Introduction

The most common oral mucosal disease is recurrent aphthous stomatitis (RAS). The fundamental etiology and pathology, however, remain unknown [1]. Every medical professional, particularly dentists, should understand the integrating clinical, histological, and molecular concepts of RAS during the initial examination. There are three major types of aphthae according to distinct RAS appearances as follows: (i) major (MaRAS or Sutton's disease)—larger and deeper RAS that heal slowly and often cause scarring, (ii) minor (MiRAS or Mikulicz's aphthae)—containing >80% of all RAS cases and measuring up to 1 cm in diameter, and (iii) herpetiform (HeRAS)—manifesting as multiple recurrent clusters of small ulcers (<4 mm in diameter) [2, 3].

The lesion exhibits self-healing within 7-10 days, without leaving a scar [4, 5]. Some patients with severe pain and difficulty in eating do not require treatment and should be treated using palliative care [6, 7]. RAS is prevalent across all ages in developed countries [7, 8]. The incidence is high in women, non-smokers, the white race, and those with high socioeconomic status [9, 10].

The largest study on recurrent aphthous ulcer (RAU) comprised 10,000 young adults from 21 different countries and demonstrated that 38.7% and 49.7% of men and women suffered from RAU in their lives [11]. RAS treatment aims to relieve pain, prevent secondary infection, and promote healing. However, topical anti-inflammatory and anti-allergic medicines play an important role in the treatment of mild aphthous ulcers [12].

There are reports on several treatment options. Amlexanox 5%, for example, speeds healing and reduces pain, erythema, and lesion size [13, 14]; laser treatment is an alternative remedy for oral disorders characterized by pain and inflammatory reactions, as well as those requiring tissue regeneration. By reducing edema and pain and promoting cellular bio-stimulation, this therapy aids anti-inflammatory responses [15].

For decades, natural herbal medications have been widely used as an alternative therapy for RAS in various countries. They have been shown to lower the severity of pain and the duration of ulcers. One of these therapeutic alternatives to sesame is a natural phenolic component and a significant lignan extracted from sesame seeds (Sesamum indicum) and sesame oil [16].

Sesamol's anti-cancer therapeutic potential has been studied in several investigations. It has antioxidant, antimutagenic, anti-hepatotoxic, anti-inflammatory, anti-aging, and chemopreventive qualities, as well as acting as a metabolic regulator [17, 18]. However, to the authors' knowledge, no previous studies have comprehensively investigated herbal medicine efficacy in RAS treatment. As a result, the purpose of this study was to look into the usage of herbal medicine and its usefulness in the treatment of RAS.

Materials and Methods

The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards were used to report this systematic study.

Search strategy

From 2010 to 2020, we conducted a comprehensive electronic search in numerous well-known databases, including Saudi Dental Library, Google Scholar, Science direct, SciELO, Directory of Open Access Journals, Cochrane Library, and PubMed, with time and language constraints.

Eligibility criteria and study selection

The inclusion criteria were as follows:

• Research was conducted from January 1, 2010, to December 30, 2020.
• Randomized clinical trials.
• Double-blinded studies.
• Triple-blinded clinical trials.
• Patients without systemic diseases.
• English publications.
• No restrictions on age, sex, and race.
• Only patients diagnosed with RAS.
• Herbal medicine as the therapeutic agent (natural products).

The exclusion criteria were as follows:

• Studies with no access to availability.
• Animal studies.
• Duplication publications.
• Cases or trials without a control group.
• Reviews.
• Books.
• Research reports without relevant or adequate information.
• Published in any foreign language.
• Published before 2010.
• Chemical products as the therapeutic agent.

Data analysis

For the interest analysis, we used Review Manager 5.4 to conduct the qualitative data synthesis. Several known databases were systematically searched, including the Saudi Dental Library, Google Scholar, Science direct, SciELO, Directory of Open Access Journals, Cochrane Library, and PubMed. We combined the search terms and limited the study to the English language. According to the PRISMA checklist, all articles were screened based on their title, abstract, and full text. The collected data were subsequently analyzed using a forest plot design.

Study selection

The electronic search approach yielded 69 papers, which were reduced to 61 when duplicate publications were removed. Among the 61 articles considered eligible for further evaluation, 50 were excluded after the title and abstract screening for irrelevant outcomes or incorrect target population. Moreover, we excluded two articles for inappropriate analysis after performing a full-text assessment. The qualitative synthesis of the present review eventually contained 9 papers  (Figure 1).

Results and Discussion

The general characteristics of the nine studies selected for this review are summarized in Table 1. Among these, two studies were conducted in China [19, 20], five in Iran [21-25], one in Saudi Arabia [26], and one in Belgium [27]. All studies were published as journal articles and/or dissertations in English from 2010 until 2020. Moreover, all studies were conducted as in vivo human trials. However, there was no difference in the research aim; all studies evaluated the efficacy and safety of different herbal medicines for RAS.

Table 1. Study characteristics, including interventions

Description of the assessed publications

From the databases indicated above, we chose 61 abstracts that were published in English. Following screening the titles and abstracts, 50 papers were deleted, and two articles were removed after the full-text review, based on the exclusion criteria. The final analysis includes a full-text assessment of the extant 9 papers that matched the inclusion criteria.

Characteristics of the included studies

The characteristics of the 9 articles are summarised in Tables 1 and 2. A total of 844 RAS patients were included in this study. Each study included a sample size ranging from 28 to 227 patients.

Table 2. Treatment, duration, main outcomes, and side effects

Thirteen types of herbal medicine were used in gargles, membranes, mucoadhesive patches, toothpaste, and gelatin preparations. One was a traditional Chinese medicine, and another was an Iranian herbal medication. The experimental period ranged from 5 days to 6 months.

Qualitative data synthesis

The ulcer size, lesion duration, and pain remission were the main result measures examined in this review (Table 3).

Table 3. Summary of research outcomes

Size of ulcers

In their research, Deshmukh et al. and Mansour et al. measured the ulcer's maximal diameter and discovered that ulcer diameters varied. At the end of the treatment, they reported a statistically significant reduction in ulcer size [26, 27]. Hoseinpour et al., on the other hand, found no statistically significant difference in ulcer size [24]. Liu et al., on the other hand, measured the ulcer's maximal diameter and vertical diameter [19].

Pain reduction

Pain reduction was the major outcome index in all included trials. Ten of the 9 studies used the visual analog scale (VAS) to estimate the pain level. Only Pourahmad et al. used the numeric rating scale to assess the pain level [25]. The VAS scores in the herbal medicine groups were considerably lower than the control groups in all of the studies analyzed.

Side effects

Ten studies reported no side effects, whereas one study reported minimal side effects. Ghalayani et al. reported minimal side effects with the topical application of a hydroalcoholic extract of Punica granatum (PG) [21]; however, the report did not contain any detailed information.

Duration of ulcers

The duration of the ulcer was documented in six trials. The average healing time for aloe vera fermentation gel and chitosan gel, according to Shi et al., was 7.40 ± 1.85 days and 7.93 ± 1.84 days, respectively [20]. According to Halayani et al., there was a significant difference in mean healing time between 8.6±0.99 days of placebo therapy and 5.3±0.81 days of PG extract treatment (P<0.001) [21].

Deshmukh et al. demonstrated a statistical significance in the ulcer duration in both groups from day 0 to day 7 [27]. However, there was no statistical significance in the duration of ulcers between group I (Curcumin gel) and group II (triamcinolone acetonide gel).

Quantitative data synthesis

Main outcomes

The major findings of the meta-analysis were the differences in the improvement in ulcer size and pain intensity within the 3^rd, 5^th, and 7^th days post-treatment. The secondary outcomes included the mean duration of ulcer healing. All results were reported using the random effect models.

There was significant reduction in ulcer size progression within the 3^rd (standardized mean difference, [SMD] -0.70; 95% confidence interval [CI] [-1.23, -0.17], P=0.010) and 5^th days (SMD -0.92; 95% CI [-1.66, -0.18], P=0.01) However, this reduction in ulcer size was not significant on the 7^th day (SMD -0.41; 95% CI [-0.97, -0.15], P=0.15) (Figure 2).

There was a significant decrease in the pain intensity within the 3^rd (SMD -2.14; 95% CI [-3.64, -0.63], P=0.005), 5^th (SMD -1.88; 95% CI [-3.17, -0.58], P=0.005), and 7^th days (SMD -1.87; 95% CI [-3.19, -0.54], P=0.006) (Figure 3). Ulcer healing duration significantly decreased after initiating the treatment (SMD -0.96; 95% CI [-1.81, -0.10], P=0.03) (Figure 4).