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 Table of Contents  
SYSTEMATIC REVIEW
Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 59-65

Therapeutic use of alpha lipoic acid in burning mouth syndrome: A meta-analysis


1 Department of Prosthodontics and Crown and Bridge, Guru Nanak Institute of Dental Sciences and Research, Kolkata, West Bengal, India
2 Consultant Periodontist and Clinical Practitioner, Kolkata, West Bengal, India

Date of Submission18-Aug-2020
Date of Decision27-Sep-2020
Date of Acceptance03-Oct-2020
Date of Web Publication03-Aug-2021

Correspondence Address:
Dr. Shubhabrata Roy
Ambuja Upohar, C2, Flat – 1002, 2052 Chak Garia, Kolkata - 700 094, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjos.SJOralSci_69_20

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  Abstract 


Introduction: Primary burning mouth syndrome (BMS) is a chronic pain disorder of the oral cavity without any apparent local or systemic etiologic factor. There is no specific therapy for primary BMS and treatment is basically supportive or symptomatic. There are many pharmacological and nonpharmacological approaches reported by different studies to alleviate pain in primary BMS. Alpha lipoic acid (ALA) has also been used as a therapeutic agent in BMS by many clinicians and researchers. Aims: The aim of this review and meta-analysis was to evaluate the double-blinded placebo controlled randomized clinical trials of ALA to determine its efficacy and potential as therapeutic agent in primary BMS. Six studies were selected for the systematic review after a thorough manual and electronic searching of the databases. Methods: Five out of the 6 selected studies were used for quantitative data synthesis. Results and discussion: The ALA therapy for 2 months provided symptomatic relief to more people in the study groups than in the placebo groups (risk ratio 2.34, 95% confidence interval [CI]: 1.71–3.19). The mean visual analog scale (VAS) scores of the test groups improved (decreased) after 2 months of ALA therapy (standardised mean difference [SMD] 0.72, 95% CI 0.20–1.24). When compared with placebo therapy, mean VAS scores improved (decreased) more with placebo than with ALA after 2 months of treatment (SMD −0.23, 95% CI: −0.70–0.24). The positive responders in the ALA groups presented less incidence of deterioration than the positive responders in placebo groups during the follow-up period. Conclusion: It was concluded from this meta-analysis that ALA could be used as a potential therapeutic agent in primary BMS. It should be administered in proper therapeutic doses and for sufficient time to elicit positive outcome. ALA can be used for a long time without any severe side effect and very few recipients complained about worsening of the situation. It certainly improves pain symptoms in a considerable number of patients when compared with placebo therapy.

Keywords: Alpha lipoic acid, burning mouth syndrome, clinical trials, double-blind study, placebo


How to cite this article:
Roy S, Raj D, Bhattacharyya J, Das S, Goel P. Therapeutic use of alpha lipoic acid in burning mouth syndrome: A meta-analysis. Saudi J Oral Sci 2021;8:59-65

How to cite this URL:
Roy S, Raj D, Bhattacharyya J, Das S, Goel P. Therapeutic use of alpha lipoic acid in burning mouth syndrome: A meta-analysis. Saudi J Oral Sci [serial online] 2021 [cited 2021 Dec 3];8:59-65. Available from: https://www.saudijos.org/text.asp?2021/8/2/59/322513




  Introduction Top


According to the International Association for the Study of Pain, burning mouth syndrome (BMS) is defined as a burning pain in the tongue or other oral mucous membrane persisting for at least 4 months and associated with normal signs and normal laboratory findings.[1],[2] The pain mainly persists in the anterior two-thirds of the tongue, followed by the dorsum and lateral borders of the tongue, the anterior aspect of the hard palate, and the labial mucosa of the lips.[2] The pain is described as burning, scalding, tingling, or numbness.[3] BMS can be accompanied by other neuro-sensory disturbances including dysgeusia or altered taste sensation, subjective xerostomia, sleep disturbances, irritability, anxiety, and depression.[3],[4]

The prevalence of BMS ranges from 0.6% to 15% of the general population with significant female predilection.[2],[3],[5] The ratio between females and males varies from 3:1 to 16:1.[2] BMS usually occurs in the 5th–7th decade of life and much more common among the postmenopausal women with a prevalence of 12%–18%.[5],[6]

BMS is classified as primary BMS and secondary BMS.[2],[7] The primary BMS (essential or idiopathic) is characterized by a specific spectrum of chronic pain within the oral cavity with or without other neuro-sensory disturbances and is presented without any clear etiologic factor.[7] The secondary BMS cases are presented with specific underlying local and/or systemic etiologic factors such as mucosal lesions (lichen planus, candidiasis, etc.,), hormonal disturbances, nutritional deficiency, diabetes, xerostomia, parafunctional habits, cranial nerve injuries, medicinal side effects, and contact hypersensitivity.[2],[3] In both subtypes, the exact etiologic role of psychogenic factors is still not clearly understood.[7]

Before considering any treatment option, a clinician must obtain a thorough medical and drug history and perform a comprehensive examination involving adjunctive tests and diagnostic imaging to determine whether the patient is suffering from primary BMS or secondary BMS.[1],[2],[3] As the etiology is not clear, there is no specific therapy for primary BMS.[8] The treatment of primary BMS is mainly supportive to provide symptomatic relief to the patient. On the other hand, secondary BMS requires appropriate diagnosis and treatment of the underlying factors to obtain favorable treatment outcome.[2],[7]

Topical or systemic administration of clonazepam is a popular treatment option for primary BMS.[9] A few studies have reported positive responses from the topical or systemic application of capsaicin.[10],[11] Apart from that, different authors have reported both systemic and topical use of various other drugs and even nonpharmacological therapy to alleviate pain in primary BMS patients.[2],[8],[12],[13],[14],[15] However, none of them has been shown to be definite treatment protocol.[4]

Alpha-lipoic acid (ALA) is a naturally occurring substance synthesized within the mitochondria of plants and animals.[16] ALA and dihydrolipoic acid (DHLA), the oxidized form, and the reduced form of lipoic acid, are a pair of powerful redox couple which can directly scavenge reactive oxygen species, chelate metals, and regenerate other antioxidants.[17] ALA and DHLA are both lipid-soluble and water-soluble and they can fully function both in intracellular and extracellular environments and even can cross blood-brain barrier.[17] In addition to synthesis, ALA is also absorbed intact from dietary sources (present in spinach, broccoli, tomato, etc.,) and it transiently accumulates in many tissues.[16],[17] ALA helps to improve endothelial dysfunction, reduces oxidative stress, protects against the development of atherosclerosis, inhibits progression of an already established atherosclerotic plaque and improves diabetes related chronic complications such as diabetic polyneuropathy.[16],[17]

Literature shows that a number of clinical trials have been conducted to find out the therapeutic efficacy of ALA in BMS. The purpose of this meta-analysis is to evaluate the available studies in determining the potential of ALA as a therapeutic agent in primary BMS. Ethical approval for the study was granted by the Ethics committee of Guru Nanak Institute of Dental Sciences and Research.


  Materials and Methods Top


The systematic review and meta-analysis were conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.[18] The research questions were formed according to the population, intervention, control, and outcomes format. This study included only double-blinded placebo controlled randomized clinical trials (RCTs). Only the articles written/available in English language were considered. The literature search was conducted by two independent reviewers (SR and DR). In case of dis-agreement between the reviewers, final decision was made by a third reviewer (SD). The initial search was done for the available literature on the treatment of “BMS” with “ALA.” The studies for data synthesis were selected based on the inclusion and exclusion criteria. The search strategy has been described in a flow chart [Figure 1]. Two independent reviewers (SR and DR) assessed the risks of bias of the individual studies. Risk of bias assessment was done according to the Cochrane collaboration's tool for assessing risk of bias.[19] The extracted quantitative data from the selected studies were analyzed statistically. The statistical analysis was done using Revman version 5.3.[20]
Figure 1: Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart

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Inclusion criteria

  • Double-blinded RCTs
  • BMS patients without any known local or systemic causative factor and treatment history
  • Studies available in English language
  • At least 1 month of ALA therapy with prescribed doses within the therapeutic range
  • The test groups should not be subjected to any other simultaneous local or systemic or psychological therapy.


Exclusion criteria

  • Insufficient data
  • Open trials
  • Heterogeneous study population including individuals suffering from other disorders with or without idiopathic BMS.


Framing of the research question

  • Population: Male and female individuals with primary BMS and without any associated relevant medical and treatment history
  • Intervention: Daily oral administration of ALA in therapeutic doses
  • Comparison: Daily administration of placebo in double blinded clinical trials
  • Outcome: To find out the therapeutic potential of ALA in BMS.



  Results Top


Out of 85 reports identified through initial search, only 13 articles were selected for full text review. Six studies fulfilled the inclusion and exclusion criteria and were selected for qualitative data synthesis.[21],[22],[23],[24],[25],[26] Among the 7 excluded studies, there were three open trials, one editorial letter, one retrospective study and in remaining two studies, study populations (as were not exclusively primary BMS cases) did not fulfill the inclusion criteria. The assessment of risks of bias of these 6 studies was done individually [Figure 2]. Quantitative data analysis was possible for 5 out of the 6 selected studies. In one study, the study design was crossover RCT with 2 cycles of 30 days each and a 20 days separating washout period.[26] Each group received ALA therapy for 1 month only. For homogeneity of data, treatment outcome at the end of continuous 2 months (8 weeks) of either ALA or placebo therapy was considered for meta-analysis. Out of the five studies, four studies reported the number of participants in each group who presented with some improvements following therapy, though the decision regarding the improvement was subjective and varied among the studies. Only two studies reported the data regarding changes in mean pain scores after 2 months of therapy.
Figure 2: Summary of risks of bias assessment

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Statistical analysis

For this meta-analysis, quantitative data from similar RCTs were pooled together into a single group. All the 366 initial participants (299 females and 67 males) were divided into test (194) and placebo groups (172). Out of 194 from the test groups, only 132 participants received ALA therapy, 22 received ALA and multi-vitamin complex, 20 received gamma-aminobutyric acid (GABA), 20 received both GABA and ALA. Total reported attrition was 41 (24 from the test groups and 17 from the placebo groups). Attrition was 15.15% for the test groups which received only ALA therapy (20 out of 132). Attrition was 9.88% for the placebo groups. Hence, data was available for 112 participants who received only ALA therapy and 155 participants who received placebo. Statistical analysis was done with Revman 5.3. The summery of the data analysis are described by the forest plots in [Table 1], [Table 2], [Table 3]. Publication bias of the four studies from [Table 1] was reported in a funnel plot [Figure 3]. It was found from the [Table 1], that the ALA therapy for 2 months provided symptomatic relief to more people in the study groups than in the placebo groups (risk ratio [RR]: 2.34, 95% confidence interval [CI]: 1.71–3.19). In terms of improvement of mean visual analog scale (VAS) score, the two included studies [Table 2] showed that the mean VAS scores improved (decreased) after 2 months of ALA therapy (standardized mean difference 0.72, 95% CI: 0.20–1.24). However, when compared with placebo therapy, mean VAS scores improved (decreased) more with placebo than with ALA after 2 months of treatment [Table 3]. [Table 4] shows the percentage of patients who positively responded to either ALA or placebo therapy, but presented with relapse during follow-up.
Table 1: Symptomatic improvements presented by the test groups in comparison with the placebo groups after 2 months of therapy

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Table 2: Improvement in VAS score after 2 months of ALA therapy

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Table 3: Comparison of change in mean VAS scores after 2 months of therapy

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Table 4: Symptomatic changes reported during follow-up period

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Figure 3: Funnel plot

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  Discussion Top


BMS is a chronic pain disorder which can severely affect the quality of life.[1],[4] Although many authors believe that it is of neurogenic in origin, but exact patho-physiology of idiopathic BMS is still unknown.[27],[28] Lauria et al. performed tongue biopsy of BMS patients and concluded that a trigeminal small-fiber sensory neuropathy affected the tongue of persistent BMS patients which was characterized by a significant loss of epithelial and subpapillary nerve fibers.[6]

It is evident that psychological dysfunctions are common among the patients suffering from different types of chronic pain disorders.[6] Many BMS patients also suffer from anxiety and depression.[28] It is also reported that many BMS patients showed symptomatic relief after administration of anxiolytic and anti-depressant medications.[4] Peripheral GABAA receptor is considered to be involved in the pathogenesis of BMS as its activation alters the mechanical sensitivity of nerve fibers.[29] Clonazepam is a benzodiazepine (GABAA receptor agonist) and has an inhibitory effect on the central nervous system and is widely used as an anxiolytic agent.[6] Therefore, clonazepam is used as a treatment for BMS. Cui et al.[29] conducted a meta-analysis on the efficacy of clonazepam for symptom remission in BMS and included three RCTs and two high-quality case–control studies involving 195 BMS patients. They concluded that clonazepam produced a positive effect in patients with BMS.[29] However, prolong use of clonazepam can produce dependence.[9],[10],[29] Studies have shown that clonazepam may cause many adverse side effects including dryness of mouth, drowsiness, and fatigue.[29] Adverse effects can appear in both topical and systemic application.[8]

Studies have shown that both topical and systemic use of capsaicin, a desensitizer of type C receptors for neurogenic inflammation, may produce favorable response in BMS patients.[10],[11],[12] However, epigastric pain has been reported as a major side effect of systemic administration of capsaicin.[14],[23]

Literature shows that there are many other drugs recommended by different researchers for treatment of BMS. The list includes topical administration of lidocaine, aloe vera, lysozyme-lactoperoxidase etc., and systemic administration of amisulpride, selective serotonin reuptake inhibitors (e.g., paroxetine), zinc supplement, GABA etc.[5],[8],[9] However, none of them can be considered as a predictable treatment option for primary BMS.

Even there are studies on nonpharmacological approaches toward BMS, including cognitive therapy and acupuncture. In an open trial, Femiano et al. found that the combination therapy with psycho-analysis and ALA produced significant improvements among otherwise healthy persons suffering from BMS.[30]

The placebo phenomenon relates to patients' perception or direct experience of a treatment, that means interpretation of visual or auditory information as well as active integration of this sensory information with memories of previous experiences and current expectations.[31] The placebo analgesia effect is defined as the measured difference in pain across an untreated and a placebo-treated group or across an untreated and placebo-treated condition within the same group.[31] Although any chronic orofacial pain disorder may have underlying neuro-physiological etiology, consideration of psychological factors and placebo effects lead to the positive treatment outcome. For this reason, double-blind studies are also important. This explains the actual improvements shown by the participants of the test and placebo groups. Even if this placebo effect is not taken into consideration, the outcome of the clinical studies can never be interpreted correctly.[31]

ALA can be considered as a potential treatment option for both primary and secondary BMS. A number of clinical trials of ALA on human have been undertaken to assess adverse health effects in the participants. Oral doses of 1800 mg ALA (600 mg 3 times a day) for 6 months did not produce any significant adverse effect compared to placebo.[16] Even intravenous administration of ALA (600 mg/day) for 3 weeks produced no evidence of serious side-effects.[16] A number of long-term multicenter studies on the effectiveness of ALA in diabetic polyneuropathy have concluded that the usual dose of 600 mg per day has efficacy and safety. The adverse effects were mainly seen in the gastrointestinal tract and were dose dependent.[17] Hence, ALA can be used for any long-term therapy.

It is also certain that ALA improves pain symptoms in primary BMS patients. All the selected studies in this meta-analysis prescribed therapeutic doses of ALA (600–800 mg daily in two or three divided doses). Femiano et al. divided pain response into five groups based on VAS scores (worsening, unchanged, slight improvement, decided improvement, and resolution). Palacios-Sánchez et al. and Carbone et al. considered 50% symptomatic relief as the cut off for deciding positive treatment response. López-Jornet et al. classified pain scores into slight (≤3.3), moderate (3.4–6.6), and severe (≥6.7). López-D'alessandro et al. divided pain response into four categories; Category 1: with negative changes (deterioration), Category 2: no changes; Category 3: with positive changes (improvements); and Category 4: with total recovery. More people in the study groups showed improvements compared to the number in the placebo group. There was definite improvement in pain symptoms which were reflected in decrease of mean VAS scores after 1 or 2 months of therapy. It was also found that overall improvement of mean VAS scores was comparable in the placebo group and the ALA group. However, studies have shown that the positive responders in the ALA group presented less incidence of deterioration than the positive responders in placebo group during the follow-up phase [Table 4].

ALA with multi-vitamin complex did not present any added benefit over only ALA therapy. However, combination therapy of ALA and GABA was proved beneficial and can be used in short-term therapies. Although 1 month therapy with ALA improved pain symptoms, as reported by both Cavalcanti et al. and López-Jornet et al., improvement was more pronounced after 2 months of therapy.

Cavalcanti et al. conducted a crossover RCT and reported that the reduction on symptoms by oral administration of ALA did not have statistical significance when compared with placebo. They also found that in the first cycle, 14 out of 17 and 11 out of 14 participants reported symptomatic improvements in ALA group and placebo group, respectively. Whereas in the second cycle, 12 out of 17 and 8 out of 14 participants reported symptomatic improvements in placebo group and ALA group, respectively. Hence, it is confirmed that symptomatic improvement was evident in both the groups.

Femiano et al. conducted an open trial and reported significant improvements in the symptomatology of BMS in up to two-thirds of patients who received ALA.[32] Steele et al. conducted a retrospective study on the BMS patients who were previously treated with ALA.[33] The mean course of treatment was 26.6 weeks (range 4–80 weeks). Out of 31 patients (22 females and 9 males), 11 (35%) reported improvement, 14 (45%) reported no difference, 2 patients (7%) reported a worsening of symptoms and 4 (13%) did not know whether there had been improvement. However, it was also reported that only 19 patients took the recommended dose of 600 mg per day.

Marino et al. conducted an open trial on primary BMS patients with capsaicin, ALA, lysozyme-lactoperoxidase mouth rinse and boric acid (control group) mouth wash.[12] They found similar effectiveness of capsaicin and ALA in controlling the symptoms of BMS (76% of the patients who received capsaicin and 57% of the patients who received ALA patients showed improvements after 2 months of treatment). At the end of 2 months of follow-up period, 67% of the patients who received capsaicin and 55% of the patients who received ALA reported improvements. One patient out of those received capsaicin, clinically worsened. These excluded studies also supporting the outcome of this meta-analysis.


  Conclusion Top


It has been concluded from this meta-analysis, that ALA can be used as a potential therapeutic agent in primary BMS. It should be administered in proper therapeutic doses and for sufficient time to elicit positive outcome. ALA can be used for a long time without any severe side effect and very few recipients complain about worsening of the situation. It certainly improves pain symptoms in a considerable number of patients when compared with placebo therapy.

The quality of the study and the risk of bias evaluation was not carried out which is the limitation of the study. Future systematic reviews should include these factors to contribute to more homogenous data suitable for quantitative analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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