Summary
Anti-oxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes mellitus, thus providing a rationale of potential therapeutic value for diabetic patients. The effects of the anti-oxidant α-lipoic acid (thioctic acid) were studied in a 3-week multicentre, randomized, double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy; ALADIN) in 328 non-insulin-dependent diabetic patients with symptomatic peripheral neuropathy who were randomly assigned to treatment with intravenous infusion of α-lipoic acid using three doses (1200, 600, or 100 mg ALA) or placebo (PLAC). Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) were scored at baseline and at each visit (days 2–5, 8–12, and 15–19) prior to infusion. In addition, the Hamburg Pain Adjective List, a multidimensional specific pain questionnaire, and the Neuropathy Symptom and Disability Scores were assessed at baseline and day 19. According to the protocol 260 (65/63/66/66) patients completed the study. The total symptom score in the feet decreased from baseline to day 19 by −4.5±3.7 (−58.6%) points (mean ± SD) in ALA 1200, −5.0±4.1 (−63.5%) points in ALA 600, −3.3±2.8 (−43.2%) points in ALA 100, and −2.6±3.2 (−38.4%) points in PLAC (ALA 1200 vs PLAC: p=0.003; ALA 600 vs PLAC: p<0.001). The response rates after 19 days, defined as an improvement in the total symptom score of at least 30%, were 70.8% in ALA 1200, 82.5% in ALA 600, 65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs PLAC; p=0.002). The total scale of the Pain Adjective List was significantly reduced in ALA 1200 and ALA 600 as compared with PLAC after 19 days (both p<0.01). The rates of adverse events were 32.6% in ALA 1200, 18.2% in ALA 600, 13.6% in ALA 100, and 20.7% in PLAC. These findings substantiate that intravenous treatment with α-lipoic acid using a dose of 600 mg/day over 3 weeks is superior to placebo in reducing symptoms of diabetic peripheral neuropathy, without causing significant adverse reactions.
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Abbreviations
- ALA:
-
α-lipoic acid
- HPAL:
-
Hamburg Pain Adjective List
- NCV:
-
nerve conduction velocity
- NDS:
-
Neuropathy Disability Score
- NSS:
-
Neuropathy Symptom Score
- TSS:
-
total symptom score
- VPT:
-
vibration perception threshold
- NIDDM:
-
non-insulin-dependent diabetes mellitus
- IDDM:
-
insulin-dependent diabetes mellitus
References
The Diabetes Control and Complications Trial Research Group (1995) The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 122: 561–568
Ziegler D, Mayer P, Mühlen H, Gries FA (1991) The natural history of somatosensory and autonomic nerve dysfunction in relation to glycaemic control during the first 5 years after diagnosis of type 1 (insulin-dependent) diabetes mellitus. Diabetologia 34: 822–829
Ziegler D, Dannehl K, Wiefels K, Gries FA (1992) Differential effects of near-normoglycaemia for 4 years on somatic nerve dysfunction and heart rate variation in type 1 diabetic patients. Diabet Med 9: 622: 629
Kennedy WR, Navarro X, Goetz FC, Sutherland DER, Najarian JS (1990) Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med 322: 1031–1037
Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R (1992) Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326: 1250–1256
Sindrup SH (1994) Antidepressants in the treatment of diabetic neuropathy symptoms. Pharmacodynamic, -kinetic, and -genetic aspects. Dan Med Bull 41: 66–78
Henry JA, Alexander CA, Sener EK (1995) Relative mortality from overdose of antidepressants. BMJ 310: 221–224
Stracke H, Meyer UE, Schumacher HE, Federlin K (1992) Mexiletine in the treatment of diabetic neuropathy. Diabetes Care 15: 1550–1555
The Capsaicin Study Group (1991) Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. Arch Intern Med 151: 2225–2229
Levy DM, Abraham RR, Tomlinson DR (1991) Topical capsaicin in the treatment of painful diabetic neuropathy. N Engl J Med 324: 776
Masson EA, Boulton AJM (1990) Aldose reductase inhibitors in the treatment of diabetic neuropathy. A review of the rationale and clinical evidence. Drugs 39: 190–202
Ziegler D, Mayer P, Rathmann W, Gries FA (1991) One-year treatment with the aldose reductase inhibitor, ponal-restat, in diabetic neuropathy. Diabetes Res Clin Pract 14: 63–74
Gregersen G (1987) Myo-inositol supplementation. In: Dyck PJ, Thomas PK, Asbury AK, Winegrad AI, Porte D (eds) Diabetic neuropathy. Saunders, Philadelphia, pp 188–189
Kihara M, Schmelzer JD, Poduslo JF et al. (1991) Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals. Proc Natl Acad Sci USA 88: 6107–6111
Thomas PK (1994) Growth factors and diabetic neuropathy. Diabet Med 11: 732–739
Cameron NE, Cotter MA (1993) Potential therapeutic approaches to the treatment or prevention of diabetic neuropathy: evidence from experimental studies. Diabet Med 10: 593–605
Jamal GA (1994) The use of gamma linolenic acid in the prevention and treatment of diabetic neuropathy. Diabet Med 11: 145–149
Quatraro A, Roca P, Donzella C, Acampora R, Marfella R, Giugliano D (1995) Acetyl-l-carnitine for symptomatic diabetic neuropathy. Diabetologia 38: 123 (Letter)
Low PA, Nickander KK (1991) Oxygen free radical effects in sciatic nerve in experimental diabetes. Diabetes 40: 873–877
Nickander KK, Schmelzer JD, Rohwer DA, Low PA (1994) Effect of α-tocopherol deficiency on indices of oxidative stress in normal and diabetic peripheral nerve. J Neurol Sci 126: 6–14
Cameron NE, Cotter MA (1994) The relationship of vascular changes to metabolic factors in diabetes mellitus and their role in the development of peripheral nerve complications. Diab Metab Rev 10: 189–224
Suzuki YJ, Tsuchiya M, Packer L (1991) Thioctic acid and dihydrolipoic acid are novel antioxidants which interact with reactive oxygen species. Free Rad Res Comms 15: 255–263
Bravenboer B, Kappelle AC, Hamers FPT, van Buren T, Erkelens DW, Gispen W (1992) Potential use of glutathione for the prevention and treatment of diabetic neuropathy in the streptozotocin-induced diabetic rat. Diabetologia 35: 813–817
Cameron NE, Cotter MA, Maxfield EK (1993) Anti-oxidant treatment prevents the development of peripheral nerve dysfunction in streptozotocin-diabetic rats. Diabetologia 36: 299–304
Cameron NE, Cotter MA, Archibald V, Dines KC, Maxfield EK (1994) Anti-oxidant and pro-oxidant effects on nerve conduction velocity, endoneurial blood flow and oxygen tension in non-diabetic and streptozotocin-diabetic rats. Diabetologia 37: 449–459
Karasu C, Dewhurst M, Stevens EJ, Tomlinson DR (1995) Effects of anti-oxidant treatment on sciatic nerve dysfunction in streptozotocin-diabetic rats; comparison with essential fatty acids. Diabetologia 38: 129–134
Nagamatsu M, Nickander KK, Schmelzer JD et al. (1995) Lipoic acid improves nerve blood flow, reduces oxidative stress and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care 18: 1160–1167
Ziegler D, Mayer P, Mühlen H, Gries FA (1993) Effekte einer Therapie mit α-LiponsÄure gegenüber Vitamin B1 bei der diabetischen Neuropathie. Diab Stoffw 2: 443–448
Scott J, Huskisson EC (1976) Graphic representation of pain. Pain 2: 175–184
Young MJ, Boulton AJM, Macleod AF, Williams DRR, Sonksen PH (1993) A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 36: 150–154
Hoppe F (1991) Hamburger Schmerz Adjektiv Liste (HSAL). Manual. Beltz-Verlag, Weinheim
Sheiner LB, Rubin DB (1995) Intention-to-treat analysis and the goals of clinical trials. Clin Pharmacol Ther 57: 6–15
Schulz B, Reichel G, Hüttl I, Zander E, Runge U (1986) Zur Wirksamkeit der ThioctsÄuretherapie bei Typ-I-Diabetikern. Wiss Z Ernst-Moritz-Arndt-UniversitÄt Greifswald, Medizinische Reihe 35: 48–50
Jörg J, Metz F, Scharafinski H (1988) Zur medikamentösen Behandlung der diabetischen Polyneuropathie mit der Alpha-LiponsÄure oder Vitamin B-PrÄparaten. Nervenarzt 59: 36–44
Sachse G, Willms B (1980) Efficacy of thioctic acid in the therapy of peripheral diabetic neuropathy. In: Gries FA, Freund HJ, Rabe F, Berger H (eds) Aspects of autonomic neuropathy in diabetes. Horm Metab Res [Suppl Series] 9: 105–108
Cavaliere D, Scorpiglione N, Belfiglio M et al. (1994) Quality assessment of randomised clinical trials on medical treatment of diabetic neuropathy. Diab Nutr Metab 7: 287–294
Young RJ, Ewing DJ, Clarke BF (1983) A controlled trial of sorbinil, an aldose reductase inhibitor, in chronic painful diabetic neuropathy. Diabetes 32: 938–942
Judzewitsch RG, Jaspan JB, Polonsky KS et al. (1983) Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. N Engl J Med 308: 119–125
Young RR, Shahani BT (1983) Nerve conduction velocity in diabetes. N Engl J Med 308: 190–191
Santiago JV, Sönksen PH, Boulton AJM et al. (1993) Withdrawal of the aldose reductase inhibitor tolrestat in patients with diabetic neuropathy: effect on nerve function. J Diab Comp 7: 170–178
Dimpfel W, Spüler M, Pierau F-K, Ulrich H (1990) Thioctic acid induces dose-dependent sprouting of neurites in cultured rat neuroblastoma cells. Dev Pharmacol Ther 14: 193–199
Kemplay S, Martin P, Wilson S (1988) The effects of thioctic acid on motor nerve terminals in acrylamide-poisoned rats. Neuropathol Appl Neurobiol 14: 275–288
Altenkirch H, Stoltenburg-Didinger G, Wagner HM, Herrmann J, Walter G (1990) Effects of lipoic adic in hexacarbon-induced neuropathy. Neurotoxicol Teratol 12: 619–622
Halliwell B (1994) Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? Lancet 344: 721–724
Jenner P (1994) Oxidative damage in neurodegenerative disease. Lancet 344: 796–798
Baynes JW (1991) Role of oxidative stress in development of complications in diabetes. Diabetes 40: 405–412
Collier A, Rumley A, Rumley AG et al. (1992) Free radical activity and hemostatic factors in NIDDM patients with and without microalbuminuria. Diabetes 41: 909–913
Yoshida K, Hirokawa J, Tagami S, Kawakami Y, Urata Y, Kondo T (1995) Weakened cellular scavenging activity against oxidative stress in diabetes mellitus: regulation of glutathione synthesis and efflux. Diabetologia 38: 201–210
Kihara M, Low PA (1995) Impaired vasoreactivity to nitric oxide in experimental diabetic neuropathy. Experimental Neurology 132: 180–185
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Ziegler, D., Hanefeld, M., Ruhnau, K.J. et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant α-lipoic acid. Diabetologia 38, 1425–1433 (1995). https://doi.org/10.1007/BF00400603
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DOI: https://doi.org/10.1007/BF00400603