ALA and Burning Mouth Syndrome

Burning Mouth Syndrome

There are no definitive therapies for BMS (50).. According to published data, ALA is reportedly one of the most effective drugs in the management of BMS. However, to date, there is no clear consensus  as many variables such as mood disorders appear to decrease effectiveness when co-existing with BMS (51).

Femiano et al. have published most of the studies that examine the efficacy of ALA in the management of BMS (22-26). They use a dose of 600 mgr/day with a follow up around 30 days in their studies, as our study. Their results have been quite effective for ALA in order to improve symptoms, very similar in general compared with our results. There are some differences to consider that we point below.

In their first study (52), they carried out an open trial of 42 patients to compare ALA treatment (600 mg/day) over placebo. In the study group, none of the patients worsened, similar to our study. 24% presented no changes and 76% reported some level of improvement. However, statistical analysis was not conducted, the sample size was small, and treatment duration was only one month.

Femiano and Scully (53) evaluated ALA at a dose of 600 mg/day in a 60-patient double-blind placebo controlled study. 97% of the patients reported some improvement with ALA, 3% showed no changes in symptomatology, and none of the patients reported worsening of symptoms. These results were statistically significant in favour of ALA. Similarly to our study, not a single patient treated with ALA worsened; but the results obtained with ALA (97% improvement) were higher than our own results. We must also highlight the important placebo effect obtained (40%).

In 2002, Femiano et al. (54) compared ALA with other products (Bethanechol 5mg/8 hours, Lactoperoxidase and 3% Xylitol). Administration of ALA showed statistically significant results.

Femiano et al. (55) in 2003 conducted an open trial of 192 patients divided into four groups: one undergoing cognitive therapy (CT), one treated with ALA (600mg/day), one combining CT and ALA, and one with placebo. The ALA group and the ALA + CT group showed statistically significant improvement compared to CT alone and the placebo group.

In 2004, Femiano et al. (56) studied the efficacy of ALA in patients treated with and without anxiolytics. Although the latter group displayed more significant results, these were not statistically significant. In 2011, López-D’Alessandro and Escovich verified the efficacy of ALA (600 mg/day) in conjunction with gamma-amino butyric acid (GABA) over placebo over a two-month period. The combination ALA + GABA proved to be the most effective according to patients’ perceptions (57).

Other authors have used ALA in higher concentrations. In 2008, Carbone et al. (58) conducted a 60-patient double-blind study to evaluate the efficacy of pure ALA 800 mg/day over ALA 800 mg/day supplemented with a vitamin complex, and in comparison with placebo. The 3 groups showed a reduction in symptoms, but with no statistical significance. López-Jornet et al. (59) used the same concentration of ALA over placebo and equally found that both groups improved, yet with no statistically significant differences.

Finally, Cavalcanti et al. (60), in their crossover trial comparing the efficacy of ALA (600mg/day) over placebo, found a reduction in symptoms in both groups. The rate of this reduction was higher in the first month than in the second month of treatment.

ALA appears to have benefits in the management of BMS, yet the results supporting its efficacy is inconclusive. Further studies, with a higher number of patients, are, therefore, needed.

Variables such as depression, long-term evolution and symptom intensity make it less likely for ALA patients to improve. This fact, together with the importance of the placebo effect, suggests the need to assess the psychological and/or psychiatric implications that may require multidisciplinary treatments.

​

Reference List

1. Paolisso G, D’Amore A, Volpe C, Balbi V, Saccomanno F, Galzerano D, Giugliano D, Varricchio M, D’Onofrio F. Evidence for a relationship between oxidative stress and insulin action in non-insulin-dependent (type II) diabetic patients. Metabolism. 1994;43:1426–9.

2. Rochette L, Ghibu S, Muresan A, Vergely C. Alpha-lipoic acid: molecular mechanisms and therapeutic potential in diabetes. Can J Physiol Pharmacol. 2015;93(12):1021-7.

3. Akbari M., Ostadmohammadi V., Tabrizi R., et al. The effects of alpha-lipoic acid supplementation on inflammatory markers among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials. Nutrition and Metabolism. 2018;15(1).

4. Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A, Tritschler HJ, Cobelli C, Usadel KH. Alpha-lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care. 1999;22: 280–7.

5. Ziegler D, Gries FA. Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes. 1997;46 Suppl 2:S62-6.

6. Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI, Augustin HJ, Dietze GJ. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittel-Forschung. 1995;45:872–874.

7. Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ. Improvement of insulinstimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes. 1996;104:284–288.

8. Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Rad Biol Med. 1999;27:309–14.

9. Evans JL, Goldfine ID. Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol Ther. 2000;2(3):401- 13.

10. Palacios-Sánchez B, Moreno-López LA, Cerero-Lapiedra R, Llamas-Martínez S, Esparza-Gómez G. Alpha lipoic acid efficacy in burning mouth syndrome. A controlled clinical trial. Med Oral Patol Oral Cir Bucal. 2015;20(4):e435–e440.

11. Femiano F, Scully C. Burning mouth syndrome (BMS): double blind controlled study of alpha-lipoic acid (thioctic acid) therapy. J Oral Pathol Med. 2002;31(5):267-9.

12. Carbone M, Pentenero M, Carrozzo M, Ippolito A, Gandolfo S. Lack of efficacy of alpha-lipoic acid in burning mouth syndrome: a double-blind, randomized, placebocontrolled study. Eur J Pain. 2009;13(5):492-6.

13. López-Jornet P, Camacho-Alonso F, Leon-Espinosa S. Efficacy of alpha lipoic acid in burning mouth syndrome: a randomized, placebo-treatment study. J Oral Rehabil. 2009;36(1):52-7.

14. Femiano F, Gombos F, Scully C, Busciolano M, De Luca P. Burning mouth syndrome (BMS): controlled open trial of the efficacy of alpha-lipoic acid (thioctic acid) on symptomatology. Oral Dis. 2000;6(5):274-7.

15. Steele JC, Bruce AJ, Drage LA, Rogers RS 3rd. Alpha-lipoic acid treatment of 31 patients with sore, burning mouth. Oral Dis. 2008;14(6):529-32.

16. Femiano F, Gombos F, Scully C. Burning mouth syndrome: the efficacy of lipoic acid on subgroups. J Eur Acad Dermatol Venereol. 2004;18(6):676-8.

17. Fatima G, Das SK, Mahdi AA. Some oxidative and antioxidative parameters and their relationship with clinical symptoms in women with fibromyalgia syndrome. Int J Rheum Dis. 2017 Jan;20(1):39-45.

18. Coskun Benlidayi I. Role of inflammation in the pathogenesis and treatment of fibromyalgia. Rheumatol Int. 2019;39(5):781-91.

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):1149–1160.

20. Yoshida K, Hirokawa J, Tagami S, Kawakami Y, Urata Y, Kondo T. Weakened cellular scavenging activity against oxidative stress in diabetes mellitus: regulation of glutathione synthesis and efflux. Diabetologia. 1995;38(2):201–210.

21. Wong A, Dukic-Stefanovic S, Gasic-Milenkovic J, Schinzel R, Wiesinger H, Riederer P, et al. Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia. Eur J Neurosci. 2001;14:1961–1967.

22. Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T, et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes. 1997;46:1481–1490.

23. Gilron I, Tu D, Holden R, et al. Innovations in the Management of Musculoskeletal Pain With Alpha-Lipoic Acid (IMPALA Trial): Study protocol for a Double-Blind, Randomized, Placebo-Controlled Crossover Trial of Alpha-Lipoic Acid for the Treatment of Fibromyalgia Pain. JMIR Res Protoc. 2017;6(3):e41.

24. Lee JS, Kim HG, Lee DS, Son CG. Oxidative Stress is a Convincing Contributor to Idiopathic Chronic Fatigue. Sci Rep. 2018;8(1):12890.

25. Morris G, Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014;12(2):168–85.

26. Maes M. A new case definition of Neuro-Inflammatory and Oxidative Fatigue (NIOF), a neuroprogressive disorder, formerly known as chronic fatigue syndrome or Myalgic Encephalomyelitis: results of multivariate pattern recognition methods and external validation by neuro-immune biomarkers. Neuro Endocrinol Lett. 2015;36(4):320-9.

27. Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Int J Clin Exp Med. 2009;2(1):1–16.

28. 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):1149–1160.

29. Solmonson A, DeBerardinis RJ. Lipoic acid metabolism and mitochondrial redox regulation. J Biol Chem. 2018;293(20):7522–30.

30. Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic Acid and diabetic neuropathy. Rev Diabet Stud. 2009;6(4):230–236.

31. Papazafeiropoulou A, Xourgia E, Papantoniou S, Trikkalinou A, Melidonis A. Effect of 3-month α-lipoic acid treatment on sural nerve conduction velocity and amplitude in patients with diabetic neuropathy: a pilot study. Arch Med Sci Atheroscler Dis. 2019;4:e141–e143.

32. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365-70.

33. Agathos E, Tentolouris A, Eleftheriadou I, et al. Effect of α-lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. J Int Med Res. 2018;46(5):1779–1790.

34. 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.

35. Mijnhout GS, Alkhalaf A, Kleefstra N, Bilo HJ. Alpha lipoic acid: a new treatment for neuropathic pain in patients with diabetes? Neth J Med. 2010;68(4):158-62.

36. Nguyen N, Takemoto JK. A Case for Alpha-Lipoic Acid as an Alternative Treatment for Diabetic Polyneuropathy. J Pharm Pharm Sci. 2018;21(1s):177s-191s.

37. Feuerecker B, Pirsig S, Seidl C, et al. Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo. Cancer Biol Ther. 2012;13(14):1425–35.

38. Na MH, Seo EY, Kim WK. Effects of alpha-lipoic acid on cell proliferation and apoptosis in MDA-MB-231 human breast cells. Nutr Res Pract. 2009;3(4):265–271.

39. Tripathy J, Tripathy A, Thangaraju M, Suar M, Elangovan S. α-Lipoic acid inhibits the migration and invasion of breast cancer cells through inhibition of TGFβ signaling. Life Sci. 2018;207:15-22.

40. Wenzel U, Nickel A, Daniel H. alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation. Apoptosis. 2005 Mar;10(2):359-68.

41. Yang L, Wen Y, Lv G, Lin Y, Tang J, Lu J, Zhang M, Liu W, Sun X. α-Lipoic acid inhibits human lung cancer cell proliferation through Grb2-mediated EGFR downregulation. Biochem Biophys Res Commun. 2017;494(1-2):325-31.

42. Skibska B, Goraca A. The Protective Effect of Lipoic Acid on Selected Cardiovascular Diseases Caused by Age-Related Oxidative Stress. Oxid Med Cell Longev. 2015;2015:313021.

43. Ying Z, Kherada N, Farrar B, et al. Lipoic acid effects on established atherosclerosis. Life Sci. 2010;86(3-4):95–102.

44. Yi X, Maeda N. alpha-Lipoic acid prevents the increase in atherosclerosis induced by diabetes in apolipoprotein E-deficient mice fed high-fat/low-cholesterol diet. Diabetes. 2006;55(8):2238-44.

45. Couch RC, Vigil M., Thomas MA, Sibert G. A dose escalation toxicity study of DL-6-8 thioctic acid (lipoic acid) in Rhesus monkeys. Annual Meeting of Toxicology; Cincinnati, Ohio; March12, 1997.

46. Vigil M, Berkson BM, Garcia AP. Adverse effects of high doses of intravenous alpha lipoic Acid on liver mitochondria. Glob Adv Health Med. 2014;3(1):25–27. doi:10.7453/gahmj.2013.011

47. Liu F, Zhang Y, Yang M, Liu B, Shen YD, Jia WP, Xiang KS. [Curative effect of alphalipoic acid on peripheral neuropathy in type 2 diabetes: a clinical study]. Zhonghua Yi Xue Za Zhi. 2007;87(38):2706-9.

49. Palacios-Sánchez B, Moreno-López LA, Cerero-Lapiedra R, Llamas-Martínez S, Esparza-Gómez G. Alpha lipoic acid efficacy in burning mouth syndrome. A controlled clinical trial. Med Oral Patol Oral Cir Bucal. 2015 Jul 1;20(4):e435-40. doi: 10.4317/medoral.20410. PMID: 26034927; PMCID: PMC4523256.

50. Sun A, Wu KM, Wang YP, Lin HP, Chen HM, Chiang CP. Burning mouth syndrome: a review and update. J Oral Pathol Med. 2013;42:649–55. [PubMed] [Google Scholar]

51. de Moraes M, do Amaral Bezerra BA, da Rocha Neto PC, de Oliveira Soares AC, Pinto LP, de Lisboa Lopes Costa A. Randomized trials for the treatment of burning mouth syndrome: an evidence-based review of the literature. J Oral Pathol Med. 2012;41:281–7. [PubMed] [Google Scholar]

52. Femiano F, Gombos F, Scully C, Busciolano M, De Luca P. Burning mouth syndrome (BMS): controlled open trial of the efficacy of alpha-lipoic acid (thioctic acid) on symptomatology. Oral Dis. 2000;6:274–7. [PubMed] [Google Scholar]

53. Femiano F, Scully C. Burning mouth syndrome (BMS): double blind controlled study of alpha-lipoic acid (thioctic acid) therapy. J Oral Pathol Med. 2002;31:267–9. [PubMed] [Google Scholar]

54. Femiano F, Gombos F, Esposito V, Nunziata M, Scully C. Burning mouth syndrome (BMS): an open trial of comparative efficacy of alpha-lipoic acid (thioctic acid) with other therapies. Minerva Stomatol. 2002;51:405–9. [PubMed] [Google Scholar]

55. Femiano F, Gombos F, Scully C. Burning mouth syndrome: the efficacy of lipoic acid on subgroups. J Eur Acad Dermatol Venereol. 2004;18:676–8. [PubMed] [Google Scholar]

56. Femiano F, Gombos F, Scully C. Síndrome de boca ardiente. Estudio de la psicoterapia, medicación con ácido alfa-lipoico y combinación de terapias. Med Oral. 2004;9:8–13. [PubMed] [Google Scholar]

57. López-D'alessandro E, Escovich L. Combination of alpha lipoic acid and gabapentin, its efficacy in the treatment of Burning Mouth Syndrome: a randomized, double-blind, placebo controlled trial. Med Oral Patol Oral Cir Bucal. 2011;16:e635–40. [PubMed] [Google Scholar]

58. Carbone M, Pentenero M, Carrozzo M, Ippolito A, Gandolfo S. Lack of efficacy of alpha-lipoic acid in burning mouth syndrome: a double-blind, randomized, placebo-controlled study. Eur J Pain. 2009;13:492–6. [PubMed] [Google Scholar]

59. López-Jornet P, Camacho-Alonso F, Leon-Espinosa S. Efficacy of alpha lipoic acid in burning mouth syndrome: a randomized, placebo-treatment study. J Oral Rehabil. 2009;36:52–7. [PubMed] [Google Scholar]

60. Cavalcanti DR, da Silveira FR. Alpha lipoic acid in burning mouth syndrome--a randomized double-blind placebo-controlled trial. J Oral Pathol Med. 2009;38:254–61. [PubMed] [Google Scholar]