Abstract
Diabetic painless and painful peripheral neuropathy remains the most frequent complication of diabetes mellitus, but the pathophysiology remains undescribed, there are no robust clinical endpoints and no efficient treatment exists. This hampers good clinical practice, fruitful clinical research and successful pharmacological trials, necessary for the development of early detection, prevention and treatment. This chapter supplies an update on background and treatment of diabetic peripheral neuropathy. Goals and perspectives for future clinical and scientific approaches are also described.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Albrecht PJ, Houk G, Ruggiero E, Dockum M, Czerwinski M, Betts J et al (2021) Keratinocyte biomarkers distinguish painful diabetic peripheral neuropathy patients and correlate with topical lidocaine responsiveness. Front Pain Res 2:102. https://doi.org/10.3389/fpain.2021.790524
Armstrong DG, Cohen K, Courric S, Bharara M, Marston W (2011) Diabetic foot ulcers and vascular insufficiency: our population has changed, but our methods have not. J Diabetes Sci Technol 5:1591–1595. https://doi.org/10.1177/193229681100500636
Armstrong DG, Boulton AJM, Bus SA (2017) Diabetic foot ulcers and their recurrence. N Engl J Med 376:2367–2375. https://doi.org/10.1056/NEJMra1615439
Aslam A, Singh J, Rajbhandari S (2014) Pathogenesis of painful diabetic neuropathy. Pain Res Treat 2014. https://doi.org/10.1155/2014/412041
Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9. https://doi.org/10.2337/diabetes.48.1.1
Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N et al (2008) Opioid complications and side effects. Pain Physician 11. https://doi.org/10.1007/978-3-540-35423-9_14
Black JA, Cummins TR, Plumpton C, Chen YH, Hormuzdiar W, Clare JJ et al (1999) Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J Neurophysiol 82:2776–2785. https://doi.org/10.1152/jn.1999.82.5.2776
Blesneac I, Themistocleous AC, Fratter C, Conrad LJ, Ramirez JD, Cox JJ et al (2018) Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy. Pain 159:469–480. https://doi.org/10.1097/j.pain.0000000000001116
Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J (2005) The global burden of diabetic foot disease. Lancet 366:1719–1724. https://doi.org/10.1016/S0140-6736(05)67698-2
Breiner A, Lovblom LE, Perkins BA, Bril V (2014) Does the prevailing hypothesis that small-fiber dysfunction precedes large-fiber dysfunction apply to type 1 diabetic patients? Diabetes Care 37:1418–1424. https://doi.org/10.2337/dc13-2005
Chalk C, Benstead TJ, Moore F (2007) Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD004572.pub2
Chen SR, Pan HL (2002) Hypersensitivity of spinothalamic tract neurons associated with diabetic neuropathic pain in rats. J Neurophysiol 87:2726–2733. https://doi.org/10.1152/jn.2002.87.6.2726
Cheng KI, Wang HC, Chuang YT, Chou CW, Tu HP, Yu YC et al (2014) Persistent mechanical allodynia positively correlates with an increase in activated microglia and increased P-p38 mitogen-activated protein kinase activation in streptozotocin-induced diabetic rats. Eur J Pain 18:162–173. https://doi.org/10.1002/j.1532-2149.2013.00356.x
Crawford F, Cezard G, Chappell FM, Murray GD, Price JF, Sheikh A et al (2015) A systematic review and individual patient data meta-analysis of prognostic factors for foot ulceration in people with diabetes: the international research collaboration for the prediction of diabetic foot ulcerations (PODUS). Health Technol Assess (Rockv) 19:1–207. https://doi.org/10.3310/hta19570
Demant DT, Lund K, Vollert J, Maier C, Segerdahl M, Finnerup NB et al (2014) The effect of oxcarbazepine in peripheral neuropathic pain depends on pain phenotype: a randomised, double-blind, placebo-controlled phenotype-stratified study. Pain 155:2263–2273. https://doi.org/10.1016/j.pain.2014.08.014
Dhage S, Ferdousi M, Adam S, Ho JH, Kalteniece A, Azmi S et al (2021) Corneal confocal microscopy identifies small fibre damage and progression of diabetic neuropathy. Sci Rep 11:1–9. https://doi.org/10.1038/s41598-021-81302-8
Dogra S, Beydoun S, Mazzola J, Hopwood M, Wan Y (2005) Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study. Eur J Pain 9:543–554. https://doi.org/10.1016/j.ejpain.2004.11.006
Doupis J, Lyons TE, Wu S, Gnardellis C, Dinh T, Veves A (2009) Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy. J Clin Endocrinol Metab 94:2157–2163. https://doi.org/10.1210/jc.2008-2385
Edmonds M, Manu C, Vas P (2021) The current burden of diabetic foot disease. J Clin Orthop Trauma 17:88–93. https://doi.org/10.1016/j.jcot.2021.01.017
Ekberg K, Brismar T, Johansson BL, Lindstr̈om P, Juntti-Berggren L, Norrby A et al (2007) C-peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy. Diabetes Care 30:71–76. https://doi.org/10.2337/dc06-1274
Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL et al (2019) Diabetic neuropathy. Nat Rev Dis Primers 5. https://doi.org/10.1038/s41572-019-0092-1
Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH et al (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14:162–173. https://doi.org/10.1016/S1474-4422(14)70251-0
Gaskell H, Derry S, Stannard C, Moore RA (2016) Oxycodone for neuropathic pain in adults. Cochrane Database Syst Rev 2016. https://doi.org/10.1002/14651858.CD010692.pub3
Giacco F, Brownlee M (2010) Oxidative stress and diabetic complications. Circ Res 107:1058–1070. https://doi.org/10.1161/CIRCRESAHA.110.223545
Griebeler ML, Morey-Vargas OL, Brito JP, Tsapas A, Wang Z, Carranza Leon BG et al (2014) Pharmacologic interventions for painful diabetic neuropathy: an umbrella systematic review and comparative effectiveness network meta-analysis. Ann Intern Med 161:639–649. https://doi.org/10.7326/M14-0511
Gruden G, Bruno G, Chaturvedi N, Burt D, Schalkwijk C, Pinach S et al (2008) Serum heat shock protein 27 and diabetes complications in the EURODIAB prospective complications study: a novel circulating marker for diabetic neuropathy. Diabetes 57:1966–1970. https://doi.org/10.2337/db08-0009
Han T, Bai J, Liu W, Hu Y (2012) A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy. Eur J Endocrinol 167:465–471. https://doi.org/10.1530/EJE-12-0555
Herder C, Bongaerts BWC, Rathmann W, Heier M, Kowall B, Koenig W et al (2013) Association of subclinical inflammation with polyneuropathy in the older population: KORA F4 study. Diabetes Care 36:3663–3670. https://doi.org/10.2337/dc13-0382
Hong S, Morrow TJ, Paulson PE, Isom LL, Wiley JW (2004) Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat. J Biol Chem 279:29341–29350. https://doi.org/10.1074/jbc.M404167200
Hotta N, Akanuma Y, Kawamori R, Matsuoka K, Oka Y, Shichiri M et al (2006) 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. https://doi.org/10.2337/dc05-2370
Javed S, Petropoulos IN, Alam U, Malik RA (2015) Treatment of painful diabetic neuropathy. Ther Adv Chronic Dis 6:15–28. https://doi.org/10.1177/2040622314552071
Karlsson P, Gylfadottir SS, Kristensen AG, Ramirez JD, Cruz P, Le N et al (2021) Axonal swellings are related to type 2 diabetes, but not to distal diabetic sensorimotor polyneuropathy. Diabetologia 64:923–931. https://doi.org/10.1007/s00125-020-05352-9
Kim J, Wei DS, Hoffman DA (2005) Kv4 potassium channel subunits control action potential repolarization and frequency-dependent broadening in rat hippocampal CA1 pyramidal neurones. J Physiol 569:41–57. https://doi.org/10.1113/jphysiol.2005.095042
Kong X, Lesser EA, Potts FA, Gozani SN (2008) Utilization of nerve conduction studies for the diagnosis of polyneuropathy in patients with diabetes: a retrospective analysis of a large patient series. J Diabetes Sci Technol 2:268–274. https://doi.org/10.1177/193229680800200217
Krishnan AV, Lin CSY, Kiernan MC (2008) Activity-dependent excitability changes suggest Na+/K+ pump dysfunction in diabetic neuropathy. Brain 131:1209–1216. https://doi.org/10.1093/BRAIN/AWN052
Lauria G, Devigili G (2007) Skin biopsy as a diagnostic tool in peripheral neuropathy. Nat Clin Pract Neurol 3:546–557. https://doi.org/10.1038/ncpneuro0630
Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G et al (2010) Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst 15:202–207. https://doi.org/10.1111/j.1529-8027.2010.00271.x
Li H-K, Rombach I, Zambellas R, Walker AS, McNally MA, Atkins BL et al (2019) Oral versus intravenous antibiotics for bone and joint infection. N Engl J Med 380:425–436. https://doi.org/10.1056/nejmoa1710926
Libby P, Ridker PM, Maseri A (2002) Inflammation and atherosclerosis. Circulation 105:1135–1143. https://doi.org/10.1161/hc0902.104353
Lunn MPT, Hughes RAC, Wiffen PJ (2014) Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev 2014. https://doi.org/10.1002/14651858.CD007115.pub3
Maddaloni E, Sabatino F (2016) In vivo corneal confocal microscopy in diabetes: where we are and where we can get. World J Diabetes 7:406. https://doi.org/10.4239/wjd.v7.i17.406
Malik RA (2014) Why are there no good treatments for diabetic neuropathy? Lancet Diabetes Endocrinol 2:607–609. https://doi.org/10.1016/S2213-8587(14)70067-1
Malik RA, Kallinikos P, Abbott CA, Van Schie CHM, Morgan P, Efron N et al (2003) Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 46:683–688. https://doi.org/10.1007/s00125-003-1086-8
Maria FLV, Carter RE, Gilbert GE, Klein RL, Jaffa M, Jenkins AJ et al (2008) Risk factors related to inflammation and endothelial dysfunction in the dcct/edic cohort and their relationship with nephropathy and macrovascular complications. Diabetes Care 31:2006–2012. https://doi.org/10.2337/dc08-0659
Mehra S, Tavakoli M, Kallinikos PA, Efron N, Boulton AJM, Augustine T et al (2007) Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care 30:2608–2612. https://doi.org/10.2337/dc07-0870
Misawa S, Sakurai K, Shibuya K, Isose S, Kanai K, Ogino J et al (2009) Neuropathic pain is associated with increased nodal persistent Na + currents in human diabetic neuropathy. J Peripher Nerv Syst 14:279–284. https://doi.org/10.1111/j.1529-8027.2009.00239.x
Musuuza J, Sutherland BL, Kurter S, Balasubramanian P, Bartels CM, Brennan MB (2020) A systematic review of multidisciplinary teams to reduce major amputations for patients with diabetic foot ulcers. J Vasc Surg 71:1433–1446.e3. https://doi.org/10.1016/j.jvs.2019.08.244
Oates PJ (2002) Polyol pathway and diabetic peripheral neuropathy. Int Rev Neurobiol 50. https://doi.org/10.1016/s0074-7742(02)50082-9
Pop-Busui R, Ang L, Holmes C, Gallagher K, Feldman EL (2016) Inflammation as a therapeutic target for diabetic neuropathies. Curr Diab Rep 16:1–10. https://doi.org/10.1007/s11892-016-0727-5
Pop-Busui R, Boulton AJM, Feldman EL, Bril V, Freeman R, Malik RA et al (2017) Diabetic neuropathy: a position statement by the American diabetes association. Diabetes Care 40:136–154. https://doi.org/10.2337/dc16-2042
Røikjer J, Mørch CD, Ejskjaer N (2020a) Diabetic peripheral neuropathy: diagnosis and treatment. Curr. Drug Saf 15. https://doi.org/10.2174/1574886315666200731173113
Røikjer JB, Jensen MH, Vestergaard P, Sørensen AM, Laursen HVB, Ejskjær N (2020b) Twenty years with diabetes and amputations: a retrospective population-based cohort study. Diabet Med:dme.14251. https://doi.org/10.1111/dme.14251
Røikjer J, Werkman NCC, Ejskjaer N, van den Bergh JPW, Vestergaard P, Schaper NC et al (2021) Incidence, hospitalization and mortality and their changes over time in people with a first ever diabetic foot ulcer. Diabet Med. https://doi.org/10.1111/DME.14725
Saarto T, Wiffen PJ (2007) Antidepressants for neuropathic pain. Cochrane Database Syst Rev:CD005454. https://doi.org/10.1002/14651858.CD005454.pub2
Said G, Baudoin D, Toyooka K (2008) Sensory loss, pains, motor deficit and axonal regeneration in length-dependent diabetic polyneuropathy. J Neurol 255:1693–1702. https://doi.org/10.1007/s00415-008-0999-z
Scarborough M, Li HK, Rombach I, Zambellas R, Walker AS, McNally M et al (2019) Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT. Health Technol Assess (Rockv) 23:1–94. https://doi.org/10.3310/hta23380
Schreiber AK (2015) Diabetic neuropathic pain: physiopathology and treatment. World J Diabetes 6:432. https://doi.org/10.4239/wjd.v6.i3.432
Schwartz S, Etropolski M, Shapiro DY, Okamoto A, Lange R, Haeussler J et al (2011) 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. https://doi.org/10.1185/03007995.2010.537589
Selvarajah D, Petrie J, White D, Julious S, Bortolami O, Cooper C et al (2018) Multicentre, double-blind, crossover trial to identify the optimal pathway for TreatIng neurOpathic paiN in diabetes mellitus (OPTION-DM): study protocol for a randomised controlled trial. Trials 19:578. https://doi.org/10.1186/s13063-018-2959-y
Selvarajah D, Wilkinson ID, Fang F, Sankar A, Davies J, Boland E et al (2019) Structural and functional abnormalities of the primary somatosensory cortex in diabetic peripheral neuropathy: a multimodal MRI study. Diabetes 68:796–806. https://doi.org/10.2337/db18-0509
Sheetz MJ, King GL (2002) Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA 288:2579–2588. https://doi.org/10.1001/jama.288.20.2579
Spallone V (2012) Management of painful diabetic neuropathy: guideline guidance or jungle? Curr Diab Rep 12:403–413. https://doi.org/10.1007/s11892-012-0287-2
Stracke H, Lindemann A, Federlin K (1996) A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes 104:311–316. https://doi.org/10.1055/s-0029-1211460
Tesfaye S, Vileikyte L, Rayman G, Sindrup SH, Perkins BA, Baconja M et al (2011) Painful diabetic peripheral neuropathy: consensus recommendations on diagnosis, assessment and management. Diabetes Metab Res Rev 27:629–638. https://doi.org/10.1002/dmrr.1225
Tesfaye S, Wilhelm S, Lledo A, Schacht A, Tölle T, Bouhassira D et al (2013) 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. https://doi.org/10.1016/j.pain.2013.05.043
Vas PRJ, Demetriou M, Papanas N (2019) Oral antibiotic therapy in diabetic foot osteomyelitis: one small step or a giant leap of faith? Ann Transl Med 7:S266–S266. https://doi.org/10.21037/atm.2019.12.53
Vincent AM, Callaghan BC, Smith AL, Feldman EL (2011) Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol 7:573–583. https://doi.org/10.1038/nrneurol.2011.137
Vollert J, Maier C, Attal N, Bennett DLH, Bouhassira D, Enax-Krumova EK et al (2017) Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations. Pain 158:1446–1455. https://doi.org/10.1097/j.pain.0000000000000935
White DM, Zimmermann M (1988) The bradykinin-induced release of substance P from nerve fibre endings in the rat saphenous nerve neuroma is not related to electrophysiological excitation. Neurosci Lett 92:108–113. https://doi.org/10.1016/0304-3940(88)90751-3
Zhang SS, Wu Z, Zhang LC, Zhang Z, Chen RP, Huang YH et al (2015) Efficacy and safety of pregabalin for treating painful diabetic peripheral neuropathy: a meta-analysis. Acta Anaesthesiol Scand 59:147–159. https://doi.org/10.1111/aas.12420
Zhou M, Chen N, He L, Yang M, Zhu C, Wu F (2017) Oxcarbazepine for neuropathic pain. Cochrane Database Syst Rev 2017. https://doi.org/10.1002/14651858.CD007963.pub3
Ziegler D, Bönhof GJ, Strom A, Straßburger K, Karusheva Y, Szendroedi J et al (2021) Progression and regression of nerve fibre pathology and dysfunction early in diabetes over 5 years. Brain 144:3251–3263. https://doi.org/10.1093/brain/awab330
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Røikjer, J., Ejskjaer, N. (2022). Diabetic Peripheral Neuropathy. In: Eckel, J., Clément, K. (eds) From Obesity to Diabetes. Handbook of Experimental Pharmacology, vol 274. Springer, Cham. https://doi.org/10.1007/164_2022_585
Download citation
DOI: https://doi.org/10.1007/164_2022_585
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-99994-0
Online ISBN: 978-3-030-99995-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)