A Review on Mechanistic and Pharmacological Findings of Diabetic Peripheral Neuropathy including Pharmacotherapy

Ruchi       Tiwari; Pranay       Wal; Priya       Singh; Gaurav       Tiwari; Awani       Rai
Abstract

Background: Chronic hyperglycemia and related complications involving peripheral nerves in diabetes are one of the most severe microvascular complications with an average prevalence of 50–60%. Diabetic neuropathy is among the vascular disorders of diabetes, the most debilitating and crippled, lethal condition impacting patients’s quality of life.
Methods: In the present review article, several hypotheses associated with the pathogenesis of Diabetic Peripheral Neuropathy (DPN) have been introduced, among them metabolic pathways associated with polyol pathway, oxidative stress, production of reactive oxygen species (ROS) amplified under chronic hyperglycemic conditions and activation of transcription factor Nuclear factor-κB (NF- κB). The review article also possesses pathogenetic and pharmacologic treatments along with others, including acupressure, lidocaine, and capsaicin for DPN.
Conclusion: It may be concluded that we can combat the pathogenesis of DPN with different suggested treatments.
Keywords: Diabetic peripheral neuropathy, pathogenesis of DPN, available treatments, pathogenetic treatments, symptomatic treatments, herbal treatments, supporting literatures.
[1] 
Bhadada SK, Sahay RK, Jyotsna VP, Agrawal JK. Diabetic Neuropathy: Current Concepts. Ind Acad Clin Med  2001; 2(4): 305-17.
[2] 
Jambart S, Ammache Z, Haddad F, et al. Prevalence of painful diabetic peripheral neuropathy among patients with diabetes mellitus in the Middle East region. J Int Med Res  2011; 39(2): 366-77.
[http://dx.doi.org/10.1177/147323001103900204] [PMID: 21672340] 
[3] 
Jordon WR, Crabtree HH. Paralysis of bladder in diabetic subjects. Arch Intern Med (Chic)  1935; 55(1): 17.
[http://dx.doi.org/10.1001/archinte.1935.00160190020003] 
[4] 
Zochodne DW, Malik RA. Diabetes and the nervous system.Handbook of Clinical Neuroloty.  Elsevier B.V. 2014; pp. 2-615.
[5] 
Cohen K, Shinkazh N, Frank J, Israel I, Fellner C. Pharmacological treatment of diabetic peripheral neuropathy. P&T  2015; 40(6): 372-88.
[PMID: 26045647] 
[6] 
Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic Neuropathy: A position statement by the American diabetes association. Diabetes Care  2017; 40(1): 136-54.
[http://dx.doi.org/10.2337/dc16-2042] [PMID: 27999003] 
[7] 
Obrosova IG. Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics  2009; 6(4): 638-47.
[http://dx.doi.org/10.1016/j.nurt.2009.07.004] [PMID: 19789069] 
[8] 
Tscherter A, David F, Ivanova T, et al. Minimal alterations in T-type calcium channel gating markedly modify physiological firing dynamics. J Physiol  2011; 589(Pt 7): 1707-24.
[http://dx.doi.org/10.1113/jphysiol.2010.203836] [PMID: 21320888] 
[9] 
Sadosky A, Schaefer C, Mann R, et al. Burden of illness associated with painful diabetic peripheral neuropathy among adults seeking treatment in the US: results from a retrospective chart review and cross-sectional survey. Diabetes Metab Syndr Obes  2013; 6: 79-92.
[http://dx.doi.org/10.2147/DMSO.S37415] [PMID: 23403729] 
[10] 
Gore M, Brandenburg NA, Hoffman DL, Tai KS, Stacey B. Burden of illness in painful diabetic peripheral neuropathy: the patients’ perspectives. J Pain  2006; 7(12): 892-900.
[http://dx.doi.org/10.1016/j.jpain.2006.04.013] [PMID: 17157775] 
[11] 
Callaghan BC, Kerber KA, Lisabeth LL, et al. Role of neurologists and diagnostic tests on the management of distal symmetric polyneuropathy. JAMA Neurol  2014; 71(9): 1143-9.
[http://dx.doi.org/10.1001/jamaneurol.2014.1279] [PMID: 25048157] 
[12] 
Abbott CA, Malik RA, van Ross ERE, Kulkarni J, Boulton AJ. 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.
[http://dx.doi.org/10.2337/dc11-1108] [PMID: 21852677] 
[13] 
Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant α-lipoic acid: a meta-analysis. Diabet Med  2004; 21(2): 114-21.
[http://dx.doi.org/10.1111/j.1464-5491.2004.01109.x] [PMID: 14984445] 
[14] 
Bril V, Buchanan RA. Long-term effects of ranirestat (AS-3201) on peripheral nerve function in patients with diabetic sensorimotor polyneuropathy. Diabetes Care  2006; 29(1): 68-72.
[http://dx.doi.org/10.2337/diacare.29.01.06.dc05-1447] [PMID: 16373898] 
[15] 
Callaghan BC, Price RS, Chen KS, Feldman EL. The importance of rare subtypes in diagnosis and treatment of peripheral neuropathy: a review. JAMA Neurol  2015; 72(12): 1510-8.
[http://dx.doi.org/10.1001/jamaneurol.2015.2347] [PMID: 26437251] 
[16] 
Myers RR, Campana WM, Shubayev VI. The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets. Drug Discov Today  2006; 11(1-2): 8-20.
[http://dx.doi.org/10.1016/S1359-6446(05)03637-8] [PMID: 16478686] 
[17] 
Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care  2011; 34(9): 2054-60.
[http://dx.doi.org/10.2337/dc11-0503] [PMID: 21775755] 
[18] 
Attal N, Cruccu G, Baron R, et al. European Federation of Neurological Societies. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol  2010; 17(9): 1113-e88.
[http://dx.doi.org/10.1111/j.1468-1331.2010.02999.x] [PMID: 20402746] 
[19] 
Zhang XL, Feng YL, Zhou BA, Wei GY. Effects of mecobalamin and a-lipoic acid on diabetic peripheral neuropathy. Shandong Yiyao  2009; 49: 48-9.
[20] 
Suo LN, Zhang D. Effects of lipoic acid and mecobalamin on diabetic peripheral neuropathy. J Tradit Chin Med  2009; 24: 1104-5.
[21] 
Andrew JMB. Management of diabetic peripheral neuropathy. Clin Diabetes  2005; 23(1): 9-15.
[http://dx.doi.org/10.2337/diaclin.23.1.9] 
[22] 
Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: Mechanisms to management. Pharmacol Ther  2008; 120(1): 1-34.
[http://dx.doi.org/10.1016/j.pharmthera.2008.05.005] [PMID: 18616962] 
[23] 
Iyer S, Tanenberg RJ. Pharmacologic management of diabetic peripheral neuropathic pain. Expert Opin Pharmacother  2013; 14(13): 1765-75.
[http://dx.doi.org/10.1517/14656566.2013.811490] [PMID: 23800105] 
[24] 
Oyenihi AB, Ayeleso AO, Mukwevho E, Masola B. Antioxidant strategies in the management of diabetic neuropathy. BioMed Res Int  2015; 2015515042.
[http://dx.doi.org/10.1155/2015/515042] [PMID: 25821809] 
[25] 
Thornalley PJ. The potential role of thiamine (vitamin B1) in diabetic complications. Curr Diabetes Rev  2005; 1(3): 287-98.
[http://dx.doi.org/10.2174/157339905774574383] [PMID: 18220605] 
[26] 
Winkler G, Pál B, Nagybéganyi E, Ory I, Porochnavec M, Kempler P. Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Arzneimittelforschung  1999; 49(3): 220-4.
[PMID: 10219465] 
[27] 
Dobretsov M, Backonja MM, Romanovsky D, Stimers JR. Animal models of diabetic neuropathic pain. Neuromethods  2011; 49: 147-69.
[http://dx.doi.org/10.1007/978-1-60761-880-5_9] 
[28] 
Balducci S, Iacobellis G, Parisi L, et al. Exercise training can modify the natural history of diabetic peripheral neuropathy. J Diabetes Complications  2006; 20(4): 216-23.
[http://dx.doi.org/10.1016/j.jdiacomp.2005.07.005] [PMID: 16798472] 
[29] 
Soskić SS, Dobutović BD, Sudar EM, et al. Regulation of inducible nitric oxide synthase (iNOS) and its potential role in insulin resistance, diabetes and heart failure. Open Cardiovasc Med J  2011; 5: 153-63.
[http://dx.doi.org/10.2174/1874192401105010153] [PMID: 21792376] 
[30] 
Woelk H, Lehrl S, Bitsch R, Köpcke W. Benfotiamine in treatment of alcoholic polyneuropathy: an 8-week randomized controlled study (BAP I Study). Alcohol Alcohol  1998; 33(6): 631-8.
[http://dx.doi.org/10.1093/alcalc/33.6.631] [PMID: 9872352] 
[31] 
Kumar A, Sharma SS. NF-kappaB inhibitory action of resveratrol: a probable mechanism of neuroprotection in experimental diabetic neuropathy. Biochem Biophys Res Commun  2010; 394(2): 360-5.
[http://dx.doi.org/10.1016/j.bbrc.2010.03.014] [PMID: 20211601] 
[32] 
Tripathi KD. Essentials of Medical Pharmacology.  6th ed. Jaypee Publication 2004; pp. 254-, 266-269.
[33] 
Vincent T, Robin L. Pain Fainsinger, in Palliative Care (Second Edition).  2011.
[34] 
Mitchell KF, Jeffrey AG, Leonard BK. Challenging neuropathic pain syndromes.  Elsevier 2018; pp. 105-11.
[35] 
Marks DM, Shah MJ, Patkar AA, Masand PS, Park GY, Pae CU. Serotonin-norepinephrine reuptake inhibitors for pain control: premise and promise. Curr Neuropharmacol  2009; 7(4): 331-6.
[http://dx.doi.org/10.2174/157015909790031201] [PMID: 20514212] 
[36] 
Ganesh Yerra V, Negi G, Sharma SS, Kumar A. Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy. Redox Biol  2013; 1: 394-7.
[http://dx.doi.org/10.1016/j.redox.2013.07.005] [PMID: 24024177] 
[37] 
Sandireddy R, Yerra VG, Areti A, Komirishetty P, Kumar A. Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets. Int J Endocrinol  2014; 2014674987
[http://dx.doi.org/10.1155/2014/674987] [PMID: 24883061] 
[38] 
Vranken JH. Mechanisms and treatment of neuropathic pain. Cent Nerv Syst Agents Med Chem  2009; 9(1): 71-8.
[http://dx.doi.org/10.2174/187152409787601932] [PMID: 20021340] 
[39] 
Brines M, Dunne AN, van Velzen M, et al. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med  2015; 20(1): 658-66.
[http://dx.doi.org/10.2119/molmed.2014.00215] [PMID: 25387363] 
[40] 
Sandberg M, Lundeberg T, Lindberg LG, Gerdle B. Effects of acupuncture on skin and muscle blood flow in healthy subjects. Eur J Appl Physiol  2003; 90(1-2): 114-9.
[http://dx.doi.org/10.1007/s00421-003-0825-3] [PMID: 12827364] 
[41] 
Amato Nesbit S, Sharma R, Waldfogel JM, et al. Non-pharmacologic treatments for symptoms of diabetic peripheral neuropathy: a systematic review. Curr Med Res Opin  2019; 35(1): 15-25.
[http://dx.doi.org/10.1080/03007995.2018.1497958] [PMID: 30114983] 
[42] 
Javed S, Petropoulos IN, Alam U, Malik RA. Treatment of painful diabetic neuropathy. Ther Adv Chronic Dis  2015; 6(1): 15-28.
[http://dx.doi.org/10.1177/2040622314552071] [PMID: 25553239] 
[43] 
Tobinick E, Davoodifar S. Efficacy of etanercept delivered by perispinal administration for chronic back and/or neck disc-related pain: a study of clinical observations in 143 patients. Curr Med Res Opin  2004; 20(7): 1075-85.
[http://dx.doi.org/10.1185/030079903125004286] [PMID: 15265252] 
[44] 
Wang X, Lin H, Xu S, Jin Y, Zhang R. Alpha lipoic acid combined with epalrestat: a therapeutic option for patients with diabetic peripheral neuropathy. Drug Des Devel Ther  2018; 12: 2827-40.
[http://dx.doi.org/10.2147/DDDT.S168878] [PMID: 30233145] 
[45] 
Ghavami H, Radfar M, Soheily S, Shamsi SA, Khalkhali HR. Effect of lifestyle interventions on diabetic peripheral neuropathy in patients with type 2 diabetes, result of a randomized clinical trial. Agri  2018; 30(4): 165-70.
[http://dx.doi.org/10.5505/agri.2018.45477] [PMID: 30403270] 
[46] 
Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev  2019; 1(1): CD007076.
[PMID: 30673120] 
[47] 
Ziegler D, Keller J, Maier C. German diabetes association, “Diabetic neuropathy. Exp Clin Endocrinol Diabetes Off J Ger Soc Endocrinol Ger Diabetes Assoc  2014; 122: 406-15.
[48] 
Noori SA, Aiyer R, Yu J, White RS, Mehta N, Gulati A. Nonopioid versus opioid agents for chronic neuropathic pain, rheumatoid arthritis pain, cancer pain and low back pain. Pain Manag  2019; 9(2): 205-16.
[http://dx.doi.org/10.2217/pmt-2018-0052] [PMID: 30681031] 
[49] 
Mottaghi T, Khorvash F, Maracy M, Bellissimo N, Askari G. Effect of folic acid supplementation on nerve conduction velocity in diabetic polyneuropathy patients. Neurol Res  2019; 41(4): 364-8.
[http://dx.doi.org/10.1080/01616412.2019.1565180] [PMID: 30730785] 
[50] 
Camargo CR, Schoueri JHM, Alves BDCA, Veiga GRLD, Fonseca FLA, Bacci MR. Uremic neuropathy: an overview of the current literature. Rev Assoc Med Bras (1992)  2019; 65(2): 281-6.
[http://dx.doi.org/10.1590/1806-9282.65.2.281] [PMID: 30892456] 
[51] 
Amin P, Sturrock ND. A pilot study of the beneficial effects of amantadine in the treatment of painful diabetic peripheral neuropathy. Diabet Med  2003; 20(2): 114-8.
[http://dx.doi.org/10.1046/j.1464-5491.2003.00882.x] [PMID: 12581262] 
[52] 
Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain  2004; 110(3): 628-38.
[http://dx.doi.org/10.1016/j.pain.2004.05.001] [PMID: 15288403] 
[53] 
Zhang DW, Fu M, Gao SH, Liu JL. Curcumin and diabetes: a systematic review. Evid Based Complement Alternat Med  2013; 2013636053
[http://dx.doi.org/10.1155/2013/636053] [PMID: 24348712] 
[54] 
Sen S, Querques MA, Chakrabarti S. North American Ginseng (Panax quinquefolius) prevents hyperglycemia and associated pancreatic abnormalities in diabetes. J Med Food  2013; 16(7): 587-92.
[http://dx.doi.org/10.1089/jmf.2012.0192] [PMID: 23875898] 
[55] 
Wirasathien L, Pengsuparp T, Suttisri R, Ueda H, Moriyasu M, Kawanishi K. Inhibitors of aldose reductase and advanced glycation end-products formation from the leaves of Stelechocarpus cauliflorus R.E. Fr. Phytomedicine  2007; 14(7-8): 546-50.
[http://dx.doi.org/10.1016/j.phymed.2006.09.001] [PMID: 17084603] 
[56] 
Giribabu N, Karim K, Kilari EK, Kassim NM, Salleh N. Anti-inflammatory, antiapoptotic and proproliferative effects of vitis vinifera seed ethanolic extract in the liver of streptozotocin-nicotinamide-induced type 2 diabetes in male rats. Can J Diabetes  2018; 42(2): 138-49.
[http://dx.doi.org/10.1016/j.jcjd.2017.04.005] [PMID: 28673757] 
[57] 
Choudhury H, Pandey M, Hua CK, et al. An update on natural compounds in the remedy of diabetes mellitus: A systematic review. J Tradit Complement Med  2017; 8(3): 361-76.
[http://dx.doi.org/10.1016/j.jtcme.2017.08.012] [PMID: 29992107] 
[58] 
Musabayane CT. The effects of medicinal plants on renal function and blood pressure in diabetes mellitus. Cardiovasc J Afr  2012; 23(8): 462-8.
[http://dx.doi.org/10.5830/CVJA-2012-025] [PMID: 23044503] 
[59] 
Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain  2004; 110(3): 697-706.
[http://dx.doi.org/10.1016/j.pain.2004.05.010] [PMID: 15288411] 
[60] 
Sima AA, Calvani M, Mehra M, Amato A. Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care  2005; 28(1): 89-94.
[http://dx.doi.org/10.2337/diacare.28.1.89] [PMID: 15616239] 
[61] 
Haupt E, Ledermann H, Köpcke W. Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study). Int J Clin Pharmacol Ther  2005; 43(2): 71-7.
[http://dx.doi.org/10.5414/CPP43071] [PMID: 15726875] 
[62] 
Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev  2005; 19(4)CD003345
[http://dx.doi.org/10.1002/14651858.CD003345.pub2] [PMID: 16235318] 
[63] 
Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care  2006; 29(11): 2365-70.
[http://dx.doi.org/10.2337/dc06-1216] [PMID: 17065669] 
[64] 
Thisted RA, Klaff L, Schwartz SL, et al. Dextromethorphan and quinidine in adult patients with uncontrolled painful diabetic peripheral neuropathy: a 29-day, multicenter, open-label, dose-escalation study. Clin Ther  2006; 28(10): 1607-18.
[http://dx.doi.org/10.1016/j.clinthera.2006.10.005] [PMID: 17157116] 
[65] 
Rodríguez MJ, Díaz S, Vera-Llonch M, Dukes E, Rejas J. Cost-effectiveness analysis of pregabalin versus gabapentin in the management of neuropathic pain due to diabetic polyneuropathy or post-herpetic neuralgia. Curr Med Res Opin  2007; 23(10): 2585-96.
[http://dx.doi.org/10.1185/030079907X233151] [PMID: 17875242] 
[66] 
Agarwal S, Polydefkis M, Block B, Haythornthwaite J, Raja SN. Transdermal fentanyl reduces pain and improves functional activity in neuropathic pain states. Pain Med  2007; 8(7): 554-62.
[http://dx.doi.org/10.1111/j.1526-4637.2006.00246.x] [PMID: 17883740] 
[67] 
Kadiroglu AK, Sit D, Kayabasi H, Tuzcu AK, Tasdemir N, Yilmaz ME. The effect of venlafaxine HCl on painful peripheral diabetic neuropathy in patients with type 2 diabetes mellitus. J Diabetes Complications  2008; 22(4): 241-5.
[http://dx.doi.org/10.1016/j.jdiacomp.2007.03.010] [PMID: 18413214] 
[68] 
Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials. BMC Neurol  2008; 8: 29.
[http://dx.doi.org/10.1186/1471-2377-8-29] [PMID: 18673529] 
Cite As
Current Diabetes Reviews

A Review on Mechanistic and Pharmacological Findings of Diabetic Peripheral Neuropathy including Pharmacotherapy

Abstract
