Hostname: page-component-77f85d65b8-t6st2 Total loading time: 0 Render date: 2026-04-19T22:08:42.041Z Has data issue: false hasContentIssue false
  • English
  • Français

Status of Current Clinical Trials in Diabetic Polyneuropathy

Published online by Cambridge University Press:  02 December 2014

Vera Bril
Vera Bril*
Affiliation:
Toronto General Hospital, UHN, University of Toronto, Toronto, Ontario, Canada
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the 'Save PDF' action button.

Peripheral polyneuropathy is the most frequent complication of diabetic mellitus. In spite of many clinical trials of different specific interventions for diabetic polyneuropathy, intensive glycemic control remains the only effective specific therapy currently available for this troublesome complication. This systematic overview reports the status of current clinical trials in diabetic polyneuropathy with an emphasis on those interventions directed towards specific pathophysiological derangements. A discussion of clinical trials of agents directed towards relieving painful symptoms of diabetic polyneuropathy concludes this overview.

Résumé

RÉSUMÉ

La polyneuropathie périphérique est la complication la plus fréquente du diabète. En dépit de nombreux essais cliniques, le contrôle glycémique intensif demeure le seul traitement spécifique efficace disponible actuellement pour traiter cette complication importante. Cette revue systématique fait le point sur les essais cliniques en cours ciblant des perturbations physiopathologiques spécifiques. Une discussion des essais cliniques d’agents utilisés pour soulager la douleur due à la polyneuropathie diabétique est présentée en guise de conclusion À cette revue.

Information

Type
Research Article
Information
Canadian Journal of Neurological Sciences , Volume 28 , Issue 3 , August 2001 , pp. 191 - 198
Copyright
Copyright © The Canadian Journal of Neurological 2001

References

1. Diabetes Control and Complications Trial Research Group. Theeffect 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;329:977–986.Google Scholar
2. Diabetes Control and Complications Trial (DCCT) Research Group. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995;38:869–880.Google Scholar
3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853.Google Scholar
4. National Diabetes Data Group. Factors in development of diabeticneuropathy. Baseline analysis of neuropathy in feasibility phase of Diabetes Control and Complications Trial (DCCT). The DCCTResearch Group. Diabetes 1988;37:476–481.Google Scholar
5. Zochodne, D. Diabetic neuropathies: features and mechanisms. Brain Pathol 1999;9:369–391.Google Scholar
6. Vinik, A. Diabetic neuropathy: pathogenesis and therapy. Am J Med 1999;107:17S-26S.Google Scholar
7. Sima, A, Bril, V, Nathaniel, V, et al. Regeneration and Repair ofMyelinated Fibers in Sural Nerve Biopsy Specimens from Patients with Diabetic Neuropathy Treated with Sorbinil. N Engl J Med 1988;319:548–555.Google Scholar
8. Greene, D, Stevens, M, Feldman, E. Glycemic control. In: Dyck, P, Thomas, P, eds. Diabetic Neuropathy. Philadelphia: W B Saunders, 1999:297–316.Google ScholarPubMed
9. Low, P, Nichander, K, Scionti, L. Role of hypoxia, oxidative stress,and excitatory neurotoxins in diabetic neuropathy. In: Dyck, P, Thomas, P, eds. Diabetic Neuropathy. Philadelphia: W B Saunders, 1999:317–329.Google Scholar
10. Tomlinson, D. Role of aldose reductase inhibitors in the treatment of diabetic polyneuropathy. In: Dyck, P, Thomas, P, eds. Diabetic Neuropathy. Philadelphia: WB Saunders, 1999:330–340.Google Scholar
11. Brimijoin, S. Axonal transport in diabetic neuropathy. In: Dyck, P, Thomas, P, eds. Diabetic Neuropathy. Philadelphia: WB Saunders, 1999:341–352.Google Scholar
12. Brownlee, M. Advanced glycation end products and diabeticperipheral neuropathy. In: Dyck, P, Thomas, P, eds. Diabetic Neuropathy. Philadelphia: WB Saunders, 1999: 353–358.Google Scholar
13. Cameron, N, Cotter, M. Role of linolenic acid in diabeticpolyneuropathy. In: Dyck, P, Thomas, P, eds. Diabetic Neuropathy. Philadelphia: WB Saunders, 1999:359–367.Google Scholar
14. Yasuda, H, Kikkawa, R. Role of antiprostaglandins in diabeticneuropathy. In: Dyck, P, Thomas, P, eds. Diabetic Neuropathy. Philadelphia: WB Saunders, 1999:368–376.Google ScholarPubMed
15. Feldman, E, Windebank, A. Growthfactorsand peripheralneuropathy. In: Dyck, P, Thomas, P, eds. Diabetic Neuropathy. Philadelphia: WB Saunders, 1999:377–386.Google Scholar
16. Melton, L, Dyck, P. Epidemiology. In: Dyck, P, Thomas, P, eds. Diabetic Neuropathy. Philadelphia: WB Saunders, 1999:239–254.Google Scholar
17. Tovi, J, Svanborg, E, Nilsson, B, Engfeldt, P. Diabetic neuropathy inelderly Type 2 diabetic patients: effects of insulin treatment. Acta Neurol Scand 1998;98:346–353.Google Scholar
18. Reichard, P, Nilsson, B, Rosenqvist, U. The effect of long-termintensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993;329:304–309.Google Scholar
19. Navarro, X, Sutherland, D, Kennedy, W. Long-term effects ofpancreatic transplantation on diabetic neuropathy. Ann Neurol 1997;42:727–736.Google Scholar
20. Pirart, J. Diabetes mellitus and its degenerative complications: aprospective study of 4,400 patients observed between 1947 and 1973. Diabete Metab 1978;1:168–188, 252–263.Google Scholar
21. Pirart, J. 1998 Clinical practice guidelines for the management of diabetes in Canada. Can Med Assoc J 1998;159:159.Google Scholar
22. ADA. Clinical practice recommendations 2001. Diabetes Care 2001; 24(Suppl 1): S33-S43.Google Scholar
23. Green, A, Jaspan, J. Treatment of diabetic neuropathy with inhibitorsof the aldose reductase enzyme. J Diabet Complications 1990;4:138–144.Google Scholar
24. Greene, D, Lattimer, S, Sima, A. Sorbitol, phospholipids, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 1987;316:599–606.Google Scholar
25. Sorbinil Retinopathy Trial Research Group. The sorbinil retinopathytrial: neuropathy results. Sorbinil Retinopathy Trial Research Group. Neurology 1993;43:1141–1149.Google Scholar
26. Sundkvist, G, Armstrong, F, Bradbury, J, et al and UnitedKingdom/Scandinavian Ponalrestat Trial. Peripheral and autonomic nerve function in 259 diabetic patients with peripheral neuropathy treated with ponalrestat (an aldose reductase inhibitor) or placebo for 18 months. United Kingdom/Scandinavian Ponalrestat Trial. J Diabetes Complications 1992;6:123–130.Google Scholar
27. Ghahary, A, Chakrabarti, S, Sima, A, Murphy, L. Effect of insulin andstatil on aldose reductase expression in diabetic rats. Diabetes 1991;40:1391–1396.Google Scholar
28. Willars, G, Calcutt, N, Tomlinson, D. Reduced anterograde andretrograde accumulation of axonally transported phosphofructokinase in streptozotocin-diabetic rats: effects of insulin and the aldose reductase inhibitor ‘Statil’. Diabetologia 1987;30:239–243.Google Scholar
29. Faes, T, Yff, G, De Weerdt, O, et al. Treatment of diabetic autonomicneuropathy with an aldose reductase inhibitor. J Neurol 1993;240:156–160.Google Scholar
30. Sima, A, Greene, D, Brown, M, et al and Tolrestat Study Group. Effect of hyperglycemia and the aldose reductase inhibitor tolrestat on sural nerve biochemistry and morphometry in advanced diabetic peripheral polyneuropathy. The Tolrestat Study Group. J Diabetes Complications 1993;7:157–169.Google Scholar
31. Asbury, A, Porte, D. Report and recommendations of the San Antonioconference on diabetic neuropathy. Ann Neurol 1988;24:99–104.Google Scholar
32. Cameron, N, Cotter, M, Dines, K, et al. Aldose reductase inhibition,nerve perfusion, oxygenation and function in streptozotocin-diabetic rats: dose-response considerations and independence from a myo-inositol mechanism. Diabetologia 1994;37:651–653.Google Scholar
33. Greene, D, Arezzo, J, Brown, M and Zenarestat Study Group. Effectof aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology 1999;53:580–591.Google Scholar
34. Uchida, K, Kigoshi, T, Nakano, S, et al. Effect of 24 weeks oftreatment with epalrestat, an aldose reductase inhibitor, on peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. Clin Ther 1995;17:460–466.Google Scholar
35. Hotta, N, Sakamoto, N, Shigeta, Y, Kikkawa, R, Goto, Y. Clinicalinvestigation of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy in Japan: multicenter study. Diabetic Neuropathy Study Group in Japan. J Diabetes Complications 1996;10:168–172.Google Scholar
36. Di Giulio, A, Lesma, E, Gorio, A. Diabetic neuropathy in the rat: 1. Alcar augments the reduced levels and axoplasmic transport of substance P. J Neurosci Res 1995;40:414–419.Google Scholar
37. Williamson, J, Arrigoni-Martelli, E. The roles of glucose-inducedmetabolic hypoxia and imbalances in carnitine metabolism in mediating diabetes-induced vascular dysfunction. Int J Clin Pharm Res 1992;12:247–252.Google ScholarPubMed
38. Gorio, A, Di Giulio, A, Tenconi, B, et al. Peptide alterations inautonomic diabetic neuropathy prevented by acetyl-L-carnitine. Int J Clin Pharmacol Res 1992;12:225–230.Google Scholar
39. Gorio, A, Di Giulio, A, Donadoni, L, et al. Early neurochemicalchanges in the autonomic neuropathy of the gut in experimentaldiabetes. Int J Clin Pharmacol Res 1992;12:217–224.Google Scholar
40. Bril, V, Ellison, R, Ngo, M, et al and Roche Neuropathy Study Group. Electrophysiological monitoring in clinical trials. Roche Neuropathy Study Group. Muscle Nerve 1998;21:1368–1373.Google Scholar
41. Apfel, S. Neurotrophicfactors inperipheral neuropathies:therapeutic implications. Brain Pathol 1999;9:393–413.Google Scholar
42. Apfel, S. Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med 1999;107: 34S-42S.Google Scholar
43. Rogers, B. Development of recombinant human nerve growth factor(rhNGF) as a treatment for peripheral neuropathic disease. Neurotoxicology 1996;17:865–870.Google Scholar
44. Apfel, S, Kessler, J, Adornato, B, et al. Recombinant human nervegrowth factor in the treatment of diabetic polyneuropathy. NGFStudy Group. Neurology 1998;51:695–702.CrossRefGoogle Scholar
45. Freeman, R. Human studies of recombinant human nerve growthfactor and diabetic peripheral neuropathy. Eur Neurol 1999;41:20–26.Google Scholar
46. Apfel, S, Schwartz, S, Adornato, B, et al. Efficacy and safety ofrecombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial. JAMA 2000;284:2215–2221.Google Scholar
47. Dyck, P, Kratz, K, Lehman, K, et al. The Rochester DiabeticNeuropathy Study: design, criteria for types of neuropathy, selectionbias, andreproducibility of neuropathic tests. Neurology 1991;41:799–807.Google Scholar
48. Bril, V. NIS-LL: The primary measurement scale for clinical trialendpoints in diabetic peripheral neuropathy. Eur Neurol 1999;41:8–13.Google Scholar
49. O’Brien, J, Carson, G, Seo, H, Hiraiwa, M, Kishimoto, Y. Identification of prosaposin as a neurotrophic factor. Proc Natl Acad Sci USA 1994;91:9593–9596.Google Scholar
50. Calcutt, N, Campana, W, Eskeland, N, et al. Prosaposin geneexpressin and the efficacy of a prosaposin-derived peptide in preventing structural and functional disorders of peripheral nerve in diabetic rats. J Neuropathol Exp Neurol 1999;58:628–636.Google Scholar
51. Ziegler, D, Reljanovic, M, Mehnert, H, Gries, F. Alpha-lipoic acid inthe treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes 1999;107:421–430.Google Scholar
52. Ziegler, D, Hanefeld, M, Ruhnau, K, et al. Treatment of symptomaticdiabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995;38:1425–1433.Google Scholar
53. Shiba, T, Inoguchi, T, Sportsman, J, et al. Correlation ofdiacylglycerol level and protein kinase C activity in the rat retinato retinal circulation. Am J Physiol 1993;265q: E783-E793.Google Scholar
54. Cohen R. Dysfunction of vascular endothelium in diabetes mellitus.Circulation 1993; 87(suppl): V67-V76.Google Scholar
55. Cohen, K, Lucibello, F, Chomiak, M. Lack of effect of clonidine andpentoxifylline in short-term therapy of diabetic peripheralneuropathy. Diabetes Care 1990;13:1074–1077.Google Scholar
56. Cohen, S, Mathews, T. Pentoxifylline in the treatment of distaldiabetic neuropathy. Angiology 1991;42:741–746.Google Scholar
57. Hendriksen, P, Oey, P, Wieneke, GH., Banga, J, van Dam, P. Antihypoxic treatment at an early stage of diabetic neuropathy: an electrophysiological study with sabeluzole. Acta Neurol Scand 1992;86:506–511.Google Scholar
58. Keen, H, Payan, J, Allawi, J, et al. Treatment of diabetic neuropathywith gamma-linolenic acid. The Gamma-Linolenic A c i d Multicenter Trial Group. Diabetes Care 1993; 16: 8–15.Google Scholar
59. Keen, H, Payan, J, Allawi, J, et al. Treatment of diabetic neuropathywith gamma-linolenic acid. The Gamma-Linolenic A c i d Multicenter Trial Group. Diabetes Care 1993; 16: 8–15.Google Scholar
60. Bril, V, Ellison, R, Ngo, M, et al. Electrophysiological monitoring inclinical trials. Muscle Nerve 1998;21:1368–1373.Google Scholar
61. Harati, Y. Diabetes and the nervous system. Endocrinol Metab ClinNorth Am 1996; 25: 325–359.Google Scholar
62. Perkins, B, Olaleye, D, Zinman, B, Bril, V. Simple screening tests forperipheral neuropathy in the diabetes clinic. Diabetes Care 2001;24:250–256.Google Scholar
61. Tanaka, S, Wild, DK, Seligman, PJ, et al. The USprevalence of self-reported carpal tunnel syndrome. 1988 National Health interview survey data. Am J Pub Health 1994;84:1846–1848.Google Scholar
64. Pfeifer, M, Ross, D, Schrage, J, et al. A highly successful and novelmodel for treatment of chronic painful diabetic peripheral neuropathy. Diabetes Care 1993;16:1103–1115.Google Scholar
65. Portenoy, RK, Kanner, RM, eds. Pain Management: Theory andPractice. Contemporary Neurology Series. vol 68. Philadelphia: Davis, FA, 1996.Google Scholar
66. McQuay, H, Carroll, D, Jadad, A, Wiffen, P, Moore, A. Anticonvulsantdrugs for management of pain: a systematic review. Br Med J 1995; 311: 1047–1052.Google Scholar
67. McQuay, H, Tramer, M, Nye, B, et al. A systematic review ofantidepressants in neuropathic pain. Pain 1996; 68: 217–227.Google Scholar
68. Harati, Y, Gooch, C, Swenson, M, et al. Double-blind randomized trialof tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50: 1842–1846.CrossRefGoogle Scholar
69. Watson, C, Watt-Watson, J. Treatment of neuropathic pain: focus onantidepressants, opioids and gabapentin. Pain Res Manage 1999; 4: 168–178.CrossRefGoogle Scholar
70. Max, M, Culnane, M, Schafer, S, et al. Amitriptylione relievesdiabetic neuropathy pain in patients with normal or depressedmood. Neurology 1987; 37: 589–596.CrossRefGoogle ScholarPubMed
71. .Max, M,Lynch, S, Muir, J, et al. Effectsof desipramine,amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992; 326: 1250–1256.Google Scholar
72. Kvinesdal, B, Molin, J, Froland, A, Gram, L. Imipramine treatment ofpainful diabetic neuropathy. JAMA 1984; 251: 1727–1730.Google Scholar
73. Rull, J, Quibrera, R, Gonzalez-Millan, H, Lozano Castaneda, O. Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine (Tegretol®): double-blind cross-over trial. Diabetologia 1969; 5: 215–218.Google Scholar
74. Gomez-Perez, F, Rull, J, Dies, H, et al. Nortriptyline and fluphenazinein the symptomatic treatment of diabetic neuropathy. A double-blind cross-over study. Pain 1985; 23: 395–400. Google Scholar
75. Gomez-Perez, F, Choza, R, Rios, J, et al. Nortriptyline-fluphenazinevs. carbamazepine in the symptomatic treatment of diabeticneuropathy. Arch Med Res 1996; 27: 525–529.Google Scholar
76. Wright, J, Oki, J, Graves, L. Mexiletine in the symptomatic treatment ofdiabetic peripheral neuropathy. Ann Pharmacother 1997;31:29–34.Google Scholar
77. Kastrup, J, Angelo, H, Petersen, P, Dejgard, A, Hilsted, J. Treatment ofchronic painful diabetic neuropathy with intravenous lidocaine infusion. Br Med J (Clin Res Ed) 1986; 292: 173.Google Scholar
78. Backonja, M, Beydoun, A, Edwards, K, et al and Gabapentin DiabeticNeuropathy Study Group. Gabapentin for the Symptomatic Treatment of Painful Neuropathy in Patients with DiabetesMellitus. A Randomized Controlled Trail. JAMA 1998; 280: 1831–1836.Google Scholar
79. Morello, C, Leckband, S, Stoner, C, Moorhouse, D, Sahagian, G. Randomized double-blind study comparing the efficacy of gabapentin with amitriptyline on diabetic peripheral neuropathy pain. Arch Intern Med 1999; 159: 1931–1937.CrossRefGoogle ScholarPubMed
80. Galer, B. Neuropathic pain of peripheral origin: advances inpharmacologic treatment. Neurology 1995; 45: S17–S25; discussion S35–36.CrossRefGoogle ScholarPubMed
81. Vrethem, M, Boivie, J, Arnqvist, H, et al. A comparison ofamitriptyline and maprotiline in the treatment of painful diabetic neuropathy in diabetics and nondiabetics. Clin J Pain 1997; 13: 313–323.Google Scholar
82. Young, R, Clarke, B. Pain relief in diabetic neuropathy: theeffectiveness of imipramine and related drugs. Diabet Med 1985; 2: 363–366.Google Scholar
83. Davis, J, Smith, R. Painful peripheral diabetic neuropathy treatedwith venlafaxine HCl extended release capsules. Diabetes Care 1999; 22: 1909–1910.Google Scholar
84. Kiayias, J, Vlachou, E, Lakka-Papadodima, E. Venlafaxine HCl in thetreatment of painful peripheral diabetic neuropathy. DiabetesCare 2000; 23: 699.Google Scholar
85. Chakrabarti, A, Samantaray, S. Diabetic peripheral neuropathy: nerveconduction studies before, during and after carbamazepinetherapy. Aust N Z J Med 1976; 6: 565–568.Google Scholar
86. Backonja, M. Anticonvulsants (antineuropathics) for neuropathicpain syndromes. Clin J Pain 2000; 16: S67–S72.Google Scholar
87. Jarvis, B, Coukell, A. Mexiletine. A review of its therapeutic use inpainful diabetic neuropathy. Drugs 1998; 56: 691–707.Google Scholar
88. Oskarsson P, Ljunggren J, Lins P and Mexiletine Study Group.Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. The Mexiletine Study Group. Diabetes Care 1997; 20: 1594-1597.Google Scholar
89. Stracke, H, Meyer, U, Schumacher, H, Federlin, K. Mexiletine in thetreatment of diabetic neuropathy. Diabetes Care 1992; 15: 1550–1555.Google Scholar
90. Tandan, R, Lewis, G, Krusinski, P, Badger, G, Fries, T. Topicalcapsaicin in painful diabetic neuropathy. Controlled study with long-term follow-up. Diabetes Care 1992; 15: 8–14.Google Scholar
91. Capsaicin Study Group. Treatment of painful diabetic neuropathywith topical capsaicin. A multicenter, double-blind, vehicle-controlled study. The Capsaicin Study Group. Arch Intern Med 1991; 151: 2225–2229.Google Scholar
92. Harati, Y, Gooch, C, Swenson, M, et al. Maintenance of the long-termeffectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Complications 2000; 14: 65–70.Google Scholar
93. Sindrup, S,Jensen, T. Pharmacologic treatment of pain inpolyneuropathy. Neurology 2000; 55: 915–920.Google Scholar