Advances in Pharmaceutical Options and Current Clinical Trials for the Treatment of Painful Diabetic Polyneuropathy

  • Abd A. Tahrani
  • Q. Altaf
  • Martin J. Stevens


Painful neuropathy is a very common diabetes-related complication and is associated with significant morbidity and has a negative impact on patients’ quality of life (QOL). The pathogenesis of diabetic painful neuropathy is complex and remains unclear but involves multiple levels of the peripheral and central nervous systems (CNSs). Despite our improved understanding of the pathogenesis of this condition, there are few disease-modifying treatments. There are several agents currently in use to ameliorate and reduce the impact of pain. These treatments can be used alone or in combination, although data regarding combination therapies are rather limited. Novel therapies are currently in development, some of which are symptomatic and others based on the pathogenesis of painful neuropathy. It is important to have a holistic approach to patients with painful diabetic neuropathy (PDN) and not to focus only on pain relief but to also assess the impact on QOL. In this chapter we review the currently available treatments for PDN and future treatments that are in development and we describe our approach to the management of patients with this troublesome condition.


Diabetic Neuropathy Total Symptom Score Isosorbide Dinitrate Painful Diabetic Neuropathy Ascorbyl Palmitate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Mahmood D, Singh BK, Akhtar M. Diabetic neuropathy: therapies on the horizon. J Pharm Pharmacol. 2009;61(9):1137–45.PubMedCrossRefGoogle Scholar
  2. 2.
    Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia. 2000;43(8):957–73.PubMedCrossRefGoogle Scholar
  3. 3.
    Tesfaye S, Selvarajah D. Recent advances in the pharmacological management of painful diabetic neuropathy. Br J Diabetes Vasc Dis. 2009;9(6):283–7.CrossRefGoogle Scholar
  4. 4.
    Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev. 2012;28:8–14.PubMedCrossRefGoogle Scholar
  5. 5.
    Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy. Diabetes Care. 2008;31(3):464–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Franklin GM, Kahn LB, Baxter J, Marshall JA, Hamman RF. Sensory neuropathy in non-insulin-dependent diabetes mellitus. Am J Epidemiol. 1990;131(4):633–43.PubMedGoogle Scholar
  7. 7.
    Hartemann A, Attal N, Bouhassira D, Dumont I, Gin H, Jeanne S, et al. Painful diabetic neuropathy: diagnosis and management. Diabetes Metab. 2011;37(5):377–88.PubMedCrossRefGoogle Scholar
  8. 8.
    Van Acker K, Bouhassira D, De Bacquer D, Weiss S, Matthys K, Raemen H, 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. 2009;35(3):206–13.PubMedCrossRefGoogle Scholar
  9. 9.
    Zelman DC, Brandenburg NA, Gore M. Sleep impairment in patients with painful diabetic peripheral neuropathy. Clin J Pain. 2006;22(8):681–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Tolle T, Xu X, Sadosky AB. Painful diabetic neuropathy: a cross-sectional survey of health state impairment and treatment patterns. J Diabetes Complications. 2006;20(1):26–33.PubMedCrossRefGoogle Scholar
  11. 11.
    Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract. 2000;47(2):123–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Veves A, Backonja M, Malik RA. Painful diabetic neuropathy: epidemiology, natural history, early diagnosis, and treatment options. Pain Med. 2008;9(6):660–74.PubMedCrossRefGoogle Scholar
  13. 13.
    Orstavik K, Namer B, Schmidt R, Schmelz M, Hilliges M, Weidner C, et al. Abnormal function of C-fibers in patients with diabetic neuropathy. J Neurosci. 2006;26(44):11287–94.PubMedCrossRefGoogle Scholar
  14. 14.
    Schmeichel AM, Schmelzer JD, Low PA. Oxidative injury and apoptosis of dorsal root ganglion neurons in chronic experimental diabetic neuropathy. Diabetes. 2003;52(1):165–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Quattrini C, Harris ND, Malik RA, Tesfaye S. Impaired skin microvascular reactivity in painful diabetic neuropathy. Diabetes Care. 2007;30(3):655–9.PubMedCrossRefGoogle Scholar
  16. 16.
    The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):977–86.Google Scholar
  17. 17.
    Sorensen L, Molyneaux L, Yue DK. Insensate versus painful diabetic neuropathy: the effects of height, gender, ethnicity and glycaemic control. Diabetes Res Clin Pract. 2002;57(1):45–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Boulton AJ, Drury J, Clarke B, Ward JD. Continuous subcutaneous insulin infusion in the management of painful diabetic neuropathy. Diabetes Care. 1982;5(4):386–90.PubMedCrossRefGoogle Scholar
  19. 19.
    Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta. 2009;1790(10):1149–60.PubMedCrossRefGoogle Scholar
  20. 20.
    Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schütte K, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant lipoic acid. Diabetologia. 1995;38(12):1425–33.PubMedCrossRefGoogle Scholar
  21. 21.
    Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, et al. Oral treatment with lipoic acid improves symptomatic diabetic polyneuropathy. Diabetes Care. 2006;29(11):2365–70.PubMedCrossRefGoogle Scholar
  22. 22.
    Reljanovic M, Reichel G, Rett K, Lobisch M, Schuette K, Möller W, et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Free Radic Res. 2009;31(3):171–9.CrossRefGoogle Scholar
  23. 23.
    Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schütte K, 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. 1999;22(8):1296–301.PubMedCrossRefGoogle Scholar
  24. 24.
    Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21(2):114–21.PubMedCrossRefGoogle Scholar
  25. 25.
    Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N, Bilo HJ. Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2012;2012:456279.PubMedGoogle Scholar
  26. 26.
    Ziegler D. Painful diabetic neuropathy. Diabetes Care. 2009;32 Suppl 2:S414–S9.PubMedCrossRefGoogle Scholar
  27. 27.
    Vrethem M, Boivie J, Arnqvist H, Holmgren H, Lindström T, Thorell LH. A comparison of amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Clin J Pain. 1997;13(4):313–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, 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. PM R. 2011;3(4):345–52.PubMedCrossRefGoogle Scholar
  29. 29.
    Max MB. Endogenous monoamine analgesic systems: amitriptyline in painful diabetic neuropathy. Anesth Prog. 1987;34(4):123–7.PubMedGoogle Scholar
  30. 30.
    Max MB, Culnane M, Schafer SC. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987;37(4):589–96.PubMedCrossRefGoogle Scholar
  31. 31.
    Kvinesdal B, Molin J, Froland A, Gram LF. Imipramine treatment of painful diabetic neuropathy. J Am Med Assoc. 1984;251(13):1727–30.CrossRefGoogle Scholar
  32. 32.
    Gomez-Perez FJ, Rull JA, Dies H. Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy. A double-blind cross-over study. Pain. 1985;23(4):395–400.PubMedCrossRefGoogle Scholar
  33. 33.
    Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326(19):1250–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118(3):289–305.PubMedCrossRefGoogle Scholar
  35. 35.
    Ray WA, Meredith S, Thapa PB, Hall K, Murray KT. Cyclic antidepressants and the risk of sudden cardiac death[ast]. Clin Pharmacol Ther. 2004;75(3):234–41.PubMedCrossRefGoogle Scholar
  36. 36.
    Attal N, Cruccu G, Baron R, Haanpaa M, Hansson P, Jensen TS, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2009 revision. Eur J Neurol. 2010;17(9):1113–e88. Epub 2010 Apr 9.PubMedCrossRefGoogle Scholar
  37. 37.
    Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116(1–2):109–18.PubMedCrossRefGoogle Scholar
  38. 38.
    Raskin J, Pritchett YL, Wang F, D’Souza DN, Waninger AL, Iyengar S, et al. A double-blind, randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Pain Med. 2005;6(5):346–56.PubMedCrossRefGoogle Scholar
  39. 39.
    Wernicke JF, Pritchett YL, D’Souza DN, Waninger A, Tran P, Iyengar S, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology. 2006;67(8):1411–20.PubMedCrossRefGoogle Scholar
  40. 40.
    Kajdasz DK, Iyengar S, Desaiah D, Backonja MM, Farrar JT, Fishbain DA, et al. Duloxetine for the management of diabetic peripheral neuropathic pain: evidence-based findings from post hoc analysis of three multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. Clin Ther. 2007;29(11, Supplement 1):2536–46.PubMedCrossRefGoogle Scholar
  41. 41.
    Ziegler D, Pritchett YL, Wang F, Desaiah D, Robinson MJ, Hall JA, et al. Impact of disease characteristics on the efficacy of duloxetine in diabetic peripheral neuropathic pain. Diabetes Care. 2007;30(3):664–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Hardy T, Sachson R, Shen S, Armbruster M, Boulton AJM. Does treatment with duloxetine for neuropathic pain impact glycemic control? Diabetes Care. 2007;30(1):21–6.PubMedCrossRefGoogle Scholar
  43. 43.
    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.PubMedCrossRefGoogle Scholar
  44. 44.
    Simpson DA. Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscul Dis. 2001;3(2):53–62.PubMedCrossRefGoogle Scholar
  45. 45.
    Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280(21):1831–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Gorson KC, Schott C, Herman R, Ropper AH, Rand WM. Gabapentin in the treatment of painful diabetic neuropathy: a placebo controlled, double blind, crossover trial. J Neurol Neurosurg Psychiatry. 1999;66(2):251–2.PubMedCrossRefGoogle Scholar
  47. 47.
    Chou R, Carson S, Chan B. Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: discrepancies between direct and indirect meta-analyses of randomized controlled trials. J Gen Intern Med. 2009;24(2):178–88.PubMedCrossRefGoogle Scholar
  48. 48.
    Freeman R, Durso-DeCruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy. Diabetes Care. 2008;31(7):1448–54.PubMedCrossRefGoogle Scholar
  49. 49.
    Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose–response trials. Anesthesiology. 2002;96(5):1053–61.PubMedCrossRefGoogle Scholar
  50. 50.
    Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology. 1997;48(5):1212–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352(13):1324–34.PubMedCrossRefGoogle Scholar
  52. 52.
    Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50(6):1842–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Sindrup SH, Andersen G, Madsen C, Smith T, Brøsen K, Jensen TS. Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain. 1999;83(1):85–90.PubMedCrossRefGoogle Scholar
  54. 54.
    Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology. 2003;60(6):927–34.PubMedCrossRefGoogle Scholar
  55. 55.
    Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain. 2003;105(1–2):71–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Hanna M, O’Brien C, Wilson MC. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur J Pain. 2008;12(6):804–13.PubMedCrossRefGoogle Scholar
  57. 57.
    Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999;81(1–2):135–45.PubMedCrossRefGoogle Scholar
  58. 58.
    Mason L, Moore RA, Derry S, Edwards JE, McQuay HJ. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004;328(7446):991.PubMedCrossRefGoogle Scholar
  59. 59.
    Argoff CE, Galer BS, Jensen MP, Oleka N, Gammaitoni AR. Effectiveness of the lidocaine patch 5% on pain qualities in three chronic pain states: assessment with the neuropathic pain scale. Curr Med Res Opin. 2004;20 Suppl 2:S21–S8.PubMedCrossRefGoogle Scholar
  60. 60.
    Barbano RL, Herrmann DN, Hart-Gouleau S, Pennella-Vaughan J, Lodewick PA, Dworkin RH. Effectiveness, tolerability, and impact on quality of life of the 5% lidocaine patch in diabetic polyneuropathy. Arch Neurol. 2004;61(6):914–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M. 5% lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study. Curr Med Res Opin. 2009;25(7):1663–76.PubMedCrossRefGoogle Scholar
  62. 62.
    Kochar DK, Rawat N, Agrawal RP, Vyas A, Beniwal R, Kochar SK, et al. Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study. QJM. 2004;97(1):33–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Kochar DK, Jain N, Agarwal RP, Srivastava T, Agarwal P, Gupta S. Sodium valproate in the management of painful neuropathy in type 2 diabetes—a randomized placebo controlled study. Acta Neurol Scand. 2002;106(5):248–52.PubMedCrossRefGoogle Scholar
  64. 64.
    Pitei DL, Watkins PJ, Edmonds ME. NO-dependent smooth muscle vasodilatation is reduced in NIDDM patients with peripheral sensory neuropathy. Diabet Med. 1997;14(4):284–90.PubMedCrossRefGoogle Scholar
  65. 65.
    Rodella L, Rezzani R, Corsetti G, Bianchi R. Nitric oxide involvement in the trigeminal hyperalgesia in diabetic rats. Brain Res. 2000;865(1):112–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Agrawal RP, Choudhary R, Sharma P, Sharma S, Beniwal R, Kaswan K, et al. Glyceryl trinitrate spray in the management of painful diabetic neuropathy: a randomized double blind placebo controlled cross-over study. Diabetes Res Clin Pract. 2007;77(2):161–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Yuen KCJ, Baker NR, Rayman G. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray. Diabetes Care. 2002;25(10):1699–703.PubMedCrossRefGoogle Scholar
  68. 68.
    Rayman G, Baker NR, Krishnan STM. Glyceryl trinitrate patches as an alternative to isosorbide dinitrate spray in the treatment of chronic painful diabetic neuropathy [5]. Diabetes Care. 2003;26(9):2697–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Foster AV, Eaton C, McConville DO, Edmonds ME. Application of OpSite film: a new and effective treatment of painful diabetic neuropathy. Diabet Med. 1994;11(8):768–72.PubMedCrossRefGoogle Scholar
  70. 70.
    Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet. 2010;374(9697):1252–61.CrossRefGoogle Scholar
  71. 71.
    Wilhelm S, Tölle T, Bouhassira D, Perrot S, Kosek E, Micó JA, et al. Initial treatment with duloxetine or pregabaline in patients with painful diabetic neuropathy. Data from the randomised, double-blind, parallel-group COMBO-DN Study. Diabetologia. 2012;55([Suppl1] S26):OP49.Google Scholar
  72. 72.
    Keller DM. No Added Benefit of Duloxetine-Pregabalin Combo in DPNP. http://www.­ Accessed 29 Dec 2012.
  73. 73.
    Morello CM, Leckband SG, Stoner CP, Moorhouse DF, Sahagian GA. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med. 1999;159(16):1931–7.PubMedCrossRefGoogle Scholar
  74. 74.
    Bansal D, Bhansali A, Hota D, Chakrabarti A, Dutta P. Amitriptyline vs. pregabalin in painful diabetic neuropathy: a randomized double blind clinical trial. Diabet Med. 2009;26(10):1019–26.PubMedCrossRefGoogle Scholar
  75. 75.
    Kaur H, Hota D, Bhansali A, Dutta P, Bansal D, Chakrabarti A. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy. Diabetes Care. 2011;34(4):818–22.PubMedCrossRefGoogle Scholar
  76. 76.
    Hotta N, Akanuma Y, Kawamori R, Matsuoka K, Oka Y, Shichiri M, et al. Long-term clinical effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy. Diabetes Care. 2006;29(7):1538–44.PubMedCrossRefGoogle Scholar
  77. 77.
    Valensi P, Le Devehat C, Richard JL, Farez C, Khodabandehlou T, Rosenbloom RA, et al. A multicenter, double-blind, safety study of QR-333 for the treatment of symptomatic diabetic peripheral neuropathy: a preliminary report. J Diabetes Complications. 2005;19(5):247–53.PubMedCrossRefGoogle Scholar
  78. 78.
    Danis RP, Sheetz MJ. Ruboxistaurin: PKC-beta inhibition for complications of diabetes. Expert Opin Pharmacother. 2009;10(17):2913–25.PubMedCrossRefGoogle Scholar
  79. 79.
    Casellini CM, Barlow PM, Rice AL, Casey M, Simmons K, Pittenger G, et al. A 6-month, randomized, double-masked, placebo-controlled study evaluating the effects of the protein kinase C-beta inhibitor ruboxistaurin on skin microvascular blood flow and other measures of diabetic peripheral neuropathy. Diabetes Care. 2007;30(4):896–902.PubMedCrossRefGoogle Scholar
  80. 80.
    Brooks B, Delaney-Robinson C, Molyneaux L, Yue DK. Endothelial and neural regulation of skin microvascular blood flow in patients with diabetic peripheral neuropathy: effect of treatment with the isoform-specific protein kinase C beta inhibitor, ruboxistaurin. J Diabetes Complications. 2008;22(2):88–95.PubMedCrossRefGoogle Scholar
  81. 81.
    Hayase F, Matsuura H, Sanada M, Kitada-Hamada K, Omatsu-Kanbe M, Maeda K, et al. Inhibitory action of protein kinase Cβ inhibitor on tetrodotoxin-resistant Na  +  current in small dorsal root ganglion neurons in diabetic rats. Neurosci Lett. 2007;417(1):90–4.PubMedCrossRefGoogle Scholar
  82. 82.
    Cruccu G. Treatment of painful neuropathy. Curr Opin Neurol. 2007;20(5):531–5.PubMedGoogle Scholar
  83. 83.
    Tahrani AA, Askwith T, Stevens MJ. Emerging drugs for diabetic neuropathy. Expert Opin Emerg Drugs. 2010;15(4):661–83.PubMedCrossRefGoogle Scholar
  84. 84.
    Villetti G, Bergamaschi M, Bassani F, Bolzoni PT, Maiorino M, Pietra C, et al. Antinociceptive activity of the N-methyl-d-aspartate receptor antagonist N-(2-indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain. J Pharmacol Exp Ther. 2003;306(2):804–14.PubMedCrossRefGoogle Scholar
  85. 85.
    Chen SR, Samoriski G, Pan HL. Antinociceptive effects of chronic administration of uncompetitive NMDA receptor antagonists in a rat model of diabetic neuropathic pain. Neuropharmacology. 2009;57(2):121–6.PubMedCrossRefGoogle Scholar
  86. 86.
    Evans JD, Jacobs TF, Evans EW. Role of acetyl-L-carnitine in the treatment of diabetic peripheral neuropathy. Ann Pharmacother. 2008;42(11):1686–91.PubMedCrossRefGoogle Scholar
  87. 87.
    Xiao WH, Zheng FY, Bennett GJ, Bordet T, Pruss RM. Olesoxime (cholest-4-en-3-one, oxime): analgesic and neuroprotective effects in a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel. Pain. 2009;147(1–3):202–9.PubMedCrossRefGoogle Scholar
  88. 88.
    Bordet T, Buisson B, Michaud M, Abitbol JL, Marchand F, Grist J, et al. Specific antinociceptive activity of cholest-4-en-3-one, oxime (TRO19622) in experimental models of painful diabetic and chemotherapy-induced neuropathy. J Pharmacol Exp Ther. 2008;326(2):623–32.PubMedCrossRefGoogle Scholar
  89. 89.
    Ropper AH, Gorson KC, Gooch CL, Weinberg DH, Pieczek A, Ware JH, et al. Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: a randomized, double-blinded trial. Ann Neurol. 2009;65(4):386–93.PubMedCrossRefGoogle Scholar
  90. 90.
    Cohen KL, Lucibello FE, Chomiak M. Lack of effect of clonidine and pentoxifylline in short-term therapy of diabetic peripheral neuropathy. Diabetes Care. 1990;13(10):1074–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Obrosova IG, Xu W, Lyzogubov VV, Ilnytska O, Mashtalir N, Vareniuk I, et al. PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy. Free Radic Biol Med. 2008;44(6):972–81.PubMedCrossRefGoogle Scholar
  92. 92.
    Li F, Abatan OI, Kim H, Burnett D, Larkin D, Obrosova IG, et al. Taurine reverses neurological and neurovascular deficits in Zucker diabetic fatty rats. Neurobiol Dis. 2006;22(3):669–76.PubMedCrossRefGoogle Scholar
  93. 93.
    Li F, Obrosova IG, Abatan O, Tian D, Larkin D, Stuenkel EL, et al. Taurine replacement attenuates hyperalgesia and abnormal calcium signaling in sensory neurons of STZ-D rats. Am J Physiol Endocrinol Metab. 2005;288(1):E29–36.PubMedCrossRefGoogle Scholar
  94. 94.
    Christoph T, De VJ, Tzschentke TM. Tapentadol, but not morphine, selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Neurosci Lett. 2010;470(2):91–4.PubMedCrossRefGoogle Scholar
  95. 95.
    Etropolski M, Shapiro D, Okamoto A, Rauschkolb-Loffler C, Lange R, Haussler J. Safety and tolerability of tapentadol extended release (ER) in patients with painful diabetic peripheral neuropathy (DPN): results of a randomized-withdrawal phase 3 study. Diabetes. 2009;58:A226–A7.Google Scholar
  96. 96.
    Kamiya H, Zhang W, Sima AA. C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. Ann Neurol. 2004;56(6):827–35.PubMedCrossRefGoogle Scholar
  97. 97.
    Soderstrom LH, Johnson SP, Diaz VA, Mainous AG 3rd. Association between vitamin D and diabetic neuropathy in a nationally representative sample: results from 2001–2004 NHANES. Diabet Med. 2012;29(1):50–5. doi:10.1111/j.1464-5491.2011.03379.x.Google Scholar
  98. 98.
    Abbott CA, Malik RA, van Ross ER, 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. doi:10.2337/dc11-1108.Google Scholar
  99. 99.
    NICE. Neuropathic pain. NICE, 2010. 17-4-2102. Ref Type: Online Source.

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Abd A. Tahrani
    • 1
    • 2
  • Q. Altaf
    • 2
  • Martin J. Stevens
    • 1
    • 2
  1. 1.Centre of Endocrinology Diabetes and MetabolismUniversity of BirminghamBirminghamUK
  2. 2.Department of Diabetes and EndocrinologyBirmingham Heartlands HospitalBirminghamUK

Personalised recommendations