Background
One of the most common lesions in the oral cavity and mucosa is recurrent aphthous stomatitis (RAS) [
1]. The origin of the term “aphtae” is the Greek word “ophthi” which implies inflammation. Because of the painful and inflammatory nature of RAS, it can decrease the quality of life and affect the daily performance of the patient [
2]. The prevalence rates of RAS are 25 and 40% among adults and children, respectively [
3]. Many factors, including infections, endocrine and immune system disorders, stress, genetics, nutritional deficiencies, and trauma, can cause RAS [
4]. Oxidative stress also plays an important role in the formation of an aphthous lesion by damaging DNA [
5]. Several methods are used to control the pain, inflammation, and infection of a mucosal lesion, including systemic therapies like vitamin B12 and folate [
1], as well as topical formulations such as chlorhexidine rinse, a mouthwash of doxycycline or minocycline, lidocaine ointment and spray, and topical corticosteroids [
6].
Zinc is one of the critical trace elements in humans [
7]. It plays crucial roles in physiological functions, such as growth and reproduction of cells, normal functioning of the immune system, collagen synthesis, and wound healing [
8,
9]. It has been proven that zinc deficiency is associated with numerous physiological defects and the pathogenesis of some oral mucosal diseases. It has been found that the administration of supplements containing zinc may improve such ulcers [
10]. Although zinc deficiency among RAS patients has not been investigated yet, the delay in wound healing in zinc deficiency indicates the importance of this trace element for the metabolic responses appropriate for wound healing [
7].
Deficiency of antioxidants is one of the main causes of RAS and zinc has been suggested as a useful agent for balancing cellular oxidation and reduction reactions. It is also an anti-inflammatory agent and is recommended as the sulfate salt, especially in the treatment of RAS in patients who are treated simultaneously with radiotherapy or chemotherapy [
11,
12]. The efficacy of oral zinc formulation (150 mg daily) [
6] and its mucoadhesive formulation (as zinc sulfate) has been reported in several clinical trials in the oral ulcer healing process [
13]. A mouthwash of 5% zinc sulfate is also effective in both prophylaxis and treatment of recurrent oral ulcers [
14].
Mucoadhesive tablet is a drug delivery system that attaches to the mucosal layer and provides prolonged local release of the drug from the mucosal surface. Using this medication form protects drug molecules from the first pass metabolism and a higher drug concentration is achieved on the intended location [
15].
Considering the anti-inflammatory and pharmacological effects of zinc sulfate in oral ulcers and no previous study on the evaluation of zinc mucoadhesive form, this study was conducted on patients with RAS.
Discussion
This paper was the first placebo-controlled clinical trial on using a mucoadhesive tablet of zinc sulfate in RAS. The primary outcome of this study showed that ‘the mucoadhesive formulation of zinc sulfate in patients with RAS dramatically accelerated inflammation and pain of the aphthous lesion in comparison to the placebo’. There was a significant reduction in wound diameter and its inflammation on days 3, 5, and 7 in the intervention group compared to the placebo group, which can be attributed to the anti-inflammatory and protective properties of topical zinc. On the fourth day of the study, the pain in the intervention group was significantly lower compared to the placebo group and it was resolved in the intervention group at the end of the study. No complication related to the intervention was reported during this study.
Recurrent aphthous stomatitis is a common disorder of mucosa in the oral cavity that is characterized by painful and recurrent inflammatory ulcers on the oral mucosa [
20]. It has no definitive treatment because the exact etiology of RAS is still unknown [
21]. The goal of treatment is to reduce the pain, duration of inflammation, and restoring normal oral function. The secondary objective is to reduce the frequency and intensity of relapse and to maintain the recovery of the disease [
22]. Treatments used to improve RAS include topical anesthetics, anti-inflammatory drugs, topical corticosteroids, and local antibiotic therapy (tetracycline) [
23]. Other agents like zinc supplements have also been reported in the recovery of aphthous ulcers [
10]. However, based on several clinical trials, it seems that systemic zinc supplement therapy in RAS is still a matter of debate [
24‐
26].
Contact time with mucosal tissue is important in drug delivery to the mucosa [
27]. Topical zinc application leads to the regeneration of epithelial cells, reducing inflammation, and inhibition of bacterial growth [
28]. Topical forms of this trace element have more predictable and effective pharmacological results in RAS remission and patients show more compliance to use such formulations [
15,
29]. In the present research, the mucoadhesive tablet was placed on the aphthous wound and with its proper adhesion to the mucosa, it kept zinc in direct contact with the wound to exert its therapeutic effects. Zinc, as a micronutrient, plays a key role in proliferation regulation, immunity status, and wound healing. It adjusts DNA and RNA regeneration and renovation processes. It also controls the activities of macrophages, neutrophils, cytotoxic T cells, as well as the complement system [
30]. Zinc also has antioxidant properties, including the prevention of ultraviolet radiation damage and a reduction in the risk of malignancy and is considered as an anti-inflammatory agent [
11,
31‐
33].
Parya Haghpanah et al. reported that muco-bioadhesive containing Ginger extract was effective in the management of RAS pain but no significant impact on the size of aphthous lesions. In the present study, zinc was effective in the management of both pain intensity and the diameter of the ulcer. The sample size was also small in the mentioned study compared to our study [
34].
Yanxiong Shao and Haiwen Zhou showed that reduction in ulcer size in the treated group with a mucoadhesive film containing chitosan was significantly more than that of the control group but there was no significant difference in terms of pain score, reduction in pain score and ulcer size between two groups [
35]. They presented chitosan as an effective agent to use in the oral mucoadhesive film for the healing of RAS. While in this study both pain score and diameter of the lesion were lower in zinc mucoadhesive tablet group compared to the placebo group and zinc is suggested to manage RAS due to its several mechanisms like anti-inflammatory property.
Skaare et al. suggested the effectiveness of zinc and triclosan on oral ulcer healing, which was confirmed by the zinc supportive effect and the anti-inflammatory effect of triclosan [
36]. In our study, because of the anti-inflammatory effect of zinc, it can be effective in the healing of aphthous ulcers.
Jahanshahi et al. designed a study to evaluate the efficacy of triamcinolone in the symptomatic treatment of RAS. The study was done by adding triamcinolone to the mucous adhesive base on 40 patients. In the intervention group, the diameter of lesion and pain in the second session were significantly lower than the placebo group (
P = 0.043). However, no significant difference was observed in the third session (
P > 0.05) [
37]. Meanwhile, in our study by adding zinc sulfate to the mucous adhesive base, there was a significant decrease in the diameter of the lesions in the intervention group from the second to the fifth day of the study.
Since pain in the ulcer tissue is usually due to the secondary infection or mechanical and chemical stimulators [
38], the use of the mucoadhesive formulation as coverage and protective agent can cause premature anesthesia and accelerate the recovery time. According to the results of the present study, zinc can reduce the pain, diameter of the wound, its surrounding inflammation, and accelerates the recovery time of RAS. ‘The limitation of this project was that the patients were not directly monitored for right dose consumption’. It is recommended that a multi-center study be conducted in the future to gain more reliable results.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.