. A. et al. Methylglyoxal evokes pain by stimulating TRPA1. PLOS ONE 8, e77986 (2013).

  108. 108.

    Calvo, M. et al. Altered potassium channel distribution and composition in myelinated axons suppresses hyperexcitability following injury. eLife 5, e12661 (2016).

  109. 109.

    Zenker, J. et al. Altered distribution of juxtaparanodal kv1.2 subunits mediates peripheral nerve hyperexcitability in type 2 diabetes mellitus. J. Neurosci. 32, 7493–7498 (2012).

  110. 110.

    Dib-Hajj, S. D., Yang, Y., Black, J. A. & Waxman, S. G. The NaV1.7 sodium channel: from molecule to man. Nat. Rev. Neurosci. 14, 49–62 (2013).

  111. 111.

    Li, Q. S. et al. SCN9A variants may be implicated in neuropathic pain associated with diabetic peripheral neuropathy and pain severity. Clin. J. Pain 31, 976–982 (2015).

  112. 112.

    Blesneac, I. et al. Rare Nav1.7 variants associated with painful diabetic peripheral neuropathy. Pain 159, 469–480 (2017).

  113. 113.

    Wadhawan, S. et al. NaV channel variants in patients with painful and nonpainful peripheral neuropathy. Neurol. Genet. 3, e207 (2017).

  114. 114.

    McDonnell, A. et al. Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy. Pain 159, 1465–1476 (2018).

  115. 115.

    Zakrzewska, J. M. et al. Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. Lancet Neurol. 16, 291–300 (2017).

  116. 116.

    Orestes, P. et al. Reversal of neuropathic pain in diabetes by targeting glycosylation of CaV3.2T-type calcium channels. Diabetes 62, 3828–3838 (2013).

  117. 117.

    Messinger, R. B. et al. In vivo silencing of the Ca(V)3.2T-type calcium channels in sensory neurons alleviates hyperalgesia in rats with streptozocin-induced diabetic neuropathy. Pain 145, 184–195 (2009).

  118. 118.

    Cooper, M. A. et al. Modulation of diet-induced mechanical allodynia by metabolic parameters and inflammation. J. Peripher. Nerv. Syst. 22, 39–46 (2017).

  119. 119.

    Woolf, C. J. Central sensitization: implications for the diagnosis and treatment of pain. Pain 152, S2–15 (2011).

  120. 120.

    Tan, A. M. et al. Maladaptive dendritic spine remodeling contributes to diabetic neuropathic pain. J. Neurosci. 32, 6795–6807 (2012).

  121. 121.

    Salter, M. W. & Beggs, S. Sublime microglia: expanding roles for the guardians of the CNS. Cell 158, 15–24 (2014).

  122. 122.

    Tsuda, M., Ueno, H., Kataoka, A., Tozaki-Saitoh, H. & Inoue, K. Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signaling. Glia 56, 378–386 (2008).

  123. 123.

    Liao, Y. H. et al. Spinal astrocytic activation contributes to mechanical allodynia in a mouse model of type 2 diabetes. Brain Res. 1368, 324–335 (2011).

  124. 124.

    Wodarski, R., Clark, A. K., Grist, J., Marchand, F. & Malcangio, M. Gabapentin reverses microglial activation in the spinal cord of streptozotocin-induced diabetic rats. Eur. J. Pain 13, 807–811 (2009).

  125. 125.

    West, S. J., Bannister, K., Dickenson, A. H. & Bennett, D. L. Circuitry and plasticity of the dorsal horn — toward a better understanding of neuropathic pain. Neuroscience 300, 254–275 (2015).

  126. 126.

    Marshall, A. G. et al. Spinal disinhibition in experimental and clinical painful diabetic neuropathy. Diabetes 66, 1380–1390 (2017).

  127. 127.

    Segerdahl, A. R., Themistocleous, A. C., Fido, D., Bennett, D. L. & Tracey, I. A brain-based pain facilitation mechanism contributes to painful diabetic polyneuropathy. Brain 141, 357–364 (2018).

  128. 128.

    Yarnitsky, D., Granot, M., Nahman-Averbuch, H., Khamaisi, M. & Granovsky, Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain 153, 1193–1198 (2012).

  129. 129.

    Cauda, F. et al. Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in diabetic neuropathic pain. BMC Neurosci. 10, 138 (2009).

  130. 130.

    Selvarajah, D. et al. Magnetic resonance neuroimaging study of brain structural differences in diabetic peripheral neuropathy. Diabetes Care 37, 1681–1688 (2014).

  131. 131.

    Vileikyte, L. & Gonzalez, J. S. Recognition and management of psychosocial issues in diabetic neuropathy. Handb. Clin. Neurol. 126, 195–209 (2014).

  132. 132.

    Sieberg, C. B. et al. Neuropathic pain drives anxiety behavior in mice, results consistent with anxiety levels in diabetic neuropathy patients. Pain Rep. 3, e651 (2018).

  133. 133.

    Tesfaye, S. et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33, 2285–2293 (2010). This update presents the results of the October 2009 Toronto Diabetic Neuropathy Expert Group discussion on the classification, definition, diagnostic criteria and treatments of diabetic peripheral, autonomic and painful neuropathies.

  134. 134.

    Divisova, S. et al. Prediabetes/early diabetes-associated neuropathy predominantly involves sensory small fibres. J. Peripher. Nerv. Syst. 17, 341–350 (2012).

  135. 135.

    Bril, V. & Perkins, B. A. Validation of the Toronto Clinical Scoring System for diabetic polyneuropathy. Diabetes Care 25, 2048–2052 (2002).

  136. 136.

    Bril, V., Tomioka, S., Buchanan, R. A. & Perkins, B. A., the mTCNS Study Group. Reliability and validity of the modified Toronto Clinical Neuropathy Score in diabetic sensorimotor polyneuropathy. Diabet. Med. 26, 240–246 (2009).

  137. 137.

    Feldman, E. L. et al. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 17, 1281–1289 (1994).

  138. 138.

    Dyck, P. J. et al. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab. Res. Rev. 27, 620–628 (2011).

  139. 139.

    Weisman, A. et al. Identification and prediction of diabetic sensorimotor polyneuropathy using individual and simple combinations of nerve conduction study parameters. PLOS ONE 8, e58783 (2013).

  140. 140.

    Singleton, J. R. et al. The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy. J. Peripher. Nerv. Syst. 13, 218–227 (2008).

  141. 141.

    Andersson, C., Guttorp, P. & Sarkka, A. Discovering early diabetic neuropathy from epidermal nerve fiber patterns. Stat. Med. 35, 4427–4442 (2016).

  142. 142.

    Devigili, G. et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 131, 1912–1925 (2008).

  143. 143.

    Jensen, T. S., Bach, F. W., Kastrup, J., Dejgaard, A. & Brennum, J. Vibratory and thermal thresholds in diabetics with and without clinical neuropathy. Acta Neurol. Scand. 84, 326–333 (1991).

  144. 144.

    Krishnan, S. T. & Rayman, G. The LDIflare: a novel test of C-fiber function demonstrates early neuropathy in type 2 diabetes. Diabetes Care 27, 2930–2935 (2004).

  145. 145.

    Sivaskandarajah, G. A. et al. Structure-function relationship between corneal nerves and conventional small-fiber tests in type 1 diabetes. Diabetes Care 36, 2748–2755 (2013).

  146. 146.

    Breiner, A., Lovblom, L. E., Perkins, B. A. & Bril, V. Does the prevailing hypothesis that small-fiber dysfunction precedes large-fiber dysfunction apply to type 1 diabetic patients? Diabetes Care 37, 1418–1424 (2014).

  147. 147.

    Yang, W., Cai, X. L., Wu, H. & Ji, L. Associations between metformin use and vitamin B12 level, anemia and neuropathy in patients with diabetes: a meta-analysis. J. Diabetes. https://doi.org/10.1111/1753-0407.12900 (2019).

  148. 148.

    England, J. D. et al. Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R. 1, 5–13 (2009).

  149. 149.

    Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018).

  150. 150.

    Benson, M. D. et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 22–31 (2018).

  151. 151.

    Diabetes Canada Clinical Practice Guidelines Expert Committee, Bril, V., Breiner, A., Perkins, B. A. & Zochodne, D. Neuropathy. Can. J. Diabetes 42 (Suppl. 1), S217–S221 (2018).

  152. 152.

    Olaleye, D., Perkins, B. A. & Bril, V. Evaluation of three screening tests and a risk assessment model for diagnosing peripheral neuropathy in the diabetes clinic. Diabetes Res. Clin. Pract. 54, 115–128 (2001).

  153. 153.

    Perkins, B. A., Olaleye, D., Zinman, B. & Bril, V. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care 24, 250–256 (2001).

  154. 154.

    Perkins, B. A. et al. Prediction of incident diabetic neuropathy using the monofilament examination: a 4-year prospective study. Diabetes Care 33, 1549–1554 (2010).

  155. 155.

    Boulton, A. J. et al. Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care 31, 1679–1685 (2008).

  156. 156.

    Kanji, J. N., Anglin, R. E., Hunt, D. L. & Panju, A. Does this patient with diabetes have large-fiber peripheral neuropathy? JAMA 303, 1526–1532 (2010).

  157. 157.

    Beghi, E., Treviso, M., Ferri, P. & Di Mascio, R. Diagnosis of diabetic polyneuropathy. Correlation between clinical and instrumental findings and assessment of simple diagnostic criteria. Ital. J. Neurol. Sci. 9, 577–582 (1988).

  158. 158.

    Herman, W. H. et al. Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications. Diabet Med. 29, 937–944 (2012).

  159. 159.

    Callaghan, B. C., Little, A. A., Feldman, E. L. & Hughes, R. A. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst. Rev. 6, CD007543 (2012). This analysis of clinical studies evaluating the impact of glycaemic control on neuropathy outcomes in T1DM and T2DM reveals that enhanced glucose control significantly attenuates neuropathy development in T1DM but not in T2DM.

  160. 160.

    The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977–986 (1993).

  161. 161.

    Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129–139 (2009).

  162. 162.

    Ismail-Beigi, F. et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 376, 419–430 (2010).

  163. 163.

    Charles, M. et al. Prevalence of neuropathy and peripheral arterial disease and the impact of treatment in people with screen-detected type 2 diabetes: the ADDITION-Denmark study. Diabetes Care 34, 2244–2249 (2011).

  164. 164.

    Singleton, J. R. et al. Exercise increases cutaneous nerve density in diabetic patients without neuropathy. Ann. Clin. Transl Neurol. 1, 844–849 (2014).

  165. 165.

    Muller-Stich, B. P. et al. Gastric bypass leads to improvement of diabetic neuropathy independent of glucose normalization—results of a prospective cohort study (DiaSurg 1 study). Ann. Surg. 258, 760–765 (2013).

  166. 166.

    Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358, 2545–2559 (2008).

  167. 167.

    Qaseem, A. et al. Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: a guidance statement update from the American College of Physicians. Ann. Intern. Med. 168, 569–576 (2018).

  168. 168.

    Ziegler, D., Behler, M., Schroers-Teuber, M. & Roden, M. Near-normoglycaemia and development of neuropathy: a 24-year prospective study from diagnosis of type 1 diabetes. BMJ Open 5, e006559 (2015).

  169. 169.

    Dahl-Jorgensen, K. et al. Effect of near normoglycaemia for two years on progression of early diabetic retinopathy, nephropathy, and neuropathy: the Oslo study. Br. Med. J. (Clin. Res. Ed) 293, 1195–1199 (1986).

  170. 170.

    Ohkubo, Y. et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res. Clin. Pract. 28, 103–117 (1995).

  171. 171.

    Ishibashi, F., Taniguchi, M., Kosaka, A., Uetake, H. & Tavakoli, M. Improvement in neuropathy outcomes with normalizing HbA1c in patients with type 2 diabetes. Diabetes Care 42, 110–118 (2018).

  172. 172.

    Balducci, S. et al. Exercise training can modify the natural history of diabetic peripheral neuropathy. J. Diabetes Complicat. 20, 216–223 (2006).

  173. 173.

    Kluding, P. M. et al. The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy. J. Diabetes Complicat. 26, 424–429 (2012).

  174. 174.

    Singleton, J. R., Marcus, R. L., Lessard, M. K., Jackson, J. E. & Smith, A. G. Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients. Ann. Neurol. 77, 146–153 (2015).

  175. 175.

    Smith, A. G. et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care 29, 1294–1299 (2006).

  176. 176.

    Ziegler, D. et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-lipoic acid in diabetic neuropathy. Diabetes Care 22, 1296–1301 (1999).

  177. 177.

    Ziegler, D. et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 29, 2365–2370 (2006).

  178. 178.

    Ziegler, D. et al. Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care 34, 2054–2060 (2011). This multicentre, randomized, double-blind, parallel-group trial of α-lipoic acid in 460 individuals with diabetes and neuropathy does not meet the primary composite end point. There is a beneficial effect in the α-lipoic-acid-treated cohort on secondary end points, including the NIS.

  179. 179.

    Balakumar, P., Rohilla, A., Krishan, P., Solairaj, P. & Thangathirupathi, A. The multifaceted therapeutic potential of benfotiamine. Pharmacol. Res. 61, 482–488 (2010).

  180. 180.

    Zilliox, L. & Russell, J. W. Treatment of diabetic sensory polyneuropathy. Curr. Treat. Options Neurol. 13, 143–159 (2011).

  181. 181.

    Stracke, H., Gaus, W., Achenbach, U., Federlin, K. & Bretzel, R. G. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp. Clin. Endocrinol. Diabetes 116, 600–605 (2008).

  182. 182.

    Fraser, D. A. et al. The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: a 24-month, double-blind, randomized, placebo-controlled trial. Diabetes Care 35, 1095–1097 (2012).

  183. 183.

    Lewis, E. J. H. et al. Effect of omega-3 supplementation on neuropathy in type 1 diabetes: a 12-month pilot trial. Neurology 88, 2294–2301 (2017).

  184. 184.

    Hotta, N. et al. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy: the 3-year, multicenter, comparative Aldose Reductase Inhibitor-Diabetes Complications Trial. Diabetes Care 29, 1538–1544 (2006).

  185. 185.

    Attal, N. et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur. J. Neurol. 17, 1113–e88 (2010).

  186. 186.

    Bril, V. et al. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 76, 1758–1765 (2011). This article presents an evidenced-based guideline for the treatment of painful diabetic neuropathy.

  187. 187.

    Finnerup, N. B. et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 14, 162–173 (2015). This systematic review and meta-analysis provides support for a revision to the NeuPSIG recommendations for the treatment of neuropathic pain.

  188. 188.

    Griebeler, M. L. et al. Pharmacologic interventions for painful diabetic neuropathy: An umbrella systematic review and comparative effectiveness network meta-analysis. Ann. Intern. Med. 161, 639–649 (2014).

  189. 189.

    Waldfogel, J. M. et al. Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life: a systematic review. Neurology 88, 1958–1967 (2017).

  190. 190.

    Callaghan, B. C. & Feldman, E. L. Painful diabetic neuropathy: many similarly effective therapies with widely dissimilar costs. Ann. Intern. Med. 161, 674–675 (2014).

  191. 191.

    Backonja, M. & Glanzman, R. L. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin. Ther. 25, 81–104 (2003).

  192. 192.

    Freeman, R., Durso-Decruz, E. & Emir, B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care 31, 1448–1454 (2008).

  193. 193.

    Moore, R. A., Straube, S., Wiffen, P. J., Derry, S. & McQuay, H. J. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst. Rev. 8, CD007076 (2009).

  194. 194.

    Ziegler, D., Duan, W. R., An, G., Thomas, J. W. & Nothaft, W. A randomized double-blind, placebo-, and active-controlled study of T-type calcium channel blocker ABT-639 in patients with diabetic peripheral neuropathic pain. Pain 156, 2013–2020 (2015).

  195. 195.

    Quilici, S. et al. Meta-analysis of duloxetine versus pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurol. 9, 6 (2009).

  196. 196.

    Raskin, P. et al. Pregabalin in patients with inadequately treated painful diabetic peripheral neuropathy: a randomized withdrawal trial. Clin. J. Pain 30, 379–390 (2014).

  197. 197.

    Dworkin, R. H., Jensen, M. P., Gammaitoni, A. R., Olaleye, D. O. & Galer, B. S. Symptom profiles differ in patients with neuropathic versus non-neuropathic pain. J. Pain 8, 118–126 (2007).

  198. 198.

    Goldstein, D. J., Lu, Y., Detke, M. J., Lee, T. C. & Iyengar, S. Duloxetine versus placebo in patients with painful diabetic neuropathy. Pain 116, 109–118 (2005).

  199. 199.

    Tesfaye, S. et al. Duloxetine and pregabalin: High-dose monotherapy or their combination? The “COMBO-DN study” - a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain 154, 2616–2625 (2013).

  200. 200.

    Wernicke, J. F. et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 67, 1411–1420 (2006).

  201. 201.

    Zilliox, L. & Russell, J. W. Maintaining efficacy in the treatment of diabetic peripheral neuropathic pain: role of duloxetine. Diabetes Metab. Syndr. Obes. 3, 7–17 (2010).

  202. 202.

    Rowbotham, M. C., Goli, V., Kunz, N. R. & Lei, D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain 110, 697–706 (2004).

  203. 203.

    Sindrup, S. H., Bach, F. W., Madsen, C., Gram, L. F. & Jensen, T. S. Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Neurology 60, 1284–1289 (2003).

  204. 204.

    Boyle, J. et al. Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain: impact on pain, polysomnographic sleep, daytime functioning, and quality of life. Diabetes Care 35, 2451–2458 (2012).

  205. 205.

    Max, M. B. et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 37, 589–596 (1987).

  206. 206.

    Max, M. B. et al. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain 45, 3–9 (1991).

  207. 207.

    Max, M. B. et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N. Engl. J. Med. 326, 1250–1256 (1992).

  208. 208.

    Derry, S., Wiffen, P. J., Aldington, D. & Moore, R. A. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst. Rev. 1, CD011209 (2015).

  209. 209.

    Dowell, D., Haegerich, T. M. & Chou, R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA 315, 1624–1645 (2016).

  210. 210.

    Franklin, G. M. Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology 83, 1277–1284 (2014). This article reviews the safety and efficacy evidence, state and federal policies and recommendations for practising neurologists regarding safe and effective opioid use in chronic pain conditions.

  211. 211.

    Schwartz, S. et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr. Med. Res. Opin. 27, 151–162 (2011).

  212. 212.

    Vinik, A. I. et al. A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy. Diabetes Care 37, 2302–2309 (2014).

  213. 213.

    Raffa, R. B. et al. Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an ‘atypical’ opioid analgesic. J. Pharmacol. Exp. Ther. 260, 275–285 (1992).

  214. 214.

    Harati, Y. et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 50, 1842–1846 (1998).

  215. 215.

    Freeman, R. et al. Randomized study of tramadol/acetaminophen versus placebo in painful diabetic peripheral neuropathy. Curr. Med. Res. Opin. 23, 147–161 (2007).

  216. 216.

    Harati, Y. et al. Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J. Diabetes Complicat. 14, 65–70 (2000).

  217. 217.

    Gimbel, J. S., Richards, P. & Portenoy, R. K. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 60, 927–934 (2003).

  218. 218.

    Watson, C. P., Moulin, D., Watt-Watson, J., Gordon, A. & Eisenhoffer, J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 105, 71–78 (2003).

  219. 219.

    Jalal, H. et al. Changing dynamics of the drug overdose epidemic in the United States from 1979 through 2016. Science 361, eaau1184 (2018).

  220. 220.

    Fisher, L., Hessler, D. M., Polonsky, W. H. & Mullan, J. When is diabetes distress clinically meaningful?: establishing cut points for the Diabetes Distress Scale. Diabetes Care 35, 259–264 (2012).

  221. 221.

    Callaghan, B. et al. Longitudinal patient-oriented outcomes in neuropathy: Importance of early detection and falls. Neurology 85, 71–79 (2015).

  222. 222.

    Van Acker, K. et al. Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics. Diabetes Metab. 35, 206–213 (2009).

  223. 223.

    Ind, I. S. G. Burden of neuropathic pain in Indian patients attending urban, specialty clinics: results from a cross sectional study. Pain Pract. 8, 362–378 (2008).

  224. 224.

    Trikkalinou, A., Papazafiropoulou, A. K. & Melidonis, A. Type 2 diabetes and quality of life. World J. Diabetes 8, 120–129 (2017).

  225. 225.

    Benbow, S. J., Wallymahmed, M. E. & MacFarlane, I. A. Diabetic peripheral neuropathy and quality of life. QJM 91, 733–737 (1998).

  226. 226.

    Meyer-Rosberg, K. et al. Peripheral neuropathic pain — a multidimensional burden for patients. Eur. J. Pain 5, 379–389 (2001).

  227. 227.

    Amalraj, M. J., Anitha Rani, A. & Viswanathan, V. A study on positive impact of intensive psychological counseling on psychological well-being of type 2 diabetic patients undergoing amputation. Int. J. Psychol. Couns. 9, 10–16 (2017).

  228. 228.

    Thorn, B. E. et al. Literacy-adapted cognitive behavioral therapy versus education for chronic pain at low-income clinics: a randomized controlled trial. Ann. Intern. Med. 168, 471–480 (2018).

  229. 229.

    Freeman, R. Diabetic autonomic neuropathy. Handb. Clin. Neurol. 126, 63–79 (2014).

  230. 230.

    Peltier, A., Goutman, S. A. & Callaghan, B. C. Painful diabetic neuropathy. BMJ 348, g1799 (2014).

  231. 231.

    Tesfaye, S., Boulton, A. J. M. & Dickenson, A. H. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care 36, 2456–2465 (2013).

  232. 232.

    Lauria, G. & Devigili, G. Skin biopsy as a diagnostic tool in peripheral neuropathy. Nat. Clin. Pract. Neurol. 3, 546–557 (2007).

Download references

Acknowledgements

E.L.F. acknowledges support from the NIH (R24DK082841 and R01D107956) and the NovoNordisk Foundation (NNF14OC0011633). B.C.C. acknowledges support from the NIH (K23NS079417 and R01DK115687) and a VA Clinical Science Research and Development (CSRD) Merit (CX001504). R.P.B. acknowledges support from the NIH (R01D107956). D.W.Z. acknowledges support from the Canadian Institutes of Health Research (RN192747-298730) and Diabetes Canada (RN271389-OG-3-15-5025-DZ). D.E.W. acknowledges support from the NIH (R01NS0433314-14). D.L.B. acknowledges support from the NovoNordisk Foundation (NNF14OC0011633) and the Wellcome Trust (102645/Z/13/Z, 202747/Z/16/Z) and is a member of the DOLORisk Consortium funded by the European Commission Horizon 2020 (ID633491). J.W.R. acknowledges support from the NIH (R01DK107007), the US Department of Veterans Affairs (101RX001030), the Diabetes Action Research and Education Foundation and the Baltimore Geriatric Research Education and Clinical Center (GRECC). The authors thank S. Sakowski Jacoby for manuscript preparation and editorial assistance.

Author information

Introduction (E.L.F.); Epidemiology (B.C.C. and E.L.F.); Diagnosis, screening and prevention (B.C.C. and V.B.); Mechanisms/pathophysiology of diabetic neuropathy (D.W.Z., D.E.W. and E.L.F.); Mechanisms/pathophysiology of pain (D.L.B.); Management (R.P.-B., J.W.R. and E.L.F.); Quality of life (V.V.); Outlook (E.L.F.); Overview of the Primer (E.L.F.).

Correspondence to Eva L. Feldman.

Ethics declarations

Competing interests

B.C.C. consults for a Patient-Centered Outcomes Research Institute (PCORI) grant, the Immune Tolerance Network and DynaMed and performs medical legal consultations. D.L.B. has undertaken consultancy work on behalf of Oxford Innovation for Abide, Biogen, GSK, Lilly, Mitsubishi Tanabe, Mundipharma, Teva and Theranexus. All other authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading