2022 Volume 10 Issue 1

NATURAL THERAPEUTIC AGENTS IN THE TREATMENT OF RECURRENT APHTHOUS ULCER: A SYSTEMATIC REVIEW AND META-ANALYSIS

Baraa Issam Abdulrahman1*, Abdulmohsen Jamal Alanazi2, Abdulmajeed Jamal Alanazi2, Faisal Fahad Idrees2, Abdulaziz Abuabah2, Iman T El Mansy3, Ammar AbuMostafa3, Khalid Jamal Alanazi4

1Department of OMFS and Diagnostic Sciences, College of Dentistry, Riyadh Elm University, Riyadh, Saudi Arabia. [email protected]

2College of Dentistry, Riyadh Elm University, Riyadh, Saudi Arabia.

3Department of Restorative Dentistry, College of Dentistry, Riyadh Elm University, Riyadh, Saudi Arabia.

4Department of Dental, Ministry of Health, Riyadh, Saudi Arabia.


ABSTRACT

Recurrent aphthous ulcer is a painful oral mucosa ulcer that affects about 20% of the population. Researchers have recently presented new therapeutic options, including herbal pharmaceuticals. We wanted to see how different herbal therapeutic agents affected the size of the aphthous ulcer, pain intensity, and healing time in this systematic review and meta-analysis. A systematic search was performed to extract articles from the Saudi Dental Library, Google Scholar, Science direct, SciELO, Directory of Open Access Journals, Cochrane Library, and PubMed. We included 9 articles with a total of 844 patients (441 cases and 403 controls). The ulcer size progression was significantly reduced on the 3rd (SMD -0.70; 95 percent confidence interval (CI) [-1.23, -0.17], P=0.010) and 5th days (SMD -0.92; 95 percent CI [-1.66, -0.18], P=0.003) days. However, this reduction was not significant on the 7th day (SMD -0.41; 95% CI [-0.97, -0.15], P=0.15). There was a significant decrease in the pain intensity within the 3rd (SMD -2.14; 95% CI [-3.64, -0.63], P=0.005), 5th (SMD -1.88; 95% CI [-3.17, -0.58], P=0.005), and 7th days (SMD -1.87; 95% CI [-3.19, -0.54], P=0.006). Ulcer healing duration was significantly decreased post-treatment (SMD -0.96; 95% CI [-1.81, -0.10], P=0.03). All herbal medicines effectively reduce ulcer size and pain intensity, limiting ulcer healing duration. Aloe vera gel, hydroalcoholic extract of Punica granatum (PG), and camel thorn distillate were most effective in decreasing the ulcer size. Moreover, PG extract displayed the best prognosis in reducing pain intensity and minimizing the healing duration.

Key words: Herbal medicine, Recurrent aphthous ulcer, Meta-analysis, Systematic review, Dentistry.


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).

 

Figure 1. PRISMA flow chart

 

 

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

Authors

Country

Techniques

Vivo (Human)

Aims of study

Ghalayani et al., (2013) [21]

Iran

A randomized, double-blind, and placebo-controlled study

In vivo (Human)

To assess the efficacy of Punica granatum extract on the clinical management of RAS.

Liu et al., (2012) [19]

China

A randomized, double-blind, placebo-controlled investigation conducted across three stomatology clinical centers

In vivo (Human)

To assess the efficacy of Yunnan Baiyao herbal extract formulated in toothpaste as an alternative therapy for minor RAS.

Darakhshan et al., (2019) [22]

Iran

This study was divided into two segments: (i) laboratory procedures that involved the preparation of palmar-plantar erythrodysesthesia topical gel; (ii) a clinical trial that assessed its effects on RAS

In vivo (Human)

To determine the effects of native pomegranate from western Iran and not the central regions, on RAS lesions.

Shi et al., (2020) [20]

China

A clinical trial

In vivo (Human)

To develop and test the efficacy of aloe vera fermentation gel in reducing healing time and restoring microbial diversity in the oral cavity of patients with RAS.

Babaee et al., (2015) [23]

Iran

A triple-blind clinical trial study

In vivo (Human)

To assess the therapeutic effects of Zataria multiflora in treating oral aphthous lesions.

Hoseinpour et al., (2011) [24]

Iran

A randomized, double-blind, placebo-controlled investigation

In vivo (Human)

Mouthwash containing Rosa damascena extract was more effective than the placebo in the treatment of recurrent aphthous stomatitis.

Mansour et al., (2014) [26]

Saudi Arabia

A randomized, double-blind, and placebo-controlled study

 

In vivo (Human)

To assess the clinical efficacy and safety of novel customized natural oral mucoadhesive gels, containing aloe vera or myrrh as the active ingredients in treating MiRAS.

Deshmukh & Bagewadi, (2014) [27]

Belgium

A randomized clinical trial

In vivo (Human)

To assess and compare the efficacy of Curcumin with triamcinolone acetonide gel in treating MiRAS.

Pourahmad et al., (2010) [25]

Iran

A randomized, double-blind, and placebo-controlled clinical trial.

In vivo (Human)

To assess the effects of camel thorn distillate on RAS.

 

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

Author/Year

Treatment

course

Outcomes

(size, pain, and healing rate)

Side effects

Ghalayani et al., (2013) [21]

7 days

Pain using the Visual Analog Scale (VAS), ulcer size, and healing rate

Minimal side effects

Liu et al., (2012) [19]

5 days

Pain, ulcer size, and healing rate

No side effect

Darakhshan et al., (2019) [22]

7 days

Pain using the VAS and healing rate

No side effect

Shi et al., ( 2020) [20]

10 days

Pain and healing rate

No side effect

Babaee et al., (2015) [23]

10 days

Pain intensity and healing rate

No side effect

Hoseinpour et al., (2011) [24]

14 days

Pain and ulcer size

No side effect

Mansour et al., (2014) [26]

6 days

Pain using the VAS and ulcer size

No side effect

Deshmukh & Bagewadi, (2014) [27]

6 months

Pain using the VAS, ulcer size, and healing rate

No side effect

Pourahmad et al., (2010) [25]

2 weeks

Pain using the numeric rating scale and ulcer size

No side effect

 

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

Medications/formula

Sample size (treatment/control)

Study type

Article source

Authors/year

Punica granatum gel

40

RCT

J Res Pharm Pract. 2013 Apr-Jun; 2(2): 88–92

Ghalayani et al., (2013) [21]

Toothpaste comprising Yunnan Baiyao

227

RCT

Evid Based Complement Alternat Med. 2012; 2012: 284620

Liu et al., (2012) [19]

Pomegranate peel gel

56

RCT

Curr. Issues Pharm. Med. Sci., Vol. 32, No. 3, Pages 115-120

Darakhshan et al., (2019) [22]

Aloe vera gel

35

RCT

Canadian Journal of Infectious Diseases and Medical Microbiology Volume 2020,

Shi et al., (2020) [20]

Zataria multiflora essential oil

28

A triple-blind clinical trial study

Dent Res J (Isfahan). 2015 Sep-Oct; 12(5): 456–460.

Babaee et al., (2015) [23]

Camelthorn distillate

93

RCT

JDDG: Journal der Deutschen Dermatologischen Gesellschaft. 2010 May;8(5):348-52.

Pourahmad et al., (2010) [25]

Rosa damascene mouthwash

50

RCT

Quintessence Int. 2011 Jun;42(6):483-91.

Hoseinpour et al., (2011) [24]

Novel aloe vera and myrrh-based oral mucoadhesive gel

90

RCT

J Oral Pathol Med (2014) 43: 405–409

Mansour et al.,(2014) [26]

Curcumin with triamcinolone acetonide gel

60

RCT

Int J Pharm Investig

. 2014 Jul;4(3):138-41

Deshmukh & Bagewadi, (2014) [27]

Alcoholic and water fragments of Punica granatum var. passiflora, P. granatum var. Sweet Alak, and P. granatum var. Saveh Black w

210

Double-blind

Integr Med Res

2014 Jun;3(2):83-90.

Gavanji et al., (2014) [28]

 

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 3rd, 5th, and 7th 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 3rd (standardized mean difference, [SMD] -0.70; 95% confidence interval [CI] [-1.23, -0.17], P=0.010) and 5th days (SMD -0.92; 95% CI [-1.66, -0.18], P=0.01) However, this reduction in ulcer size was not significant on the 7th 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 3rd (SMD -2.14; 95% CI [-3.64, -0.63], P=0.005), 5th (SMD -1.88; 95% CI [-3.17, -0.58], P=0.005), and 7th 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).

 

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Figure 2. Post-treatment progression of the ulcer size after 3,5, and 7 days

 

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Figure 3. The pain intensity on 3rd, 5th and 7th day

 

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Figure 4. Ulcer healing duration

 

Heterogeneity and publication bias

The almost symmetrical distribution of data acquired from all experiments was revealed by visual inspection of the funnel plots. However, significant heterogeneity was observed in all analyses conducted on the ulcer size, pain intensity, and healing duration.

We evaluated the effects of natural and experimental treatments on the size of RAS, pain intensity, and ulcer healing length in this systematic review and meta-analysis. Different treatment modalities were introduced to improve RAS. The pooled analysis showed that the included herbs effectively reduced the ulcer size and pain intensity, lowering the healing duration. The findings regarding the ulcer size were consistent with those by Heydarpour et al., who assessed non-pharmaceutical interventions for treating RAS [29]. Compared with the control group, topical herbal medications or natural derivatives considerably relieved RAS symptoms by reducing the pain, ulcer size, and healing duration without serious side effects [29].

This review reported that aloe vera fermentation gel and hydroalcoholic extract of PG were most effective in reducing the ulcer size (SMD -1.60; 95% CI [-2.38, -0.82]) and (SMD -1.07; 95% CI [-1.74, -0.40]), respectively, within the 3rd day. Aloe vera fermentation gel improved healing and restored RAS microbiota abnormalities, according to Shi et al. [20]. It has the potential to reduce the number of dangerous oral bacteria like Actinomyces and Granulicatella, signifying a better prognosis. As a result, it may improve the quality of life for RAS patients [20]. For RAS patients, wound healing and anti-inflammation are crucial. Aloe vera is a cactus-like plant that is widely used in medicine to treat burn injuries, cutaneous lesions, and mouth ulcers, making it an ideal RAS treatment option [23].

There are limited data on the effects of PG in treating RAS; however, Ghalayani et al. reported that the topical application of PG hydroalcoholic extract might be an effective treatment for MiRAS. The benefits of using PG in RAS treatment include clinical improvements such as pain reduction and improved RAS healing time, patient compliance, convenience of usage, and minimal side effects [21].

Camelthorn distillate also revealed a good prognosis for the ulcer size on the 5th day of initiating treatment (SMD -2.32; 95% CI [-3.20, -1.43]). Pourahmad et al. reported that camel thorn distillate displays similar efficacy as other medications used to treat oral aphthous ulcers. Its medicinal activity could be attributed to the flavanones (alhagitin and alhagidin) found in this plant [25].

Aloe vera and myrrh did not significantly decrease the ulcer size within the 3rd (SMD 0.09; 95% CI [-0.42, 0.60]) and (SMD 0.00; 95% CI [-0.51, 0.51]) 7th day of treatment, compared with the medicines in other included studies. However, Mansour et al. suggested that herbal medicines could provide an alternate therapy for MiRAS. The short-term topical treatment of aloe vera and myrrh has proven beneficial in RAS management. Although aloe vera is more effective in reducing ulcer size, erythema, and exudation, myrrh was more effective in reducing pain. In addition, the absence of side effects with any of the three mucoadhesive gels credences these medication formulations' safety [26].

Aloe vera's wound-healing qualities have been linked to numerous mechanisms, including keeping the wound moist, encouraging epithelial cell migration, accelerating collagen maturation, enhancing collagen cross-linking, and increasing blood flow [30-34].

PG hydroalcoholic extract demonstrated the best prognosis in decreasing pain intensity within the 3rd (SMD -7.30; 95% CI [-9.10, -5.51]), 5th (SMD -5.81; 95% CI [-7.29, -4.33]), and 7th days (SMD -19.19; 95% CI [-23.66, -14.72]). Furthermore, it was most effective in minimizing the healing duration (SMD -3.80; 95% CI [-4.87, -2.72]).

Ghalayani et al. reported a decrease in pain elimination by 3.4 days, compared with the control group (5.7 days) [21]. The antioxidant activity of PG neutralizes oxygen free radicals, which are vital in the inflammatory process and the development of aphthous ulcers. This, in turn, may promote the healing process [35]. Considering its ability to prevent enterotoxin production, Braga et al. proposed PG extract as a promising antibacterial therapeutic agent. The effectiveness of PG products can be attributed to their anti-irritant and anti-inflammatory properties [36].

This review has a few limitations. The included trials displayed poor homogeneity with several factors such as different types of treatment, sample size, dosage, application strategy, test measure, and treatment period. In addition, the details regarding the measurement of outcomes were not mentioned. The key outcome indicators, according to current data, are ulcer size, lesion duration, and pain intensity. However, the researchers did not follow the standard method to assess them, particularly the ulcer size. The ulcer size could have been underestimated based on the maximum diameter measurement. Only Liu et al. used the greatest diameter and vertical diameter to determine the ulcer size [19]

Conclusion

The pooled results suggested that all included herbs effectively reduced the ulcer size and pain intensity, besides limiting the healing duration within the 3rd, 5th, and 7th days after initiating the treatment. Aloe vera gel, PG hydroalcoholic extract, and camel thorn distillate were most effective in decreasing the ulcer size. PG extract resulted in the best prognosis in reducing the pain intensity and minimizing the healing duration of the ulcer. The formula, dosage, therapy duration, and application procedures of the herbal medication, as well as the control intervention, should be included in future investigations.

Acknowledgments: We want to thank the Research and Innovation Center of Riyadh Elm University for providing the required help and support for conducting this study.

Conflict of interest: None

Financial support: None

Ethics statement: This study was approved by the ethics committee of Riyadh

Elm University’s research and innovation center (IRB No: FUGRP/2021/216/378/371).

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Issue 3 Volume 10 - 2022
Call for Papers