Diabetic peripheral neuropathy: pain management


  • Chrystal D. Antoine-Frank Department of Anatomical Sciences, St. George’s University, True Blue, Grand Anse, St. George, Grenada, West Indies
  • Kaydeonne T. Ellis Torbay Hospital, Torbay and South Devon NHS Foundation Trust, United Kingdom
  • Malcolm R. Antoine Department of Microbiology, St. George’s University, True Blue, Grand Anse, St. George, Grenada, West Indies
  • Pars Daniel Annan Department of Pharmacy, Scarborough General Hospital, Signal Hill, Tobago
  • Rimanatou Seyni-Boureima Department of Anaesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China




Diabetic peripheral neuropathy, Diabetes mellitus, Complications of diabetes mellitus


As diabetes mellitus continues to be a global health issue, more and more cases of macro-vascular and micro-vascular complications are being commonly observed amongst this category of patients. One micro-vascular complication often seen in diabetic patients is diabetic neuropathy as at least 50% of diabetic patients will experience some form of neuropathy following a diagnosis of diabetes for about 25 years. Even though diabetic patients are at risk for developing various types of neuropathies, polyneuropathies are most commonly observed and develop mainly develop due to hyperglycaemia, dyslipidemia and abnormal insulin signaling. Polyneuropathies are commonly accompanied by bilateral sensory loss in the distal limbs. Varying degrees of pain are also observed with this complication and pain management may serve to be very complicated. Therefore, this review discusses neuropathy focusing specifically on the effective management of the pain that commonly accompanies this diabetic complication.    


Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol. 2017;13(4):208-19.

Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88-98.

IDF Diabetes Atlas 9th edition 2019 [Internet]. [cited 2020 Apr 24]. Available at: https://diabetesatlas.org/en.

Huang D, Refaat M, Mohammedi K, Jayyousi A, Al Suwaidi J, Abi Khalil C. Macrovascular Complications in Patients with Diabetes and Prediabetes [Internet]. Vol. 2017, BioMed Research International. Hindawi; 2017 [cited 2020 Apr 24]. p. e7839101. Available at: https://www.hindawi.com/journals/bmri/2017/7839101.

Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Practice. 2000;47(2):123-8.

Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurology. 2012;11(6):521-34.

Vincent AM, Hinder LM, Pop‐Busui R, Feldman EL. Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J Peripheral Nervous System. 2009;14(4):257-67.

Sima AAF, Zhang W, Grunberger G. Type 1 Diabetic Neuropathy and C-peptide [Internet]. Vol. 5, Experimental Diabesity Research. Hindawi; 5 [cited 2020 Apr 26]. p. e15438600490424540. Available at: https://www.hindawi.com/journals/jdr/2004/476429.

Kim B, Feldman EL. Insulin resistance in the nervous system. Trends Endocrinology Metabolism. 2012;23(3):133-41.

Vincent AM, Russell JW, Low P, Feldman EL. Oxidative Stress in the Pathogenesis of Diabetic Neuropathy. Endocr Rev. 2004;25(4):612-28.

Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol. 2011;7(10):573-83.

Tattersall R. Alpha-glucosidase inhibition as an adjunct to the treatment of type 1 diabetes. Diabet Med. 1993;10(8):688-93.

Issad T, Kuo M. O-GlcNAc modification of transcription factors, glucose sensing and glucotoxicity. Trends Endocrinology Metabolism. 2008;19(10):380-9.

Duran-Jimenez B, Dobler D, Moffatt S, Rabbani N, Streuli CH, Thornalley PJ, et al. Advanced Glycation End Products in Extracellular Matrix Proteins Contribute to the Failure of Sensory Nerve Regeneration in Diabetes. Diabetes. 2009;58(12):2893-903.

Miyazawa T, Nakagawa K, Shimasaki S, Nagai R. Lipid glycation and protein glycation in diabetes and atherosclerosis. Amino Acids. 2012;42(4):1163-70.

Vincent AM, Perrone L, Sullivan KA, Backus C, Sastry AM, Lastoskie C, et al. Receptor for Advanced Glycation End Products Activation Injures Primary Sensory Neurons via Oxidative Stress. Endocrinology. 2007;148(2):548-58.

Drel VR, Pacher P, Stevens MJ, Obrosova IG. Aldose reductase inhibition counteracts nitrosative stress and poly (ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. Free Radical Biology Med. 2006;40(8):1454-65.

Obrosova IG. Diabetes and the peripheral nerve. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2009;1792(10):931-40.

Yagihashi S, Yamagishi SI, Wada R. Pathology and pathogenetic mechanisms of diabetic neuropathy: Correlation with clinical signs and symptoms. Diabetes Res Clinical Practice. 2007;77(3):184-9.

Veves A, King GL. Can VEGF reverse diabetic neuropathy in human subjects? J Clin Invest. 2001;107(10):1215-8.

Arikawa E, Ma RCW, Isshiki K, Luptak I, He Z, Yasuda Y, et al. Effects of insulin replacements, inhibitors of angiotensin, and PKC beta’s actions to normalize cardiac gene expression and fuel metabolism in diabetic rats. Diabetes. 2007;56(5):1410-20.

Evcimen DN, King GL. The role of protein kinase C activation and the vascular complications of diabetes. Pharmacol Res. 2007;55(6):498-510.

Edwards AS, Faux MC, Scott JD, Newton AC. Carboxyl-terminal Phosphorylation Regulates the Function and Subcellular Localization of Protein Kinase C βII. J Biol Chem. 1999;274(10):6461-8.

Williams B, Gallacher B, Patel H, Orme C. Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes. 1997;46(9):1497-503.

Nakamura J, Kato K, Hamada Y, Nakayama M, Chaya S, Nakashima E, et al. A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes. 1999;48(10):2090-5.

Cortright RN, Azevedo JL, Zhou Q, Sinha M, Pories WJ, Itani SI, et al. Protein kinase C modulates insulin action in human skeletal muscle. Am J Physiol Endocrinol Metab. 2000;278(3):553-62.

K N, C R-M, N T, Sw H, K S, Kj W, et al. Activation of Vascular Protein Kinase C-beta Inhibits Akt-dependent Endothelial Nitric Oxide Synthase Function in Obesity-Associated Insulin Resistance [Internet]. Vol. 55, Diabetes. Diabetes; 2006 [cited 2020 Jun 22]. Available at: https://pubmed.ncbi.nlm.nih.gov/16505232.

Padilla A, Descorbeth M, Almeyda AL, Payne K, Leon DM. Hyperglycemia magnifies Schwann cell dysfunction and cell death triggered by PA-induced lipotoxicity. Brain Research. 2011;1370:64-79.

McCall KD, Holliday D, Dickerson E, Wallace B, Schwartz AL, Schwartz C, et al. Phenylmethimazole blocks palmitate-mediated induction of inflammatory cytokine pathways in 3T3L1 adipocytes and RAW 264.7 macrophages. J Endocrinology. 2010;207(3):343.

Vincent AM, Hayes JM, McLean LL, Vivekanandan-Giri A, Pennathur S, Feldman EL. Dyslipidemia-Induced Neuropathy in Mice: The Role of oxLDL/LOX-1. Diabetes. 2009;58(10):2376-85.

Jang ER, Lee CS. 7-Ketocholesterol induces apoptosis in differentiated PC12 cells via reactive oxygen species-dependent activation of NF-κB and Akt pathways. Neurochemistry Int. 2011;58(1):52-9.

Viader A, Sasaki Y, Kim S, Strickland A, Workman CS, Yang K, et al. Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron. 2013;77(5):886-98.

Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):1-18.

Rumora AE, Lentz SI, Hinder LM, Jackson SW, Valesano A, Levinson GE, et al. Dyslipidemia impairs mitochondrial trafficking and function in sensory neurons. FASEB J. 2018;32(1):195-207.

Legrand-Poels S, Esser N, L’homme L, Scheen A, Paquot N, Piette J. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochemical Pharmacol. 2014;92(1):131-41.

Brussee V, Cunningham FA, Zochodne DW. Direct Insulin Signaling of Neurons Reverses Diabetic Neuropathy. Diabetes. 2004;53(7):1824-30.

Sugimoto K, Murakawa Y, Zhang W, Xu G, Sima AA. Insulin receptor in rat peripheral nerve: its localization and alternatively spliced isoforms. Diabetes Metab Res Rev. 2000;16(5):354-63.

Toth C, Brussee V, Martinez JA, McDonald D, Cunningham FA, Zochodne DW. Rescue and regeneration of injured peripheral nerve axons by intrathecal insulin. Neuroscience. 2006;139(2):429-49.

Xu QG, Li XQ, Kotecha SA, Cheng C, Sun HS, Zochodne DW. Insulin as an in vivo growth factor. Experimental Neurology. 2004;188(1):43-51.

Fernyhough P, Willars GB, Lindsay RM, Tomlinson DR. Insulin and insulin-like growth factor I enhance regeneration in cultured adult rat sensory neurones. Brain Res. 1993;607(1-2):117-24.

Kim H, Kim J, Yoon Y. Emerging Therapy for Diabetic Neuropathy: Cell Therapy Targeting Vessels and Nerves. Endocrine Metabolic Immune Disorders Drug Targets. 2012;12(2):168-78.

Nowicki M, Kosacka J, Serke H, Blüher 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 Neuroscience Res. 2012;90(1):122-31.

Coppey L, Gellett J, Davidson E, Dunlap J, Lund D, Yorek M. 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. 2001;50(8):1927-37.

Schratzberger P, Walter DH, Rittig K, Bahlmann FH, Pola R, Curry C, et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest. 2001;107(9):1083-92.

Abbott CA, Malik RA, Ross EREV, Kulkarni J, Boulton AJM. Prevalence and Characteristics of Painful Diabetic Neuropathy in a Large Community-Based Diabetic Population in the U. K. Diabetes Care. 2011;34(10):2220-4.

Hehn VCA, Baron R, Woolf CJ. Deconstructing the Neuropathic Pain Phenotype to Reveal Neural Mechanisms. Neuron. 2012;73(4):638-52.

Khdour MR. Treatment of diabetic peripheral neuropathy: a review. J Pharmacy Pharmacol. 2020;72(7):863-72.

Ong CK, Forbes D. Embracing Cicely Saunders’s concept of total pain. BMJ. 2005;331(7516):576-7.

Cohen K, Shinkazh N, Frank J, Israel I, Fellner C. Pharmacological Treatment of Diabetic Peripheral Neuropathy. P T. 2015;40(6):372-88.

Obata H. Analgesic Mechanisms of Antidepressants for Neuropathic Pain. Int J Mol Sci [Internet]. 2017 Nov 21 [cited 2020 Nov 23];18(11). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713449.

Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17(9):1113-88.

Alam U, Sloan G, Tesfaye S. Treating Pain in Diabetic Neuropathy: Current and Developmental Drugs. Drugs. 2020;80(4):363-84.

Vinik AI. Diagnosis and management of diabetic neuropathy. Clin Geriatr Med. 1999;15(2):293-320.

Edwards JL, Vincent A, Cheng T, Feldman EL. Diabetic Neuropathy: Mechanisms to Management. Pharmacol Ther. 2008;120(1):1-34.

Suvas S. Role of Substance P neuropeptide in inflammation, wound healing and tissue homeostasis. J Immunol. 2017;199(5):1543-52.

Diabetic Neuropathy: Practice Essentials, Background, Anatomy. 2020 Nov 25 [cited 2020 Dec 7]; Available at: https://emedicine.medscape.com/article/1170337-overview.

Barrett SL, Nickerson DS. Nerve Decompression Surgery Can Reverse Neuropathy of the Foot [Internet]. Practical Pain Management. [cited 2020 Dec 7]. Available at: https://www.practicalpainmanagement.com/pain/neuropathic/diabetic-neuropathy/nerve-decompression-surgery-can-reverse-neuropathy-foot.

Association AD. Dyslipidemia Management in Adults with Diabetes. Diabetes Care. 2004;27(1):68-71.






Review Articles