|Year : 2021 | Volume
| Issue : 3 | Page : 303-310
Evidence-based effectiveness of herbal treatment modality for recurrent aphthous ulcers – A systematic review and meta-analysis
Adit Srivastava1, GC ShivaKumar2, Swarnasmita Pathak3, Ekta Ingle4, Anjali Kumari5, Sahana Shivakumar6, PG Navin Kumar7, Akhilesh Kumar Singh8
1 Department of Oral Medicine and Radiology, Faculty of Dental Sciences, IMS, BHU, Varanasi, Uttar Pradesh, India
2 Department of Oral Medicine and Radiology, Peoples College of Dental Sciences, Bhanpur, Bhopal, Madhya Pradesh, India
3 Department of Oral Medicine and Radiology, Regional Dental College, Guwahati, Assam, India
4 Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Riyadh Elm University, Riyadh, Kingdom of Saudi Arabia
5 Department of Oral Medicine and Radiology, Buddha Institute of Dental Sciences and Hospital, Patna, Bihar, India
6 Department of Public Health Dentistry, Peoples College of Dental Sciences, Bhanpur, Bhopal, Madhya Pradesh, India
7 Department of Public Health Dentistry, Faculty of Dental Sciences, IMS, BHU, Varanasi, Uttar Pradesh, India
8 Department of Oral and Maxillofacial Surgery, IMS, BHU, Varanasi, Uttar Pradesh, India
|Date of Submission||21-Nov-2020|
|Date of Decision||16-Dec-2020|
|Date of Acceptance||28-Jan-2021|
|Date of Web Publication||13-Dec-2021|
Prof. Sahana Shivakumar
Professor, Oral Medicine and Radiology, Peoples College of Dental Sciences, Bhanpur, Bhopal, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Recurrent Apthous Ulcers (RAU) has affected mankind through time immemorial. It is the most commonly prevalent oral mucosal lesion manifesting as painful ulcers involving non – keratinised oral mucosa. This review was done to assess herbal intervention in RAU patients for outcomes of ulcer size and pain intensity. Literature search of published articles in Medline, Scopus, Ovid and Journal of Web upto August 2020 were reviewed for the pre-described outcomes. Revman 5.4 software was used for study analysis. Total 9 articles were finally chosen for qualitative analysis. Meta analytic comparison demonstrated the ulcer reduction (CI = -2.22 to – 0.09; p <0.001) and pain intensity (CI = -4.60 to – 0.08; p <0.001) was reduced in the herbal group as compared to the controls. A definite evidence of herbal intervention was noted in alleviating RAU signs and symptoms.
Keywords: Erythema, exudates, herbal formulations, pain intensity, recurrent aphthous ulcers, ulcer size
|How to cite this article:|
Srivastava A, ShivaKumar G C, Pathak S, Ingle E, Kumari A, Shivakumar S, Navin Kumar P G, Singh AK. Evidence-based effectiveness of herbal treatment modality for recurrent aphthous ulcers – A systematic review and meta-analysis. Natl J Maxillofac Surg 2021;12:303-10
|How to cite this URL:|
Srivastava A, ShivaKumar G C, Pathak S, Ingle E, Kumari A, Shivakumar S, Navin Kumar P G, Singh AK. Evidence-based effectiveness of herbal treatment modality for recurrent aphthous ulcers – A systematic review and meta-analysis. Natl J Maxillofac Surg [serial online] 2021 [cited 2022 Sep 29];12:303-10. Available from: https://www.njms.in/text.asp?2021/12/3/303/332314
| Introduction|| |
A solitary/multiple aphthous ulcers, occurring at different intraoral sites have recurrent tendency leading to recurrent aphthous ulcers/Stomatitis (RAU), is/are the most common oral mucosal lesion, with a prevalence rate of 25%. It manifests as a painful, shallow ulcer with a very well-defined erythematous margin and has a yellowish-gray pseudomembranous center. It has a predilection for affecting women and higher socioeconomic status individuals.,
The lesion manifests clinically as a recurrent, painful ulcer with a necrotic base. The lesion presents as three clinical subtypes depending on the severity, number, and frequency of outbreaks into minor, major, and herpetiform types., Minor RAU presents itself as small, recurrent, and round ulcers that heal in 10–14 days without scarring. Major RAU are painful ulcers that are >5 mm in diameter and take a longer time to heal (6 weeks), leaving behind scars. Herpetiform RAU is characterized by numerous clusters of pinpoint ulcers that heal within 10 days.
The etiology of the lesion is diverse. Various predisposing factors such as food allergens, trauma, genes, hormonal fluctuations as in menstrual cycles and pregnancy, periods of stress, and exposure to certain chemicals and microbes are reported in the literature., Most of the time, the outbreak is self-limiting. As the causative factors and pathogenesis of RAU remain ambiguous, no definite treatment protocol exists. Conventionally, the treatment is provided to alleviate pain and lessen lesion duration. Commonly recommended are topical anesthetics, analgesics, and corticosteroids for recalcitrant lesions. Frequent exposure and long-term therapy to these medications can result in fungal pathologies and drug resistance, which further can lead to adverse effects and even life-threatening risks.
Alternative therapy in the form of herbal formulations for RAU treatment is widely employed across the globe for decades. A Plethora of Herbal mixtures is used in treating RAU. Literature evidence of such treatment has reported favorable effects in decreasing discomfort and ulcer duration. Hence, this analysis was undertaken to evaluate and reaffirm the efficacy of alternative herbal therapy in RAU.
| Methods|| |
Protocol and registration
The PRISMA checklist, used for reporting systematic reviews and meta-analysis (Moher et al., 2009) was employed for this analysis. The review was registered in PROSPERO bearing the registration number CRD42020213755.
The research question was focused using the “PICOS” framework. The research question formulated was used to determine the inclusion and exclusion criteria.
- Population – Adult patients affected with recurrent aphthous ulcer condition
- Intervention – Herbal formulation in any form (toothpaste, solution, mucogel)
- Comparison – Population-free from RAU infection formed the comparison group
- Outcome – The primary outcome assessed was ulcer reduction and pain intensity. Secondary outcomes of the level of exudate and erythema were also taken into consideration wherever mentioned
- Setting – Private practice or hospital or cases reported in the normal population
- Inclusion criteria – Randomized Control Trials and Controlled Clinical Trial studies assessing the outcome of herbal formulation treated RAU patients were included. Studies which recruited RAU patients based on “The diagnosis and management of recurrent aphthous stomatitis: A consensus approach,” which met the RAU diagnostic criteria. The experimental group received herbal medications used singly without any allopathic medicine. Control groups were recognized as those who were either placebo-treated or chlorhexidine rinse treated
- Exclusion criteria – Editorials, case reports, commentaries, animal studies, and articles written in a language other than English were excluded. Even randomized controlled trials (RCTs) done without a control group was not included.
Search engines such as MEDLINE, Ovid, Scopus, and Journal on web databases were searched for literature. All searches were performed through EBSCO. All relevant articles identified, which were obtained in full, through electronic and other search methods were checked. Abstract and conference proceedings were used to search and identify unpublished studies.
Key terms were used for the search: (1) recurrent aphthous ulcers; (2) herbal formulation; (3) recurrent aphthous stomatitis; (4) herbal medicine; (5) ulcer reduction; (6) pain scale; (7) level of exudates; and (8) level of erythema
The Boolean operator 'OR' was employed to complement truncated synonyms in each search theme. The Boolean operator 'AND' makes up the sum of each four main search themes to specifically output papers that give at least one result for each time.
Searches incorporated the literature from the year 2000 up until 2020 as the concluding year for the search. Only sources in English were used.
Process of study identification
Endnote X8 was used to import the results of the search data and to remove the duplicates. The screening of abstracts will be carried out by the use of the eligibility criteria and for those not excluded; full-text articles were searched for. These were, then, assessed for inclusion and upon acceptance, underwent data extraction, and quality assessment. Articles, failing to meet inclusion criteria, were omitted.
All the titles and the extracts were independently screened by the reviewers and on a meticulous review of the full-text articles, the data were extracted and documented in a data extraction table, which shows depicting data items evaluated for the review.
The data extraction table will include study ID, sample size, location, type of herbal formulation, outcome assessed, results, and adverse events.
Risk of bias in individual studies
Cochrane Handbook for Systemic Review of Interventions was used for assessing the quality of recruited studies. Criteria assessed were random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias).
Out of the 6 articles reviewed, 3 articles were processed for data synthesis as the rest did not provide data on the comparison group.
Data analysis was carried out using RevMan 5.4 software (Cochrane Review Group).
| Results|| |
The search results yielded a total of 429 manuscripts, of which were excluded as they were in duplicate. 286 articles were removed as only abstracts were available in search engines. Seventy-two articles were removed because of duplication. Further 72 articles had to be excluded as only abstracts were obtained of these articles. After assessing for the eligibility, 10 articles were included for qualitative evaluation and 9 analyzed quantitatively [Figure 1].
The systematic review evaluated 9 articles, all of which were RCTs in patients having recurrent aphthous ulcers, including both males and females. The herbal formulations reviewed were diverse, delivered in the form of mouthwashes, solution, toothpaste, essential oils, and gelatine preparations. Herbal formulation reviewed were Zataria multiflora, curcumin, pudilan extract, Echinacea, aloe vera, honey, myrrh, berberine, Yunnan Baiyao, and Camelthorn. Subjects assessed in the age range of 18–50 years in the analysis and were evaluated for 3–10 days (mean of 5.24 + 1.43). The study characteristics are summarized in [Table 1].
A total of 9 studies were included in the meta-analysis.
Ulcer size reduction
Ulcer reduction was reported in 9 studies, with 382 subjects in the herbal group and 367 in the control group. A highly significant reduction in ulcer (measured in mm) was observed in the experimental group than the control, with a mean difference of −1.16 (confidence interval [CI] = −2.22 to– 0.09; P < 0.001**; Z = 2.13) from the treatment initiation to pre-fixed follow-up period [Figure 2].
|Figure 2: Forest plot depicting ulcer size reduction between herbal and control group|
Click here to view
Pain scale intensity
Pain intensity was reported in 5 studies, with 221 subjects in the herbal group and 205 in the control group. A statistically significant reduction in the intensity of the pain (measured by visual analog scale) was found in the study group as compared to the control, with a mean difference of −2.26 (CI = −4.60 to –0.08; P < 0.001**; Z = 1.90) from the start of the treatment to the end of follow-up period. Four studies had to be excluded as they reported the percentage reduction of pain in participants [Figure 3].
|Figure 3: Forest plot depicting pain scale intensity between herbal and control group|
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Level of erythema
Erythema level was reported in 3 studies, with 132 subjects in the herbal group and 121 in the control group. A statistically significant reduction in the level of erythema (considered at level 3) was seen in the study group as compared to the control group, with a mean difference of −1.35 (CI = −1.86 to −0.84; P < 0.001**; Z = 5.20) from the beginning of the trial to the end of follow-up period. Only those studies that reported erythema levels were included [Figure 4].
|Figure 4: Forest plot depicting the level of erythema between herbal and control group|
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Level of exudate
The level of exudate was analyzed in 2 studies, with 65 subjects in each of the groups. A highly significant reduction in the level of exudates was observed in the study group as compared to the control population, with a mean difference of −1.30 (CI = −1.69 to −0.91; P < 0.001**; Z = 6.50) from baseline to the end [Figure 5].
|Figure 5: Forest plot depicting the level of exudate between herbal and control group|
Click here to view
| Discussion|| |
Since ancient times, natural products have been utilized to prepare curative agents for every possible ailment. They are either used in medicinal form or as food supplements. In the current era too, patients prefer natural or alternative medicine therapy to avoid the adverse effects associated with synthetic medications. Natural herbs possess least to no cytotoxic properties. Literature reports favorable results when efficacious herbal formulations are used as therapy. Results of our study are in similar lines to the review of Heydarpour et al. and Philips et al. evaluating herbal interventions for RAU and found a significant reduction in signs and symptoms. Herbs have exhibited antibacterial, anti-inflammatory, immunomodulatory, and antiviral benefits.
Overall 749 patients in a total of 9 clinical trials were evaluated for the current analysis. In comparison to the control group, the herbal formulation group statistically facilitated the recovery of RAU lesions measured by reduction in ulcer diameter, pain alleviation, level of exudates, and erythema.
Pudilan extract is a mixture of dandelion, Isatis root, Bunge corydalis herb, Scutellaria baicalensis, gallnut, and propolis. It exhibits significant anti-inflammatory effects mediated by tumor necrosis factor-alpha inhibition and secretion of interleukin along with a decrease in nitric oxide and prostaglandin E2 inflammatory mediators. It inhibits bacterial growth through ATP synthesis interference; analgesic and antipyretic action by decreasing production of arachidonic acid and exudates reduction by protein precipitation promotion., Myrtus communis or myrtle found commonly in North Iran is a perennial shrub widely employed for candidiasis treatment in Persia. This extract has shown antibacterial, analgesic, and anti-inflammatory properties., Camel thorn can preserve even in the challenging non-favorable ecological oral conditions and exhibits anti-inflammatory and protective membrane characteristics. It inhibits histidine decarboxylase thus facilitating the prevention of ulcer formation. Turmeric is found as a dry rhizomatous plant possessing anti-inflammatory and antioxidative effects preventing and suppressing the process of inflammation. Yunnan Baiyao is widely employed for treating RAU.
An attempt to reduce heterogeneity was made by the inclusion of only those articles which evaluated RAU patients receiving herbal formulations without any combinations and placebo groups. Yet, some elements of heterogeneity cannot be overlooked as the studies did not employ a consistent approach in RAU diagnosis. Further, the time duration of follow-up for all the outcomes assessed was also not the same.
The risk assessment of the studies was mostly of unknown type, owing to poor study design and greater risks in the performance, detection, attrition, and reporting bias [Table 2]. These calls for multi-centered clinical trial analysis designed with precise criteria and standardized methodology to assure high-quality studies.
All the included studies in this analysis employed clinical trial design-making for Grade A (Level 1) level of evidence-based on the criteria given by the Oxford Center for Evidence-Based Medicine. Incorporation of Randomised control trial in meta – analysis ranks it to be of highest evidence, when designed and implemented correctly. This is the best design to be employed to elicit causal relationship.
The main outcome measured in all the studies were the size of the ulcer and the pain intensity scale. An inconsistency in studies was noted with regards to the ulcer size in terms of size, duration time, and level of pain. A standard manner of measurement was lacking especially with ulcer size. RAU can present as a single ulcer, multiple ulcers of various shapes in the mucosa, making it nonsuitable to measure ulcer diameter accurately. Hypothetically, calculating ulcer diameter may sound better, but calculating it precisely in clinics is questionable. Liu et al., hence in their study, proposed that the specific way to address this is to measure maximum and vertical diameter, which is also convenient.
Till date, a definitive treatment choice is not available for prevention or to cure aphthous ulcers. The existing options aim for symptomatic improvement such as reduction in lesion count or extension of lesion-free intervals. A thorough consideration for all predisposing factors must be given such as testing of blood samples for iron, folate, ferritin, and Vitamin B12.
Visual analog scale was used for pain assessment in all the included studies, which measured a range of “no pain” to “unbearable pain” on a 100 mm horizontal line. The use of this scale demonstrated greater reliability.
Herbal formulations seemed to be effective in RAU therapy, but still, further research in this arena is needed placing stress on specific protocols, type of intervention, and standard measures of assessment. In addition, homogenizing the dose and application technique will help provide a better picture. Although the present analysis yielded favorable results, the applicability of these results clinically is yet not clear.
Herbal formulations provide a broader range of therapeutic choices for both practitioners and patients. Owing to their minimal adverse effects, it is of great utility as alternative to chemical medicine.
| Conclusion|| |
Owing to the complex pathogenesis of RAU lesions and the unpredictable outcome associated with the existing intervention modalities, coupled with the potential risk of adverse effects of systemic medications, herbal formulations are preferred. They offer the advantage of producing less adverse effects and are significantly efficacious.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]