Abstract
Background and Aims
Patients with burning mouth syndrome (BMS) experience an annoying feeling without clinical evidence of any mucosal lesion. Deficiency or excess of micronutrients is a common feature in secondary BMS. There is limited knowledge among oral healthcare providers regarding the significance of micronutrients in oral health, so the current review focuses on the critical role of these elements in oral health implications as secondary BMS.
Methods
For the data collection, the authors searched for key terms without time limitation (1900–2021) in databases comprised of PubMed, Google Scholar, Scopus, Web of Science (SCI), and Embase.
Results
The total number of matched articles with inclusion criteria involved in this review article was 59 original articles. Among these, 20 randomized clinical trials (RCT), 31 case‐control or Crossectional, and 8 case reports/series are reviewed in this review article.
Conclusion
One of the important etiological factors in patients with secondary BMS is micronutrient imbalance. The iron, zinc, vitamin B family, vitamin D deficiency and increased levels of homocysteine and oxidant agents were examined in secondary BMS patients. In addition, oral medicine specialists must consider the possible toxic effects of some elements in restorations and dental prostheses. Further studies, such as RCTs in the future, are recommended.
Keywords: antioxidants, burning mouth syndrome, micronutrient, trace elements, vitamins
1. INTRODUCTION
For the first time, burning mouth syndrome (BMS) was introduced by the International Headache Society in 2004. In this clinical entity, patients complain about a constant burning sensation in various areas of the oral cavity, especially the anterior part of the tongue, lower lip, or even hard palate. BMS patients experience this annoying feeling for more than 3 months over 2 h every day. Oral mucosa appears normal without any sign of clinical or histological abnormality. Often, the burning sensation is accompanied by pain, dysphasia, dysgeusia, and xerostomia. 1 , 2 , 3 , 4 BMS occurs nearly seven times more often in women than in men, especially during the perimenopausal stage. The primary form of BMS is idiopathic, as defined above, but it can be associated with central or peripheral neuropathy 5 and histopathologic alteration of the nerve fibers. 6 The secondary form is related to local or systemic etiologic factors such as hyposalivation, temporomandibular joint disorders, allergies, psychiatric disorders, autoimmune conditions, endocrine disorders, candidiasis, and nutritional deficiency. 6 , 7
All the cells and tissues of the human body, as part of a whole, need appropriate nutrition to preserve a healthy state. Disturbances in micronutrient homeostasis may cause pathological changes in critical functions of cells, such as regenerative processes, clearance of oxidative stress, and immune system defense. 8 Nowadays, deficiency or excess of micronutrients is a common feature of modern humans. Excessive levels of trace elements usually occur due to external materials for supplement therapy or undesirable ecological conditions, while undernutrition is often associated with insufficient diet. 9 Healthful nutritional habits with sufficient absorption of essential trace elements, vitamins, and antioxidants are important to general especially oral health. The imbalance of micronutrients can lead to a burning sensation in different sites of the oral mucosa. 10 Understanding the personalized analysis of micronutrient pattern is a pivotal approach to diagnosing and successfully treating BMS conditions. 8
Assuming that oral healthcare providers may not be as knowledgeable about the significance of micronutrients in oral health, the current review focuses on the critical role of these elements in oral health and their implications in BMS.
2. MATERIALS AND METHODS
The authors searched the terms “Stomatodynia” OR “Stomatopyrosis” OR “Glossodynia” OR “Glossopyrosis” OR “Burning mouth syndrome” OR “BMS” OR “Burning mouth sensation” OR “Burning Tongue” OR “oral dysesthesia” AND, “oral disorder” OR “Oral diseases” AND, “micronutrient” OR “nutrient element” AND, “trace element” OR “essential trace elements” OR “toxic trace elements” AND, “antioxidant” AND, “vitamin” AND, “oxidative stress” AND, “malnutrition” without time limitation (1900–2021) in databases comprise of MEDLINE via PubMed, Google Scholar, Scopus, Web of Science (SCI), and EMBASE. The inclusion criteria were original articles comprised of case‐control, case reports, case series, and Clinical Trials. The authors included studies evaluated one of the micronutrients in secondary BMS patients, confirmation of BMS according to clinical examination based on oral constant burning sensations for more than 3 months, with no evidence of clinical oral mucosal lesions. The articles measured the level of micronutrients in at least one medium, saliva, serum, or transudate/tissue specimens, and interventional studies evaluated the efficacy of micronutrients supplements in secondary BMS symptoms included. Also, the authors assessed articles that evaluated toxic levels of trace elements in oral burning sensation. All articles are written in the English language.
Two authors assessed full‐text of randomized trials articles for eligibility by CONSORT guidelines, observational studies by STROBE guidelines, and case reports by CARE guidelines. All of the included articles contained ethical approval and informed consent details.
3. RESULT
The authors searched different databases and found 895 related studies. After eliminating duplicated articles and evaluating abstracts, 213 articles were identified and included. The authors extracted the full text of 110 articles in PDF format. Ultimately, 59 matched articles with the inclusion criteria considered in this review article (Figure 1). Two authors (N. G. and N. S.) searched databases and independently evaluated all eligible publications. The included articles were from 1988 to 2021.
Figure 1.
PRISMA flowchart of the literature search, determination of eligibility, and inclusion in the review article.
Based on the results of the present review article, studies in four general categories comprised of essential trace elements, toxic trace elements, antioxidants, and vitamins have investigated the role of micronutrients in patients with secondary BMS. Most studies have directly examined micronutrient levels in BMS patients who have used the serum, saliva, or both mediums. However, some elements, such as hemoglobin or Gastric parietal cell antibody (GPCA), indirectly showed a certain micronutrient level. None of the studies examined the BMS patients' genetic changes, including single nucleotide polymorphisms associated with micronutrient genes.
Interestingly, a significant percentage of studies examined the therapeutic effects of different micronutrients in improving patients' symptoms in clinical trials (CT). Of these, 3 are before‐after studies, and 17 are randomized clinical trials (RCT). Case reports and series studies accounted for a relatively small percentage of treatment studies. Almost all treatment studies used visual or numerical analog scales (VAS or NAS) as the response measures. Only one study, in addition to VAS, measured changes in the level of inflammatory cytokine (tumor necrosis factor‐alpha) (Table 4).
Table 4.
List of articles that evaluated therapeutic effects of micronutrients in BMS patients.
| Reference | Micronutrient | Study design | Study groups | Results | p Value |
|---|---|---|---|---|---|
| Lamey and Lamb 13 | Vitamin B1, B2, B6, B12, iron | RCT (before‐after) |
Vitamin B1 (300 mg/day), Vitamin B2 (20 mg/day), and Vitamin B6 (150 mg/day) 30 days Ferrous sulfate (200 mg) tid, 3 months or 1000 mg cyanocobalamin 6 weeks. |
Alleviation of symptoms in 34 of the 150 patients Total alleviation of symptoms in 8 and partial alleviation in 5 of the 19 patients |
|
| Hugoson and Thorstensson 3 | Vitamin B1, B2, B6 | RCT |
Group 1 = B Complex (n = 8) Group 2 = placebo (n = 8) |
No effect on BMS of vitamin replacement therapy or placebo therapy | – |
| Femiano 40 | ALA | RCT |
Group 1 = ALA (n = 20), Group 2 = Bethanecol (n = 20) Group 3 = Biotene (n = 20) Group 4 = placebo (n = 20) |
ALA was statistically superior to other groups |
p < 0.001 |
| Femiano and Scully 41 | ALA | RCT |
Group 1 = ALA (n = 30) Group 2 = placebo (n = 30) |
There was a statistically significant symptomatic improvement with ALA (97%) used over 2 months, compared with placebo (40%) | p < 0.001 |
| Lehman et al. 42 | B12 | Case‐report |
A 73‐year‐old woman with BMS Oral B12 supplement for 3 months |
Remission of burning sensation | – |
| Cavalcanti and Da Silveira 43 | ALA | RCT |
Group 1 = ALA (n = 17) Group 2 = placebo (n = 14) |
Comparison of the oral assessment scores failed to demonstrate the effectiveness of ALA over placebo | p = 0.75 |
| López‐Jornet et al. 44 | ALA | RCT |
Group 1 = ALA (n = 23) Group 2 = placebo (n = 16) |
There was no significant between two groups. | p = 0.485 |
| Cho et al. 45 | Zinc | RCT |
Group 1: steroid gargle and once‐daily zinc tablets Group 2: steroid gargle |
Reduced numerical pain scale Group 1 > group 2 |
p = 0.004 |
| Marino et al. 46 | ALA | RCT |
Group 1: capsaicin, (n = 14) Group 2: ALA (n = 14) Group 3: lysozyme lactoperoxidase (n = 14) Group 4: placebo (n = 14) |
Significant reduction in the symptom scores in groups 1, 2, and 3. After 2 months, only group 1 showed significant results | p < 0.01 |
| De Giuseppe et al. 47 | B12 | Case‐report | A 73‐year‐old man with BMS treated with vitamin B12 monthly for 3 months | After 2 years complete remission of burning mouth | |
| López‐D'alessandro and Escovich 48 | ALA | RCT |
Group 1 = ALA (n = 20) Group 2 = gabapentin (n = 20) Group 3 = ALA + gabapentin (n = 20) Group 4, 5, 6 = placebo (n = 60) |
Groups 1, 2, and 3 were statistically superior to placebo (groups 4, 5, and 6) The best response was group 3 with 70% of the cases with reduced burning and a 13.2 times greater chance of positive changes than those taking placebo. |
p < 0.001 |
| López‐Jornet et al. 49 | Aloe vera | RCT |
Group 1 = Tongue protector (n = 25) Group 2 = Tongue protector + Aloe vera (n = 25) Group 3 = Tongue protector + placebo (n = 25) |
The pain values improved for all three study groups but without statistically significant | p = 0.210 |
| Sun et al. 50 | Vitamin B12 folic acid, iron | RCT (before‐after) |
Group I: BMS without hematinic deficiency (n = 222): B‐complex Group II: BMS with hematinic deficiency (n = 177): B‐complex + supplements base on deficient hematinic |
177 patient's oral symptoms had disappeared Reduced serum homocysteine Group I Group II |
p < 0.001 p < 0.01 |
| Cano‐Carrillo et al. 51 | Lycopene | RCT |
Group I = Lycopene (n = 30) Group II = Placebo (n = 30) |
Significant reduction in the symptoms: Group I Group II No significant differences between groups. |
p = 0.013 p = 0.043 p = 0.8 |
| Arbabi‐Kalati and Tahmtan 52 | Zinc | RCT |
Group 1 = zinc (n = 30) Group 2 = placebo (n = 30) |
Reduced severity of burning sensation Group 1 > group 2 |
p = 0.001 |
| Palacios‐Sánchez et al. 53 | ALA | RCT |
Group 1 = ALA (n = 25) Group 2 = placebo (n = 29) |
ALA was statistically superior to placebo. 64% of ALA patients reported some level of improvement, with a level of maintenance of 68.75% 1 month after treatment. |
p = 0.009 |
| Sun et al. 54 | vitamin B12 | RCT (before‐after) | 71 GPCA + BMS patients treated with vitamin B12, B‐complex, supplements according to deficient hematinic | 59 patients showed complete remission of all oral symptoms | |
| Çınar et al. 55 | ALA | RCT |
Group I: Clonazepam (n = 30) Group II: Pregabalin (n = 30) Group III: ALA (n = 30) |
There was nearly 20% decrease in the mean VAS score of the ALA group, which was not statistically significant. | – |
| Barbosa et al. 56 | ALA | RCT |
Group 1 = low level laser (n = 10) Group 2 = ALA (n = 5) |
Significant reduction in symptoms was observed in each group and when two methods analyzed together. |
p = 0.003 p = 0.042 p < 0.001 |
| Milani et al. 57 | Chamomile | Case‐ series | Cognitive therapy plus chamomile tea (n = 2) | Significant reduction in the symptom scores | – |
| Varoni et al. 58 | Melatonin | RCT |
Group I = Melatonin (n = 20) Group II = placebo (n = 20) |
Melatonin did not exhibit higher efficacy in reducing pain to placebo. | p > 0.05 |
| Chirchiglia et al. 59 | Ultramicronized palmitoylethanolamide (umPEA) | Case report | Gabapentin + umPEA | The frequency and intensity of the pain had improved. | – |
| Pakfetrat et al. 60 | Crocin isolated from saffron | RCT |
BMS = Citalopram (n = 21) BMS = Crocin (n = 26) |
Significant reduction in the pain symptom, anxiety, and depression: Group I Group II No significant difference between two groups |
p < 0.001 p < 0.001 11th weeks: p = 0.981 |
| Lecor et al. 61 | Methylene blue | Case‐ series | Mouth‐rinse (0.5%) Methylene blue (n = 5) | Significant reduction in the symptom scores at 1 week, 3 and 6 months | p < 0.05 |
Note: All p values considered as significant if they were less than 0.05.
Abbreviations: ALA, alpha‐lipoic acid; BMS, burning mouth syndrome; GPCA, antigastric parietal cell; NS, nonsignificant; tid, three times daily.
4. DISCUSSION
Micronutrients are among the critical elements that maintain body homeostasis. The development and progression of different diseases may depend on both the deficiency and excess of these micronutrients. 11 Disturbance in micronutrients homeostasis may result in the oral burning sensation through neurodegenerative changes, and central or peripheral neuropathy. Oral medicine specialists are often some of the first healthcare providers to observe oral manifestations of micronutrients disturbance in the oral mucosa. 12
According to the present review article findings, most studies were RCTs that evaluated the therapeutic effects of micronutrients in patients with secondary BMS. Most of those articles evaluate antioxidants therapeutic effects, such as alpha‐lipoic acid. It is evident that among the trace elements, only the therapeutic effects of zinc and among the vitamins, only the vitamin B family have been studied. The serum has been the most dominant medium in case‐control (n = 11) and cross‐sectional (n = 11) studies that have examined the level of micronutrients in BMS patients. Two cross‐sectional studies simultaneously evaluated the therapeutic effects of micronutrients 3 , 13 (Tables 1, 2, 3, 4). Despite the importance of saliva as a biological substance associated with the oral cavity, its changes can directly affect the health of the oral mucosa, there are relatively limited studies to examine the salivary components of BMS patients (Table 2), and few available studies have examined the salivary levels of toxin trace elements (Table 5). Only one study reported serum and salivary levels of vitamin D simultaneously 39 (Table 3). Further studies are needed to evaluate salivary levels and the correlation between serum salivary levels of micronutrients in secondary BMS patients. In secondary BMS patients, measuring the salivary levels of micronutrients can help understand the pathogenesis of the disease and estimate the therapeutic response. Saliva sampling is a simple, noninvasive, nonexpensive, and repeatable method for serial analyses than serum. 67 Among the micronutrients studied in secondary BMS patients, four of them have been considered by researchers more than others, including vitamin B12, folic acid, iron, and zinc.
Table 1.
List of articles that evaluated serum levels of micronutrients in BMS patients.
| Reference | Micronutrient | Study design | Study groups | Results | p Value |
|---|---|---|---|---|---|
| Lamey and Lamb 13 | Hb, MCV, MCH, folate, ferritin, vitamins B12, B1, B2, and B6 | Crossectional | BMS: 150 |
Number of patients with deficiency of: Iron: 1, Ferritin: 8, Vitamin B12: 12, Folate: 0, B1, B2, B6: 26 |
– |
| Maragou and Ivanyi 14 | Zinc | Case‐control |
BMS: 30 Control: 30 |
Control > BMS Zinc deficiency was (30%) in patients with BMS and (10%) in the control subjects |
p < 0.05 |
| Hugoson and Thorstensson 3 | Vitamin B1, B2, B6 | Crossectional | BMS: 16 |
Deficiencies of: Vitamins B1: 93.7%, B2: 81.2%, B6: 0% |
|
|
Vucicevic‐Boras et al. 15 |
Iron, vitamin B12, folic acid, calcium, and magnesium | Case‐control |
BMS: 41 Control: 35 |
Iron, folic acid, calcium, magnesium level Control > BMS Vitamin B12 level Control > BMS |
p > 0.05 p < 0.05 |
| Eguia Del Valle et al. 16 | Vitamin | Crossectional | BMS: 30 | Vitamin deficiency (6.7%) | |
| Sardella et al. 17 | Ferritin, iron, folate, and vitamin B12 | Case‐control |
BMS: 61 Control: 54 |
Control > BMS | p > 0.05 |
| Yoshida et al. 18 | Zinc, vitamin B12, folic acid, and copper | Crossectional | BMS: 311 |
Deficiency of: Copper (0.3%) Folic acid (0.6%) Vitamin B12 (2%) Zinc (10%) |
– |
| Tatullo et al. 19 | Total oxidant capacity and biological antioxidant potential as iron‐reducing activity | Crossectional | BMS: 18 | Significantly different levels, with respect to the general population. | p < 0.001 |
| Krasteva et al. 20 | Vitamin B12 and folic acid | Crossectional | BMS: 92 |
Deficiency of: Folic acid (68%) Vitamin B12 (17,5%) |
– |
| Lin et al. 21 |
Hb, iron, vitamin B12, folic acid Hcy, GPCA |
Case‐control |
BMS: 399 Control: 399 |
Hb, iron, B12 Control > OLP Folic acid Control > OLP Hcy, GPCA Control < OLP |
p < 0.001 p = 0.129 p < 0.001 |
| Bao et al. 4 | Zinc | Case‐control |
BMS:55 Control: 115 |
Control > BMS | p < 0.001 |
| Kim et al. 22 | Vitamin B12 deficiency | Case‐control |
BMS patients with gastrectomy: 11 BMS patients without gastrectomy: 11 |
Vitamin B12 deficiency was not statistically significant in two groups. | p = 0.895 |
| Dieb et al. 23 | Vitamin B6 | Crossectional | BMS: 42 |
Increased serum levels of vitamin B6: 7 (17%) correlation between pain severity and vitamin B6 levels |
p = 0.009 |
| Yoshida et al. 24 | Zinc, iron, MCH | Crossectional | BMS: 393 |
Deficiency of: Iron (35.9%) Zinc (12.2%) High level of MCV (39.9%) |
– |
| Halac et al. 25 | Vitamin B12, and folic acid, ferritin | Crossectional | BMS:26 |
Deficiency of: Vitamin B12, (30%) Ferritin: (11.5%) Folic acid: (3.8%) |
– |
| Campbell et al. 26 | Thiamine (vitamin B1) | Case‐report | 63 years old women with BMS | Lower B1 level than normal values in general population (66 nmol/lit) | – |
| Morr Verenzuela et al. 27 | Vitamin D3, vitamin B2, vitamin B6, zinc, vitamin B1, vitamin B12, and folic acid. | Crossectional | BMS: 659 |
Deficiencies of Vitamin D3 (15%) Vitamin B2 (15%) Vitamin B6 (5.7%) Zinc (5.7%) Vitamin B1 (5.3%) Vitamin B12 (0.8%) Folic Acid (0.7%) |
– |
| Chiang et al. 28 |
Hb, iron, vitamin B12, folic acid Hcy and MCV |
Case‐control |
Vitamin B12 deficiency+ BMS:42 Control: 442 |
Hb, iron, B12, folic acid Control > BMS Hcy and MCV Control < BMS |
p < 0.05 p < 0.05 |
| Chiang et al. 29 | Hb, vitamin B12, iron, GPCA, MCV | Case‐control |
Hcy+BMS:170 Hcy‐BMS: 714 Control:442 |
Deficiency of Hb, iron, B12 Increased GPCA and MCV Hcy+ BMS > Control Hcy+ BMS > Hcy‐BMS |
p < 0.001 p < 0.05 |
| Chiang et al. 30 |
Hb, iron, vitamin B12, folic acid Hcy, GPCA |
Case‐control |
BMS: 884 control: 442 |
Hb, iron, B12, folic acid Control > BMS Hcy, GPCA Control < BMS |
p < 0.005 p < 0.005 |
| Radochová et al. 12 | Iron, vitamin B12, and folic acid | Crossectional | BMS: 129 |
Deficiency of: Iron: 26.4%, Vitamin B12: 26.4% Folic acid: 4.7% |
– |
| Chiang et al. 31 |
Hb, vitamin B12, iron Hcy |
Case‐control |
GPCA + BMS: 109 GPCA‐BMS: 775 Control: 442 |
Deficiency of Hb, iron, B12 Increased Hcy and MCV GPCA + BMS > Control GPCA‐BMS > Control GPCA + BMS > GPCA‐BMS |
p < 0.001 p < 0.005 p < 0.01 |
| Jin et al. 32 |
Hb, iron, vitamin B12, folic acid Hcy, GPCA |
Case‐control |
IDA/BMS: 143 Control: 442 |
Hb, iron, B12 Control > BMS Folic acid Control > BMS Hcy, GPCA levels Control < BMS |
p < 0.001 p = 0.008 p < 0.001 |
| Jin et al. 33 |
MCV, Hb, iron Hcy |
Case‐control |
GPCAˉTGA + /TMA + BMS: 222 Control: 442 |
MCV, Hb, iron Control > BMS B12, acid folic Control > BMS Hcy Control < BMS |
p < 0.001 p = 0.066 p < 0.01 |
Note: All p values considered as significant if they were less than 0.05.
Abbreviations: BMS, burning mouth syndrome; GPCA, gastric parietal cell antibody; Hb, hemoglobin; Hcy, homocysteine; IDA, iron deficiency anemia; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; NS, nonsignificant; TGA, thyroglobulin antibody; TMA, thyroid microsomal antibody.
Table 2.
List of articles that evaluated salivary levels of micronutrients in BMS patients.
| Reference | Micronutrient | Study design | Study groups | Results | p Value |
|---|---|---|---|---|---|
| Syrjänen et al. 34 |
Na, CL, P Ca, Mg |
Case‐series | BMS: 10 |
Na, CL, P Control < BMS Ca, Mg Control > BMS |
p < 0.01 p < 0.01 |
| Vucicevic‐Boras et al. 35 | Mg | Case‐control | BMS + Xerostomia: 43 | Mg levels unchanged with regard to the salivary stimulation | NS (p > 0.05) |
| Hershkovich and Nagler 36 | Na, K | Case‐control |
BMS: 91 Control: 90 |
Na Control < BMS K Control < BMS |
p = 0.05 p > 0.05 |
| Granot and Nagler 37 | Na, K, Cl, Ca | Case‐control |
BMS: 35 Control: 19 |
Control < BMS | Na (p = 0.069) K (p = 0.002) Cl (p = 0.000) Ca(p = 0.042) |
| Pekiner et al. 2 | Mg, Zn, Cu | Case‐control |
BMS: 30 Control: 30 |
Mg Control > BMS Cu Control > BMS Zn Control < BMS |
p = 0.005 p = 0.9 p = 0.6 |
| Tvarijonaviciute et al. 38 | ROS | Case‐control |
BMS: 19 Control: 31 |
BMS > Control | p < 0.05 |
Note: All p values considered as significant if they were less than 0.05.
Abbreviations: BMS, burning mouth syndrome; CL, chlorine; Cu, copper; K, potassium; Mg, magnesium; NS, nonsignificant; Na, sodium; P, phosphorus; ROS, reactive oxygen species; Zn, Zinc.
Table 3.
List of articles that evaluated serum and salivary levels of micronutrients.
| Reference | Micronutrient | Study design | Study groups | Results | p Value |
|---|---|---|---|---|---|
| Jabber and Ahmed 39 | Vitamin D | Case‐control |
BMS: 28 Control: 29 |
No significant difference was detected between case and control groups in serum and saliva. | p > 0.05 |
Note: All p values considered as significant if they were less than 0.05.
Abbreviations: BMS, Burning mouth syndrome; NS, nonsignificant.
Table 5.
List of articles that evaluated levels of toxic elements in BMS patients.
| Reference | Micronutrient | Study design | Study groups | Medium | Results | p Value |
|---|---|---|---|---|---|---|
| Pigatto et al. 62 | Mercury | Case report | One BMS patient | – | Full recovery from BMS after the mercury tooth filling was removed | |
| Baričević et al. 63 | Nickel and Chromium | Case‐control |
Group I = Dental casting alloys (n = 54) Group II = Amalgam restorations (n = 14) Group III = Without metal restorations (n = 17) |
Saliva |
Frequency of BMS I > II > III Concentration of Ni and Cr in BMS patients were not statistically higher than patients without burning sensation. |
p = 0.02 p = 0.7 Ni and p = 0.2 Cr |
| Lopez‐Jornet et al. 64 | Na, K, Ca, Mg, Fe, Cu, Mn, Zn, B, P, S, Al, Pb, Cd, Cr, Ni, As, Be, Bi, Co, Li, Mo, Sb, Se, Sr, Ti, Tl, V | Case‐control |
BMS patient = (n = 28) Control = (n = 30) |
Saliva |
BMS > Control Sr, Ni, Pb, Li, Cr, B Other elements |
p = 0.000 p > 0.05 |
| Park et al. 65 | Copper, cobalt, zinc, chromium, nickel, aluminum, silver, iron, titanium, platinum, tin, palladium, and gold | Case‐control |
Group I = BMS patients, oral prosthesis for ≤5 years Group II = BMS patients, oral prosthesis for >5 years Group III = Control, oral prosthesis for ≤5 years Group IV = Control, oral prosthesis for >5 years |
Saliva |
Only the Ti levels had meaningful differences among the groups with below 5 years of prosthetic duration Group I > group III |
p = 0.016 |
| Guzzi et al. 66 | Mercury | Crossectional | BMS patients (n = 227) | Serum and saliva | Serum and salivary level were significantly higher than toxic limit. | p < 0.05 |
Note: All p values considered as significant if they were less than 0.05.
Abbreviations: Al, aluminum; As, arsenic; B, boron; Be, beryllium; Bi, bismuth; BMS, burning mouth syndrome; Ca, calcium; Cd, cadmium; CL, chlorine; Co, cobalt; Cr, chromium; Cu, copper; Fe, iron; K, potassium; Li, lithium; Mg, magnesium; Mn, manganese; Mo, molybdenum; Ni, nickel; NS, nonsignificant; Na, sodium; P, phosphorus; Pb, lead; S, sulfur; Sb, antimony; Se, selenium; Sr, strontium; Ti, titanium; TI, thallium; V, vanadium; Zn, zinc.
4.1. Vitamins
4.1.1. Vitamin B
The vitamins that examined in secondary BMS patients were limited to the B and D family. Vitamin B levels decreased in most studies in patients. Some studies reported frequent 5%–15% deficiencies of vitamins B and D in secondary BMS patients 27 other studies reported it at 80%–90%. 3 Vitamin B family members Thiamine (B1), Riboflavin (B2), and Pyridoxine (B6) are coenzyme of carbohydrate, protein (myelin), nucleic acids (RNA, DNA), and lipid metabolism pathways, they are effective in improvement of neuropathic pain because of their neuroprotective effects. Deficiency of vitamin B groups through changes in the central and peripheral nervous system can lead to disorders of the nociceptive pathway of the trigeminal nerve and the development of psychological distress in secondary BMS patients. 68 The DNA synthesis in the process of mitosis is directly dependent on the levels of folic acid and vitamin B12. 30 Vitamin B12 and folic acid deficiency may lead to hyperhomocysteinemia because these vitamins act as coenzymes in the production of methionine from homocysteine. Thrombosis in arterioles that feed the oral mucosal is related to high levels of homocysteine. 69 Deficiency of vitamin B12 and folic acid and excess of homocysteine may result in burning sensation and paresthesia of oral mucosa, hyposalivation, and dysgeusia by a disturbance in nerve sheath formation and destruction of nerve fibers, salivary glands, and taste buds. These oral disorders can cause eating difficulties and dysphasia that worsen hematinic deficiencies and exacerbate the oral symptoms in secondary BMS patients. 21 Of the studies, only two groups investigated the vitamin B12 and acid folic levels in secondary BMS patients. The first group examined only serum levels of vitamin B12/acid folic. The second group of studies simultaneously examined B12/acid folic and auto‐antibody (Ab) against parietal cells, homocysteine, and MCV level. All case‐control or cross‐sectional studies measured B12 and acid folic serum levels in secondary BMS patients without a salivary study. All serum studies have reported decreased levels of vitamin B12/acid folic, increased levels of homocysteine, MCV, and Ab against parietal cells. Also, in three clinical trials 13 , 50 , 54 and two case report studies, 42 , 47 positive therapeutic effects of these elements in reducing the symptoms of secondary BMS patients have been proven (Tables 1 and 4). In the case of vitamin B6, two studies have reported decreased levels 13 , 70 and two studies reported increased levels 3 , 23 of this vitamin in secondary BMS patients. Although much higher doses (67–105 folds) can lead to neurotoxicity, it appears that a limited increase in vitamin B6 in a background of impaired metabolic function such as stress, anxiety, and depression through a synergistic imbalance leads to dysfunction of neuroamines or steroids hormones and causes secondary BMS symptoms. 71 , 72 The results of B vitamin supplementations are also controversial. The study 3 did not show a significant difference in the improvement of patients' symptoms after taking vitamin B1 and B2 supplements compared with placebo however, another study 13 showed an improvement in 80% of patients with a deficiency of these vitamins.
4.1.2. Vitamin D
Vitamin D is introduced as a neurotrophic and neuroprotective hormone. Vitamin D applies its effects by overexpression of vitamin D receptor (VDR) and down expression of l‐type calcium channel. Several studies reported the role of vitamin D in the improvement of axonogenesis and transmission of sensory impulses in peripheral neurons sensory. 39 , 73 However, vitamin D deficiency (15%) in the serum of secondary BMS patients has been confirmed 70 one case‐control study reported no significant difference in serum and salivary levels of vitamin D compared with the control group. 39 We found no RCTs on the therapeutic effects of vitamin D in secondary BMS patients (Tables 1, 3, and 4).
4.2. Essential trace elements
4.2.1. Iron
The World Health Organization (WHO) reported that iron deficiency is a common medical problem with about 80% of prevalence in the general population, especially vegetarians. 12 Iron and hemoglobin (Hb) deficiency by reducing oxygen supply to oral mucosa causes subtle atrophy of the oral epithelium in secondary BMS patients, 2 which may be hidden from the clinician's vision during a clinical examination. The burning sensation of oral mucosa with spicy foods can be the only complaint of a patient with iron deficiency. Easily, dissemination of irritant agents from the atrophic oral epithelium into the connective tissue and irritation of nerve endings justify symptoms of patients. 50 Iron is necessary to maintain a normal turnover rate and oral epithelial cell functions. 30 Iron is one of the most common trace elements studied in patients with secondary BMS. Based on the results of the present review article, most studies that assessed the level of iron in the serum of secondary BMS patients were case‐control or cross‐sectional studies that have mainly reported a decrease in iron levels and their derivatives, hemoglobin and ferritin in secondary BMS patients. Low iron and hemoglobin levels have been reported in patients with high homocysteine. According to a clinical trial, 50 the positive effects of iron administration in improving the symptoms of BMS after iron supplementation are independent of changes in homocysteine serum levels (Tables 1 and 4).
4.2.2. Zinc
Adequate zinc levels are essential for neurological pathways, mucocutaneous barrier integrity, and emotional health. 74 Zinc deficiency causes liver metabolism of metallothionein and upregulation of pro‐inflammatory cytokines such as IL‐6, which is vital in the initiation and progression of psychological disorders, one of the etiological factors of secondary BMS. 75 Furthermore it seems that zinc deficiency can be effective in dysgeusia in secondary BMS patients by reducing salivary gustin. 50 Most studies in this field were case‐control, and cross‐sectional studies have evaluated the serum zinc level in secondary BMS patients. In general, most study results indicated zinc deficiency in secondary BMS patients. In addition, limited salivary studies have also reported secondary BMS results due to the presence of alloys used as dental restorations, which will be discussed in detail in the section on toxic trace elements. Furthermore, two clinical trial studies 45 , 52 reported the therapeutic effects of systemic zinc administration in improving secondary BMS patients' symptoms (Tables 1, 4, and 5).
4.2.3. Magnesium and calcium
Several studies have reported a prevalence of mood disturbances, such as anxiety and depression, in secondary BMS patients. A low level of magnesium (Mg) with a high level of calcium (Ca) in neural cells can lead to psychological and neurological disorders simultaneously. 76 Limited studies have examined serum and salivary levels of magnesium and calcium in secondary BMS patients, which has generally been shown to reduce the levels of these trace elements in patients. However, higher salivary levels of Mg and Ca were reported in secondary BMS patients with metal alloys in the oral cavity. 64
4.2.4. Copper
The results of studies on the salivary and serum levels of copper have been controversial, where no significance has been reported. Few studies have reported an association between higher copper levels and psychological disorders such as depression. 70 Since psychological disorders are known as a predisposing factor to secondary BMS, further studies are needed in the future to establish the relationship between copper, psychological disorders, and secondary BMS (Tables 1, 4, and 5).
4.2.5. Others
In this review article, we also found several trace elements, including Sodium (Na), chlorine (Cl), Potassium (K), and phosphorous (P), had contradictory results, which require further studies in the future to investigate the exact role of these trace elements.
4.3. Toxic trace elements
There is a narrow range of safe and adequate intake for some trace elements. Therefore, there are concerns about the potential toxicity of these elements with changes in diet. 8 Burning mouth is a common oral complaint in patients with metal restorations 65 corrosion where products of nickel‐chromium (Ni‐Cr) casting alloys can induce adverse effects on tissue reaction and hypersensitivity in the oral cavity. Elevated levels of metal ions in the oral cavity cause cytotoxicity, allergic reactions, and gene mutation. 63
A review of articles on the toxic role of elements in secondary BMS patients indicated much research on three elements: nickel, chromium, and cobalt. In addition, toxicant levels of mercury, as a main component of dental amalgams, have been observed in patients' serum and saliva. 66 Casting prostheses appears to increase the risk of symptoms in patients compared with amalgam restorations and longer exposure times. In addition to studies that reported increased levels of toxic trace elements in secondary BMS patients, there are limited reports of elevated levels of some essential trace elements, such as zinc and iron, in secondary BMS patients. These unexpected findings may be attributed to some factors, such as systemic diseases of the liver or kidney, a history of heart attack, and malnutrition. 65 Further research is needed to confirm the results of this type of study (Table 5).
4.4. Oxidant and antioxidants
Secondary BMS is a neuropathic disorder implicating the result of toxic free radical productions related to stressful conditions. 41 Oxidative stress has been introduced as an etiologic factor in neurodegenerative diseases such as ADHD (attention deficit hyperactivity disease), anxiety, and neurodegenerative changes in secondary BMS. 19 In recent years, much attention has been paid to the administration of antioxidant compounds to control the neurodegenerative processes in secondary BMS patients. Of these, alpha‐lipoic acid appears to be the most researched. Alpha‐lipoic acid or thioctic acid is an organic antioxidant that acts as a neuroprotective agent through elevation levels of cellular glutathione, neutralization of free radicals, protection of other antioxidants such as vitamin E and C that protect DNA from oxidative damage, 77 chelation of heavy toxic metals and overexpression of nerve growth factor, finally effect in nerve healing. 41 , 55 , 56
Considering that two case‐control and cross‐sectional studies reported higher serum or salivary levels of oxidants in secondary BMS patients 19 , 38 (Table 1), the role of oxidants–antioxidants in secondary BMS patients has been the subject of clinical trials. Many reports have approved significant positive therapeutic effects of plant‐derived antioxidants such as saffron, 60 aloe vera, 49 and lycopene. 51 Other antioxidant agents such as melatonin 58 and Alpha‐lipoic acid (ALA) have examined, the last of them having the highest number of clinical trial studies. The four case reports and case series studies have shown the therapeutic effects of antioxidant agents, methylene blue, 61 Chamomile, 57 ultramicronized palmitoylethanolamide 59 in secondary BMS patients (Table 4).
The micronutrient levels measurement is a crucial step in the management of patients with BMS. Considering the possible role of micronutrients in etiopathogenesis of secondary BMS, the more clinical trial studies need to evaluate the role of micronutrient supplements, dietary modifications, and replacement of dental restorations or prostheses in the improvement of secondary BMS patients' symptoms.
5. CONCLUSION
One of the important etiological factors in patients with secondary BMS is micronutrients imbalance. The iron, zinc, vitamin B family, vitamin D deficiency, and increased levels of homocysteine and oxidant agents have examined in secondary BMS patients. In addition, oral medicine specialists must consider the possible toxic effects of some elements in restorations and dental prostheses. Further studies, especially RCT in the future, are recommended.
AUTHOR CONTRIBUTIONS
Narges Gholizadeh: Conceptualization; writing—review and editing. Nafiseh Sheykhbahaei: Data curation; writing—original draft; writing—review and editing.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
TRANSPARENCY STATEMENT
The lead author Nafiseh Sheykhbahaei affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Gholizadeh N, Sheykhbahaei N. Micronutrients status as a contributing factor in secondary burning mouth syndrome: a review of the literature. Health Sci Rep. 2024;7:e1906. 10.1002/hsr2.1906
DATA AVAILABILITY STATEMENT
The authors confirm that the data supporting the findings of this study are available within the article.
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Data Availability Statement
The authors confirm that the data supporting the findings of this study are available within the article.