Journal of Dermatological Treatment
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Evidence-based recommendations for the treatment of recurrent aphthous stomatitis: insights from an umbrella review
Nader A. Al-Aizari, Hashem M. Al-Shamiri, Bayan K. AlShehri, Khalid S. Alhomood, Saeed R. Alzahrani, Waad R. Abuhasna & Sadeq Ali Al-Maweri
To cite this article: Nader A. Al-Aizari, Hashem M. Al-Shamiri, Bayan K. AlShehri, Khalid S. Alhomood, Saeed R. Alzahrani, Waad R. Abuhasna & Sadeq Ali Al-Maweri (2026) Evidence-based recommendations for the treatment of recurrent aphthous stomatitis: insights from an umbrella review, Journal of Dermatological Treatment, 37:1, 2622245, DOI: 10.1080/09546634.2026.2622245
To link to this article: https://doi.org/10.1080/09546634.2026.2622245
© 2026 The Author(s). Published with license by Taylor & Francis Group, LLC
Published online: 02 Feb 2026.
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JOURNAL OF DERMATOLOGICAL TREATMENT 2026, VOL. 37, NO. 1, 2622245 https://doi.org/10.1080/09546634.2026.2622245
REVIEW ARTICLE
Evidence-based recommendations for the treatment of recurrent aphthous stomatitis: insights from an umbrella review
Nader A. Al-Aizaria, Hashem M. Al-Shamiria, Bayan K. AlShehria, Khalid S. Alhomooda, Saeed R. Alzahrania,
Waad R. Abuhasnaa and Sadeq Ali Al-Mawerib 
aDentistry Department, Vision College in Riyadh, Riyadh, Saudi Arabia; bCollege of Dental Medicine, Qatar University, Doha, Qatar
ABSTRACT Objective: To compare the effectiveness and safety of pharmacological, physical, and complementary interventions for recurrent aphthous stomatitis (RAS) across clinically relevant outcomes. Methods: This umbrella review was conducted according to PRISMA and Cochrane guidance and registered in PROSPERO (CRD42024594292). PubMed, Scopus, and the Cochrane Library were searched through August 2025. Eligible studies were systematic reviews, meta-analyses, or network meta-analyses evaluating treatments for RAS. Methodological quality was assessed using AMSTAR 2, and overlap of primary studies was quantified using the corrected covered area. Results: A total of 41 reviews were included. Topical corticosteroids and low-level laser therapy consistently reduced pain and shortened healing time, although evidence for recurrence prevention was limited. Hyaluronic acid and herbal agents demonstrated favorable short-term efficacy with good safety profiles. Systemic agents such as colchicine and thalidomide showed benefit in severe or refractory RAS, but were constrained by the adverse effects and low-certainty evidence. Conclusion: Evidence supports topical corticosteroids, hyaluronic acid, and laser therapy for short-term symptom control in RAS, while systemic agents should be reserved for selected refractory cases.
CLINICAL SIGNIFICANCE This synthesis provides clinicians with an evidence-based overview of RAS therapies, emphasizing efficacy–safety balance and highlighting gaps requiring higher-quality comparative research.
ARTICLE HISTORY Received 7 December 2025 Accepted 21 January 2026
KEYWORDS Stomatitis; aphthous; mouth ulcers; systematic review; evidence-based dentistry; therapeutics; treatment outcome
Introduction Recurrent aphthous stomatitis (RAS) is one of the most noticeable oral mucosal disorders, characterized by the recurrent formation of painful ulcers and lesions on the oral mucosa. RAS is a highly prevalent oral disease, affecting a large percentage of the population (5% – 25%) (1), and may reach up to 60% in certain populations (2). RAS can adversely impact patients’ quality of life and can interfere with the daily oral functions, such as eating, drinking, and speaking (3).
Despite the high occurrence of RAS and its significant impact on patients’ quality of life, its exact cause and mechanism remain elusive (4,5). It is thought to be multifactorial, involving genetic, immunological, microbial, and environmental factors (4–7). The multifaceted nature of RAS necessitates a holistic treatment and management approach.
Management of RAS is quite challenging due to the disease’s clinical heterogeneity (3). A wide array of pharmacological and non-pharmacological therapies has been evaluated for management of RAS with limited success (4). However, topical corticosteroids, in particular triamcinolone acetonide, have been considered the mainstay of management for mild and moderate episodes owing to their potent anti-inflammatory properties and minimal bioavailability (8,9). In patients with severe or frequent lesions, systemic agents like corticosteroids (7,10), colchicine (11,12), and thalidomide (13) have been used. However, the systemic side effects of the above-mentioned drugs limited their use. In addition, topical antibiotics (such as tetracyclines) have been used for the management of RAS (10,11). Recently, laser therapy (14–16) has become a faster adjunctive therapy that promotes epithelial healing and reduces inflammation through photobiomodulation, which stimulates cell growth and tissue remodeling while relieving pain by changing the inflammatory mediators. In addition, biological agents (17) for TNF-α and interleukin blockade represent a new therapeutic option for unresponsive cases, thus suggesting an increasing recognition of the autoimmune nature of RAS (18).
A range of natural and herbal remedies such as Aloe vera (19), licorice root extract (20), honey (21), probiotics (22,23), and other herbal remedies (24), which are believed to possess anti-inflammatory and microbiome-modulating properties, have been proposed as adjunctive treatments (21,22). This plethora of therapeutic options highlights the need for a truly personalized, patient-centered approach that considers disease extent, recurrence frequency, comorbid conditions, and patient preferences to improve outcomes.
Despite the availability of multiple systematic reviews and meta-analysis evaluating individual therapeutic modalities for RAS, the evidence remains fragmented, heterogenous, and methodologically inconsistent. Existing reviews frequently focus on single intervention classes, and vary substantially in quality, and thus reported conflicting conclusions. Moreover, recently published network meta-analysis and systematic reviews have expanded the
© 2026 The Author(s). Published with license by Taylor & Francis Group, LLC CONTACT Sadeq Ali Al-Maweri sadali05@hotmail.com College of Dental Medicine, Qatar University, Doha, Qatar Supplemental data for this article can be accessed online at https://doi.org/10.1080/09546634.2026.2622245. https://doi.org/10.1080/09546634.2026.2622245 This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 N. A. AL-AIZARI ET AL. evidence landscape, necessitating an updated synthesis that inte grates efficacy, safety, and clinical applicability. Therefore, the pres ent umbrella review was conducted to comprehensively appraise and compare the full spectrum of available interventions and to contextualize quality and evidence overlap.
Materials and methods
The present umbrella review was conducted in full compliance with the Cochrane recommendations for umbrella reviews (25) and reported following the preferred reporting items for systematic reviews and meta-analysis (PRISMA) (26) (Supplementary material). The protocol was registered a priori on the International Prospective Register of Systematic Reviews PROSPERO in October 2024 (CRD42024594292) (https://www.crd.york.ac.uk/PROSPERO/view/ CRD42024594292).
Focused question
In patients with RAS, which pharmacological, physical, or comple mentary interventions are most effective and safe for reducing pain, accelerating healing, and preventing recurrence compared with placebo or alternative treatments?
Search strategy
A comprehensive literature search was conducted by two indepen dent reviewers (NA & HA) on three databases (PubMed, Scopus, and Cochrane Library). The complete search strategies for each database, including Boolean operators and Medical Subject Headings (MeSH), are provided in accordance with PISMA 2020 guidelines (Supplementary Table S1). We used a two-step approach. First, we searched the databases for articles published from incep tion until August 20, 2025. The search strategy included intention ally broad terms such as (treatment OR management OR laser OR corticosteroids OR antibiotics OR surgery OR immunotherapy) AND (‘oral ulcer’ OR ‘recurrent aphthous ulcer’ OR ‘aphthous stomatitis’ OR ‘recurrent aphthous’)) AND (systematic AND review OR meta-analysis). Next, we manually searched the reference lists of retrieved articles. After importing the search results into EndNote 21, all duplicates were removed.
Eligibility criteria and study selection
The identified full texts were further inspected for eligibility against a priori defined exclusion and inclusion criteria. We included origi nal articles in English that met the (PICOS) criteria as detailed in Table 1. Older systematic reviews published more than 15 years prior to the search date were excluded to ensure clinical relevance and methodological consistency with contemporary standards. Exceptions were made for older reviews when no recent evidence addressing the same interventions was available. Moreover, reviews were excluded for insufficient data when outcome measures rele vant to pain, healing, recurrence, or safety were not extractable. Reviews were excluded also for insufficient included studies when fewer than two eligible primary trials were available for synthesis. Additional exclusion criteria were applied to ensure methodologi cal robustness. Systematic reviews were excluded if they were judged to contain insufficient data, defined as the absence of extractable information on key outcomes of interest (e.g., pain intensity, healing time, recurrence), lack of clear intervention- comparator descriptions, or failure to report the number and char acteristics of included primary studies. Reviews were also excluded due to insufficient included studies, defined a priori as systematic reviews including fewer than two primary clinical studies relevant to RAS, or reviews in which eligible RAS-specific data could not be isolated from mixed populations. These criteria were applied con sistently during full-text screening.
The whole process of screening and study selection was con ducted independently by the two reviewers (NA & HA) and dis crepancies were resolved by consensus discussion. A Kappa () score was calculated to determine the level of agreement between reviewers at study selection stage. The categorization of scores was defined as a priori as indicating almost perfect agreement, indicating substantial agreement, indicating moderate agreement, indicating fair agreement, indicates slight agreement and a score = 0 indicates no agreement (27). Reviews that included mixed patient populations (e.g., RAS and other oral ulcerative con ditions) were included only if of the population had RAS or if a RAS-specific subgroup analysis was available.
Data extraction
Relevant data extraction was extracted into a standardized Excel spreadsheet, with two independent investigators (NA & HA) extracting data from a subset of the included reviews. Any dis crepancies were resolved by consensus. For each included review, the following information were extracted: authors, year, study design, number of primary studies and participants, interventions and comparators, main outcomes and findings and quality assess ment tool. Unfortunately, a de novo meta-analysis was not per formed due to substantial heterogeneity in the outcome definitions, intervention protocols, and overlap of notice among included sys tematic reviews.
Table 1. Search strategy according to the population, intervention, comparison, outcomes and study design (PICOS) model.
| Parameter | Inclusion criteria | Exclusion criteria |
|---|---|---|
| Population | Patients of any age with recurrent aphthous stomatitis (RAS) | RAS associated with other conditions like anemia, peptic ulcers, acute infectious diseases, autoimmune diseases, Behçet’s disease, Reiter syndrome, recurrent erythema multiforme, or other specific viral infections. |
| Intervention | All active interventions available for the management of RAS | Reviews not including any study on such an intervention |
| Comparison | Other interventions, conventional or placebo | Reviews not including any study on such a comparison |
| Outcomes | The primary outcome of interest was pain reduction, assessed using validated pain scales. Secondary outcomes included healing time, ulcer size reduction, recurrence frequency, and adverse events. | Review with insufficient data, defined as the absence of extractable information on key outcomes of interest (e.g., pain intensity, healing time, recurrence) |
| Study design | Systematic reviews with and without meta-analysis for only RCT | Observational study, case reports, case series, original articles, conference posters or abstracts, editorials, letters to the editor, narrative reviews, overviews. |
Quality assessment
Methodological quality of each included review was independently assessed by two reviewers using AMSTAR 2 tool (A Measurement Tool to Assess systematic Reviews 2) (28). This tool was designed to evaluate the methodological quality of systematic reviews and meta-analyses of studies examining the effects of healthcare interventions. It consists of 16 items that are used to assess the following critical domains: protocol registered before start of review; adequacy of literature search; justification for excluded studies; risk of bias for included studies; appropriateness of meta-analytical methods; consideration of risk of bias when interpreting results; and assessing presence and likely impact of publication bias. Based on critical (Items 2, 4, 7, 9, 11, 13, 15) and non-critical items (Items 1, 3, 5, 6, 8, 10, 12, 14, 16), the quality of studies can be categorized as ‘high’ (no or only one non-critical weakness), ‘moderate’ (more than one non-critical weakness), ‘low’ (one critical flaw with or without non-critical weaknesses) or ‘critically low’ (more than one critical flaw with or without non-critical weaknesses). Individual domain ratings and overall confidence judgments for each review are presented in Supplementary Table S2. A Kappa (κ) score was also calculated to determine the level of agreement between reviewers at quality assessment for included reviews.
Overlap analysis
All primary randomized controlled trial (RCTs) cited within the included systematic reviews were extracted into an Excel-based citation matrix. Each RCT was listed once for the purpose of overlap calculation using its unique identifier (PMID number or DOI). Multi-arm trials were treated as single units. Subsequently, the corrected covered area (CCA) was calculated, and the final overlap was reported for all reviews combined and visualized using GROOVE tool (29,30).
Data synthesis
Quantitative synthesis of outcome magnitudes across reviews was considered; however, it was not feasible due to substantial heterogeneity in outcome definitions, time points of assessment (ranging from 3 days to 90 days), intervention protocols and dosages, and reporting metrics. As a result, numerical aggregation or comparison of effect sizes across interventions would risk misleading interpretation.
Results
Study selection
The flowchart of the study selection process was performed by using PRISMA Flow Diagram tool (31) as shown on Figure 1. In total, 332 records were identified through literature search in three databases. After removing duplicates, 302 abstracts were screened, and 68 full texts were assessed for eligibility. Finally, 41 studies met the inclusion criteria and were included in this overview. Inter-rater reliability after full-text screening and inclusion of studies was almost perfect (κ=0.92). A list of excluded studies with reason of exclusion is provided in Supplementary Table S3.
Description of included studies
Details of included studies are shown in Table 2. The included reviews analyzed various interventions on RAS. Of the 41 included studies, three included network meta-analysis (32–34), 11 meta-analysis (15,23,35–43), 27 systematic reviews (10,16,20,24, 44–66).
Quality assessment
Among the 41 included studies, 22% (n=9) (10,32–34,37,39–42) reviews were rated as ‘high’, 12.2% (n=5) (44,46,63,64,66) as ‘moderate’, 41.4% (n=17) (20,24,38,47–53,56–58,65,67) as ‘low’, 24.4% (n=10) (15,16,23,35,43,45,54,55,59–62) as ‘critically low’ quality according to AMSTAR2 scoring system. Figure 2 presents the details of appraisal of each included study evaluated using the AMSTAR2 tool. Inter-rater reliability between reviewers for quality assessment of included studies was almost perfect (κ=0.81). Although several interventions demonstrated favorable clinical outcomes, a substantial proportion of the included reviews were rated as low or critically low. Consequently, the certainty of evidence supporting specific interventions varies, and clinical recommendations should be interpreted with appropriate caution.
Overlap of original studies
The overlap analysis showed low corrected covered area (CCA = 1.93%) across all 41 systematic reviews, representing slight overlap and suggesting minimal redundancy among the included reviews. Given this low value, sensitivity analysis for duplicate or multi-arm studies was not conducted, as it would not meaningfully alter the findings.
Findings from reviews
Pharmacological interventions
Corticosteroids
Two systematic reviews (SRs) (58,59) evaluated the efficacy of corticosteroids as an intervention for RAS. Quijano and Rodríguez (58) synthesized data from eight randomized controlled trials assessing topical corticosteroids, including triamcinolone acetonide (0.025–0.1%), betamethasone valerate (500–600 μg/day aerosol or 0.025% gel), fluocinonide (0.05%), and clobetasol propionate (0.05%), administered as adhesive pastes, aerosols, or orabase preparations. Most regimens were applied 2–4 times daily for treatment periods ranging from five days to eight weeks, depending on study design. Across trials, topical corticosteroids consistently demonstrated shorter ulcer healing time and greater pain reduction compared with placebo or inert vehicles. However, evidence regarding ulcer recurrence prevention was inconclusive, with heterogeneous definitions and follow-up durations limiting comparability. The overall methodological quality was low to moderate, with only one high-quality trial identified.
Similarly, Skučas et al. (59) reviewed 34 randomized controlled trials evaluating multiple interventions for RAS, including topical corticosteroids. The most frequently studied agents were triamcinolone acetonide, betamethasone, and clobetasol, primarily delivered in adhesive pastes or topical gels. Short-term benefits were observed for pain relief and reduction in lesion size, whereas no consistent effect on recurrence rate was demonstrated. The review highlighted substantial heterogeneity in corticosteroid potency, dosing schedules, outcome measures, and follow-up duration, alongside frequent methodological limitations such as small sample sizes and inadequate blinding. Consequently, the certainty of
Figure 1. Flow diagram of systematic literature search on different interventions on recurrent aphthous stomatitis (RAS).
evidence supporting corticosteroids was judged as variable and predominantly low to moderate.
Hyaluronic acid
One network meta-analysis (NMA) (34) & one SR (44) evaluated the effect of topical hyaluronic acid (HA) in the treatment of RAS. The SR by Al-Maweri et al. (44) synthesized evidence from nine controlled clinical trials (predominantly randomized) including 538 participants, assessing topical HA formulations only. The review reported that HA was administered as oral gels, sprays, or mouthwashes, with concentrations ranging from low-dose sprays to higher-concentration gels, and applied multiple times daily over short treatment periods, typically 5–11 days. Comparators across the included trials consisted mainly of topical corticosteroids (most commonly triamcinolone acetonide), placebo or vehicle controls, and antiseptic agents. Across outcomes, Al-Maweri et al. reported consistent short-term benefits of HA in reducing pain intensity, decreasing ulcer size, and accelerating healing time compared with placebo or antiseptic comparators. In comparisons with topical corticosteroids, HA demonstrated either comparable efficacy or modest superiority, although differences were not consistently statistically significant. Importantly, the review reported no treatment-related adverse effects across the included trials, supporting a favorable safety profile for topical HA. Nevertheless, the authors graded the overall certainty of evidence as low, citing small sample sizes, heterogeneity in formulations and outcome measures, and variable risk of bias.
The NMA by Mashrah et al. (34) compared HA with a broad range of topical, systemic, procedural, and herbal interventions for RAS. Within the network, HA ranked among the most effective interventions for early pain relief, particularly at day 4, showing a high probability of pain reduction relative to several conventional and complementary therapies. However, when analyses were restricted to direct comparisons with topical corticosteroids, HA did not demonstrate statistically significant superiority. The certainty of evidence informing HA’s ranking was judged low, reflecting clinical heterogeneity, indirect comparisons, and methodological limitations of the contributing reviews.
Overall, both reviews suggest that topical HA is a safe and potentially effective option for short-term symptom control in mild-to-moderate RAS, but the low certainty of evidence precludes firm comparative or hierarchical treatment recommendations.
Doxycycline, tetracycline
One meta-analysis (MA) (67) and two SRs (10,56) evaluated the effect of topical antibiotics and antimicrobials, particularly doxycycline and tetracycline, on RAS.
Al-Maweri et al. (67) conducted a meta-analysis focusing specifically on topical doxycycline, synthesizing evidence from five randomized controlled trials, three of which were eligible for quantitative pooling. Across the included trials, doxycycline was
<table border="1">
<tr>
<th colspan="8">Table 2. Characteristics of included systematic reviews, meta-analyses, and network meta-analyses evaluating pharmacological, physical, and complementary interventions for recurrent aphthous stomatitis (RAS).</th>
</tr>
<tr>
<th>Authors, year</th>
<th>No of included studies</th>
<th>Total participants</th>
<th>Intervention</th>
<th>Comparator</th>
<th>Outcomes</th>
<th>Main findings</th>
<th>Quality assessment method<br>AMSTAR quality rating</th>
</tr>
<tr>
<td>Abdulrahman et al., 2022 (35)</td>
<td>SR (9 RCT)<br>(only 8 MA)</td>
<td>844<br>(441 intervention /<br>403 control)</td>
<td>Herbal medicine (Aloe vera,<br>Punica granatum)</td>
<td>Placebo/no treatment</td>
<td>Size of ulcers<br>Duration of ulcers<br>Pain remission</td>
<td>*All herbal treatments significantly reduce ulcer size and pain severity, shortening ulcer healing time.<br>*The most efficient ulcer-reducing agents were Aloe vera gel, Punica granatum hydroalcoholic extract (PG), and camel thorn distillate. Furthermore, PG extract had the greatest prognosis for lowering pain intensity and shortening healing time.</td>
<td>NA<br>Critically low</td>
</tr>
<tr>
<td>Alli et al., 2019 (37)</td>
<td>SR (4 RCT) only<br>2 MA</td>
<td>124</td>
<td>Sodium lauryl sulfate<br>(SLS-containing) dentifrice</td>
<td>SLS-free dentifrice</td>
<td>Duration of ulcer, number of ulcers, number of ulcer episodes, and the severity of ulcer pain</td>
<td>SLS-free dentifrice, when compared to SLS-containing statistically significantly, reduced the number of ulcers, duration of ulcer, number of episodes, and ulcer pain.</td>
<td>Cochrane RoB (version 1)<br>High</td>
</tr>
<tr>
<td>Al-Maweri et al., 2020 (67)</td>
<td>SR (5 RCT)<br>(3 MA)</td>
<td>201</td>
<td>Topical doxycycline; single application of crushed tablets (100–150 mg) in adhesive paste or low-dose hydrogel (0.05–0.15%)</td>
<td>Placebo / no treatment</td>
<td>Pain scores and/or healing time, associated side effects, adhesive retention time</td>
<td>The results of the pooled 3 studies revealed a statistically significant decrease in the healing time in favor of the doxycycline group as compared to the control groups; however, the results showed no significant differences between doxycycline and control groups regarding pain reduction.</td>
<td>Cochrane RoB (version 1)<br>Low</td>
</tr>
<tr>
<td>Al-Maweri et al., 2021 (44)</td>
<td>SR (9 RCT)</td>
<td>538</td>
<td>Topical hyaluronic acid (gels, sprays, mouthwashes; short-term application over 5–11 days)</td>
<td>Topical corticosteroids (e.g., triamcinolone), placebo/vehicle, antiseptics</td>
<td>Pain, healing time and/or size of the ulcers, side effects of the intervention</td>
<td>The results revealed a good efficacy of HA in alleviating pain and shortening the healing time of RAS, without any reported side effects. Compared to triamcinolone, HA showed superior results in one study, and comparable results in two studies.</td>
<td>Cochrane RoB (version 1)<br>Moderate</td>
</tr>
<tr>
<td>Al-Maweri et al., 2022 (45)</td>
<td>SR (8 CT)</td>
<td>439</td>
<td>Curcumin, systemic or topical</td>
<td>Any other medical interventions or placebo</td>
<td>Pain, and/or healing time, ulcer size, adverse effects</td>
<td>Overall, the included studies reported a good efficacy of curcumin in reducing pain and ulcers size in patients with RAS. Four studies found curcumin as effective as triamcinolone in relieving signs and symptoms of RAS. Three studies reported superior results with curcumin as compared with control groups</td>
<td>Jadad scale<br>Critically low</td>
</tr>
<tr>
<td>Al-Zainal et al., 2025 (66)</td>
<td>SR (24 RCT)</td>
<td>1232</td>
<td>Low-level laser therapy/laser therapy</td>
<td>Placebo or any other treatment</td>
<td>Reduction in pain, healing time and ulcer size</td>
<td>Several trials demonstrate that lasers have a superior effect on pain compared to the conventional treatments used as controls. Regarding other parameters including ulcer size reduction, and reduction in erythema, results did not show any significant differences between lasers and controls,</td>
<td>Cochrane RoB 2<br>Moderate</td>
</tr>
<tr>
<td>Brocklehurst et al., 2012 (10)</td>
<td>SR (25 RCT)</td>
<td>1242</td>
<td>Tetracycline mouth rinses; sub-antimicrobial-dose doxycycline (SDD)</td>
<td>No active treatment or administration of a placebo, or head-to-head trials of different interventions</td>
<td>Pain, episode duration, episode frequency, drug safety</td>
<td>No single treatment was found to be effective and therefore the results remain inconclusive regarding the best systemic intervention for RAS.</td>
<td>Cochrane RoB (version 1)<br>High</td>
</tr>
</table><table border="1">
<tr>
<th colspan="8">Table 2. Continued.</th>
</tr>
<tr>
<th>Authors, year</th>
<th>No of included studies</th>
<th>Total participants</th>
<th>Intervention</th>
<th>Comparator</th>
<th>Outcomes</th>
<th>Main findings</th>
<th>Quality assessment method<br>AMSTAR quality rating</th>
</tr>
<tr>
<td>Cabras et al.,<br>2020 (46)</td>
<td>SR (5 RCT & OCT)</td>
<td>189</td>
<td>Systemic colchicine (oral;<br>0.5–1.5 mg/day,<br>8 weeks–6 months)</td>
<td>Placebo, no treatment,<br>low-dose systemic<br>corticosteroids, other<br>systemic agents (e.g.,<br>clofazimine,<br>thalidomide,<br>dapsone)</td>
<td>Pain, ulcer healing,<br>ulcer-free periods</td>
<td>Colchicine appeared less effective than<br>clofazimine, thalidomide and dapsone,<br>and with outcomes similar to<br>low-dosage corticosteroids but higher<br>gastric discomfort than prednisolone.</td>
<td>Cochrane RoB 2<br>Moderate</td>
</tr>
<tr>
<td>Cheng et al.,<br>2020 (23)</td>
<td>SR (7 RCT),<br>only 3 MA</td>
<td>334</td>
<td>Probiotics, either alone or<br>combined with other<br>drugs</td>
<td>Placebo or other drugs<br>alone</td>
<td>Severity of ulcer or oral<br>pain.</td>
<td>Probiotics alone were capable of relieving<br>oral pain but not effective in reducing<br>ulcer severity. A combination of<br>probiotics and steroids or anesthetic<br>antiseptic gel was more effective than<br>steroids or anesthetic antiseptic gel<br>alone in RAS patients.</td>
<td>Cochrane RoB<br>(version 1)<br>Critically low</td>
</tr>
<tr>
<td>Cheng et al.,<br>2023 (32)</td>
<td>SR & NMA (38<br>RCT)</td>
<td>2773</td>
<td>(Topical/Systemic)<br>LLLT; predominantly diode<br>lasers; variable<br>wavelengths (630–<br>980 nm), power outputs,<br>and application protocols,<br>Kangfuxin, compound<br>licorice, Yunnan Baiyao</td>
<td>Placebo or no treatment<br>or another type of<br>therapeutic<br>intervention</td>
<td>Reduction in pain,<br>duration of ulceration,<br>the diameter of<br>ulceration, area of<br>ulceration, safety of<br>drugs</td>
<td>Diode laser was the most effective in<br>reducing the pain score followed by<br>Amlexanox. Iralvex performed the best<br>in reducing the duration of ulceration.<br>Diode laser, acacia nilotica with licorice<br>formulation, and amlexanox were the<br>most effective interventions for<br>reduction of ulcer diameter. Majority of<br>the trials reported absence of any<br>adverse effects and those reported<br>were mild.</td>
<td>Cochrane RoB 2<br>High</td>
</tr>
<tr>
<td>Dorsareh et al.,<br>2023 (20)</td>
<td>SR (6 RCT)</td>
<td>314</td>
<td>Topical licorice</td>
<td>Placebo or no treatment<br>or another type of<br>therapeutic<br>intervention</td>
<td>Pain reduction, ulcer size,<br>and healing time</td>
<td>The result showed licorice has significant<br>effects on RAS pain reduction, ulcer<br>size, and healing time.</td>
<td>Jadad score<br>Low</td>
</tr>
<tr>
<td>Elbeshbeishy<br>et al., 2025<br>(65)</td>
<td>SR (26 RCT) &<br>MA (14 RCT<br>only)</td>
<td>4509</td>
<td>Pharmacological and<br>nonpharmacological<br>topical treatments</td>
<td>Topical triamcinolone<br>application</td>
<td>Pain relief, pain recovery<br>time, and overall ulcer<br>healing time</td>
<td>natural alternatives such as honey and<br>curcumin provide fast pain relief and<br>healing without side effects. When<br>evaluating patient satisfaction,<br>treatments such as rhus coriaria, honey,<br>curcumin, Aloe vera and Punica<br>granatum resulted in greater patient<br>satisfaction than did corticosteroids, as<br>there were no adverse reactions.<br>Compared with triamcinolone, synthetic<br>alternatives, such as laser therapy and<br>hyaluronic acid, are more effective in<br>overall healing, including reducing the<br>recurrence of aphthous ulcers for a<br>longer time</td>
<td>Cochrane RoB 2<br>Low</td>
</tr>
<tr>
<td>Halboub et al.,<br>2021 (47)</td>
<td>SR (7 CT)</td>
<td>482</td>
<td>Zinc supplement (systemic)</td>
<td>Placebo and/ or any<br>other active<br>treatments</td>
<td>Reducing the recurrence,<br>pain and duration of<br>the ulcers, side effects</td>
<td>Five studies showed significantly better<br>efficacy of zinc in reducing the<br>recurrence rates of RAS, whereas two<br>studies did not report any significant<br>differences compared to the controls.<br>Four studies reported on signs/<br>symptoms of RAS, three of which<br>showed superior outcomes in favor of<br>zinc, while one study reported<br>comparable results.</td>
<td>Jadad score<br>Low</td>
</tr>
<tr>
<td colspan="8">(Continued)</td>
</tr>
</table><table border="1">
<thead>
<tr>
<th rowspan="2">Authors, year</th>
<th rowspan="2">No of included studies</th>
<th rowspan="2">Total participants</th>
<th rowspan="2">Intervention</th>
<th rowspan="2">Comparator</th>
<th rowspan="2">Outcomes</th>
<th rowspan="2">Main findings</th>
<th rowspan="2">Quality assessment method</th>
<th rowspan="2">AMSTAR quality rating</th>
</tr>
<tr>
</tr>
</thead>
<tbody>
<tr>
<td>Han et al., 2016 (48)</td>
<td>SR (10 RCT)</td>
<td>384</td>
<td>LLLT; varied wavelengths and treatment duration</td>
<td>Placebo, or negative control supplied with some traditional drugs</td>
<td>Healing time, changes in pain level, size of ulcers</td>
<td>The results indicated that the laser therapy group showed significant changes on healing time, pain level (especially the immediate pain relief), and the size of ulcers at different follow-up times compared with the placebo group (an inactive laser probe).</td>
<td>Cochrane RoB (version 1)</td>
<td>Low</td>
</tr>
<tr>
<td>Hasanah and Hidayat, 2021 (49)</td>
<td>SR (5 RCT)</td>
<td>272</td>
<td>Herbal medicine (Aloe vera, curcumin, licorice, tobacco, and pomegranate)</td>
<td>Placebo or chemical drugs</td>
<td>Ulcer size, pain score, healing duration, and adverse effects</td>
<td>There is some evidence of the clinical efficacy and safety of herbal medicine therapy in improved outcomes of recurrent aphthous stomatitis treatment with minimum adverse effects.</td>
<td>Cochrane RoB (version 1)</td>
<td>Low</td>
</tr>
<tr>
<td>Iskandar et al., 2025 (64)</td>
<td>SR (7 RCT)</td>
<td>274</td>
<td>Licorice. (Glycyrrhiza glabra)</td>
<td>Placebo, antiseptic, or anti-inflammatory agent;</td>
<td>Pain intensity, reduction in ulcerated lesion diameter, and period of RAS healing</td>
<td>Glycyrrhiza glabra treatment in various regimens showed significant improvements in pain, ulcer diameter, and healing time in patients with RAS</td>
<td>JBI critical appraisal tool</td>
<td>Moderate</td>
</tr>
<tr>
<td>Jian et al., 2024 (38)</td>
<td>SR & MA (21 RCT)</td>
<td>1668</td>
<td>Oral thalidomide alone or thalidomide combined with other interventions</td>
<td>Placebo or any form of medical intervention except thalidomide, whether topical or systemic</td>
<td>Complete response and overall response, recurrence interval (RI), ulcer number and size, healing time, visual analogue scale (VAS), immunological data, and adverse events</td>
<td>Thalidomide significantly improved the complete response rate and overall response rate, prolonged the recurrence interval, accelerated the healing process, reduced the number and size of ulcers, and lowered TNF-α levels in the treatment of RAS. However, thalidomide significantly increases adverse events.</td>
<td>Cochrane RoB (version 1)</td>
<td>Low</td>
</tr>
<tr>
<td>Khaleel Ahmed et al., 2020 (50)</td>
<td>SR (5 RCT)</td>
<td>330</td>
<td>LLLT; subgroup analyses favored diode lasers; variable power (30–500 mW)</td>
<td>Topical medication (triamcinolone acetonide, amlexanox, granofurin, and solcoseryl)</td>
<td>Pain and size of the lesion</td>
<td>Findings showed that patients who reported lower pain and decreased aphthous ulcer lesions were more in the laser therapy group than in the topical medication group.</td>
<td>Cochrane RoB (version 1)</td>
<td>Low</td>
</tr>
<tr>
<td>Li et al., 2015 (51)</td>
<td>SR (13 RCT & CCT)</td>
<td>1515</td>
<td>Herbal medicine</td>
<td>Placebo treatment, chlorhexidine rinse</td>
<td>Ulcer size, lesion duration, and remission of pain</td>
<td>Topical treatment with natural herbal medicines seemed to benefit RAS patients by reducing ulcer size, shortening ulcer duration, and relieving pain without severe side effects.</td>
<td>Cochrane RoB (version 1)</td>
<td>Low</td>
</tr>
<tr>
<td>Liu et al., 2022 (33)</td>
<td>72 (NMA)</td>
<td>5272</td>
<td>29 Topical intervention (honey, insulin liposome gel, LLLT including diode and GaAlAs lasers; heterogeneous dosing and treatment schedules amlexanox, glycyrrhiza, triamcinolone, Probiotics, chlorhexidine, penicillin, cryotherapy, cautery, Tetracyclines and their derivatives, curcumin, glycyrrhiza, quercetin, chitosan, aloe, berberine, gelatin, diosmectite, allicin, and other extracts, Low serum zinc levels)</td>
<td>Placebo</td>
<td>Size-reducing effect, symptom-reducing effect, adverse effect, healing efficacy</td>
<td>*Honey, insulin liposome gel, laser, amlexanox, glycyrrhiza and triamcinolone had better efficacy performance.<br>*Probiotics and chlorhexidine helped to prolong ulcer intervals and reduce recurrence.<br>*Doxycycline and penicillin had a high risk of adverse events.<br>* Hematologic evaluation showed no preference.<br>*The rank possibility of size-reducing effect and symptom-reducing effect supported the short-term effect of laser and the long-term effect of probiotics.</td>
<td>Cochrane RoB (version 1)</td>
<td>High</td>
</tr>
</tbody>
</table><table border="1">
<tr>
<th rowspan="2">Authors, year</th>
<th rowspan="2">No of included<br>studies</th>
<th rowspan="2">Total participants</th>
<th rowspan="2">Intervention</th>
<th rowspan="2">Comparator</th>
<th rowspan="2">Outcomes</th>
<th rowspan="2">Main findings</th>
<th rowspan="2">Quality<br>assessment<br>method</th>
<th rowspan="2">AMSTAR<br>quality<br>rating</th>
</tr>
<tr>
</tr>
<tr>
<td>Liu et al., 2024 (39)</td>
<td>SR & MA (9 RCT)</td>
<td>883</td>
<td>Herbal / traditional Chinese<br>medicine–derived botanical drug (total<br>glucosides of peony (TGP); Oral capsules 0.6 g<br>per administration, 2–3 times daily (average daily<br>intake 1.50–1.68 g;<br>equivalent to 5–6<br>capsules/day)</td>
<td>Vitamins (and minerals),<br>placebos, or received<br>the exact same<br>medication as the<br>intervention group,<br>excluding TGP.</td>
<td>Visual analogue scale<br>(VAS), overall response<br>rate and significant<br>response rate, ulcer<br>healing time, interval,<br>number of ulcers,<br>Inflammatory markers<br>(TNF-α and IL-2),<br>adverse reactions.</td>
<td>*The VAS in the TGP group was lower than<br>that in the control group with statistical<br>significance. Subgroup analysis<br>suggested longer (>8weeks) medication<br>and observation led to a more<br>significant reduction in pain.<br>*Moreover, TGP had higher overall<br>response rate and significant response<br>rate, accelerated ulcer healing, and<br>extended intervals.<br>*The efficacy of TGP in reducing the<br>number of ulcers showed no significant<br>difference compared to the control<br>group.<br>*Moreover, TGP treatment was associated<br>with a higher incidence of abdominal<br>symptoms</td>
<td>Cochrane RoB<br>(version 1)</td>
<td>High</td>
</tr>
<tr>
<td>Mashrah et al., 2023 (34)</td>
<td>NMA (43 RCT)</td>
<td>3067</td>
<td>Topical medications<br>(triamcinolone acetonide,<br>doxycycline, curcumin,<br>amlexanox, topical<br>hyaluronic acid (various<br>formulations), laser<br>therapy; diverse<br>wavelengths and energy<br>densities, chlorhexidine,<br>N-acetylcysteine,<br>sucrelfate, placebo,<br>chamomile, coconut oil,<br>diosmectite (DS) paste,<br>basic fibroblast growth<br>factor (bFGF) paste,<br>benzocaine,<br>dexamethasone,<br>berberine, triester glycerol<br>oxide, myrrh, and Aloe<br>vera)</td>
<td>Placebo controls</td>
<td>Pain reduction and/or<br>healing time, side<br>effects of the<br>intervention and<br>adhesive retention<br>time.</td>
<td>The results failed to show a statistically<br>significant difference in terms of pain<br>reduction when different topical<br>treatments were compared with<br>placebo or compared together at<br>different time intervals. Concerning pain<br>reduction, the rank probability test<br>showed that sucralfate ranked the best<br>on Days 1 and 3 post-treatment,<br>doxycycline ranked the best on Day 2,<br>hyaluronic acid ranked the best on<br>Days 4 and 7, chamomile ranked the<br>best on Day 5, whereas diosmectite<br>plus basic fibroblast growth factor paste<br>ranked the best at Day 6. Except for<br>doxycycline, which showed a<br>statistically significant dif- ference in<br>terms of providing a favorable healing<br>time as compared with placebo, other<br>topical interventions showed no<br>statistically significant differences when<br>compared together.</td>
<td>Cochrane RoB 2</td>
<td>High</td>
</tr>
<tr>
<td>Nair et al., 2016 (52)</td>
<td>SR (4 RCT &<br>case-control)</td>
<td>350</td>
<td>Aloe vera gel, Aloe vera<br>mouthwash, Aloe vera<br>combined with other<br>active substances</td>
<td>Placebo, conventional<br>treatments</td>
<td>Pain reduction, decrease<br>of the size of the<br>lesions and the days<br>needed for the healing<br>of the lesions</td>
<td>Aloe vera is effective in pain relief and<br>lesion healing in aphthous stomatitis,<br>no adverse effects were reported.</td>
<td>Cochrane RoB<br>(version 1)</td>
<td>Low</td>
</tr>
<tr>
<td>Najeeb et al., 2016 (53)</td>
<td>SR (7 RCT)</td>
<td>318</td>
<td>Low-level laser therapy (CO2,<br>Nd:YAG, Diode, GaAIAs)</td>
<td>Placebo, conventional<br>treatments</td>
<td>Pain reduction, lesion size,<br>burning sensation,<br>erythema, healing<br>time, no effects</td>
<td>In majority of the patients, immediate pain<br>relief and accelerated ulcer healing was<br>observed following irradiation with<br>lasers.</td>
<td>CONSORT</td>
<td>Low</td>
</tr>
<tr>
<td colspan="9">(Continued)</td>
</tr>
</table>| Authors, year | No of included studies | Total participants | Intervention | Comparator | Outcomes | Main findings | Quality assessment method | AMSTAR quality rating |
|---|---|---|---|---|---|---|---|---|
| Parra-Moreno et al., 2023 (54) | SR (17 RCT) | 985 | Food supplements, topical / systemic treatments | Placebo or another treatment | Pain reduction, decrease of the size of the lesions and the days needed for the healing of the lesions | *Food supplements do not present any benefit over placebo or anesthetic gels in terms of pain reduction or days needed for lesions healing. * Minocycline 0.5% showed greater advantages in terms of pain reduction and reduction of the days needed for the healing of the lesions. * Laser provides a considerable reduction of symptomatology, of the size of the lesions since the starting of the treatment, and the time needed for healing. *There was an improvement of the symptomatology and the time needed for healing of the lesions in the group with licorice in the solution. *Systemic prednisone offers more beneficial effects in terms of reduction of symptoms and necessary time for healing compared with systemic thalidomide | NR | Critically low |
| Pavlić et al., 2015 (55) | SR (4 RCT & comparative clinical study) | 70 | LLLT with variable wavelengths and application techniques | Placebo, conventional treatments | Reduction of pain, reduction in episode duration (faster RAS healing) | The assessed literature demonstrates the benefits of laser therapy mainly due to immediate analgesia and ability to speed up a RAS healing process. | Author-defined methodological quality assessment tool | Critically low |
| Piacentini et al., 2019 (56) | SR (4 RCT) | 180 | Topical doxycycline (100–150 mg crushed tablets or hydrogels); single or repeated application | Sham or other drug. | Pain relief, clinical remission. | The present study suggests that topical doxycycline has a positive effect on the treatment of recurrent aphthous ulceration | Jadad quality assessment scale (modified version) | Low |
| Pratiwi et al., 2022 (57) | SR (5 RCT) | 267 | Curcumin | Triamcinolone acetonide | Pain and size of ulcers | Curcumin is as effective as triamcinolone acetonide required for regression in pain and size of the ulcers in RAS. | Jadad score | Low |
| Quijano and Rodríguez, 2008 (58) | SR (8 RCT) | 383 | Triamcinolone acetonide 0.025–0.1%, betamethasone valerate 500–600 μg/day, fluocinonide 0.05%, clobetasol propionate 0.05%; topical paste/aerosol; 2–4× daily | Placebo or other intervention | Pain, healing, recurrence | The studies showed that, on average, the time for healing the ulcers was shorter when using topical corticosteroids than compared with the placebo. As for evaluating the pain, the results were in favor of active treatment. Nevertheless, the measurement methods were different in the studies. With respect to the recurrences of the ulcers, the results of the studies were not conclusive. | Jadad score | Low |
| Radithia et al., 2024 (15) | SR (14 RCT) (only 3 MA) | 664 (61 MA) | LLLT; subgroup analyses favored diode lasers; variable power (30–500 mW) | placebo-controlled (sham treatment) / topical medication / antimicrobial and motivation | Pain / healing time | * Reduction in healing time after the application of LLLT compared to topical medication and placebo with high heterogeneity. * Reduction of healing time after application of CO2 laser compared to placebo with low heterogeneity. | Cochrane RoB 2 | Critically low |
| Authors, year | No of included studies | Total participants | Intervention | Comparator | Outcomes | Main findings | Quality assessment method | |
|---|---|---|---|---|---|---|---|---|
| AMSTAR quality rating | ||||||||
| Roberts et al., 2024 (40) | SR & MA (10 RCT) | 825 | Propolis (topical & systemic) | Established treatments, placebos, or no treatment | Healing time, pain levels, adverse effects, the likelihood of ulcer recurrence, and accompanying symptoms such as redness | The results indicate that topical and systemic propolis may decrease the duration of healing, alleviate pain, and reduce redness in patients with RAS compared to a placebo. However, the certainty of the evidence is very low | Cochrane RoB (version 1) | High |
| Shavakhi et al., 2022 (24) | SR (33 RCT) | 2113 | Herbal medicines | Standard treatment or a positive/negative control group, placebo | Pain, ulcer size and healing time | *Totally, 22 out of 30 studies which assessed the pain showed that herbal agents significantly decreased the pain compared with the control group or placebo. *In 17 out of 25 studies that evaluated ulcer size, herbal agents significantly reduced the size of ulcers compared with the control or placebo groups. *In 15 out of 18 studies that assessed the healing time, herbal agents significantly reduced healing time in the intervention groups compared with the placebo or control groups. | Jadad score | Low |
| Skučas et al., 2023 (59) | SR (34 RCT) | Total= 157 (Treatment with lasers) 247 (Treatment with membranes) 125 (Treatment with aerosols) 228 (Treatment as mouth rinses) 799 (Treatment in form of gel) 238 (Chinese medicine or Zinc tablets) 45 (antibiotics) 40 (omega-3 supplements) 39 (Probiotics) 164 (Thalidomide) | Topical corticosteroids (mainly triamcinolone, betamethasone, clobetasol); variable dosing and duration Laser therapy grouped among physical modalities; no standardized protocol | Placebo, no therapy or topical corticosteroid | Healing time, pain, frequency of relapse | Topical medications can promote the healing time of ulcers and relieve the pain, but most of the time can not decrease the frequency of RAS relapse. However, for continuous RAS, treatment with systemic medication should be considered. | Cochrane RoB (version 1) | Critically low |
| Suter et al., 2017 (16) | SR (10 RCT & 1 NCT) | 512 | Laser (CO2, Nd: YAG, diode) | Placebo, no therapy or topical corticosteroid | Pain relief, duration of wound healing | *Significant pain relief immediately after treatment was found in five out of six studies. Pain relief in the days following treatment was recorded in seven studies. *The duration of RAS wound healing was also reduced in five studies. However, criteria of evaluation differed between the studies. | Jadad score | Critically low |
| Authors, year | No of included studies | Total participants | Intervention | Comparator | Outcomes | Main findings | Quality assessment method | |
|---|---|---|---|---|---|---|---|---|
| AMSTAR quality rating | ||||||||
| Ullah et al., 2025 (43) | SR & MA (14 RCT) | 517 | Laser therapy | Placebo treatment | Pain, lesion size and healing time | Laser therapy significantly reduced pain intensity compared to placebo and was associated with a shorter healing time. Changes in ulcer size were not significant. | NA | Critically low |
| Vale et al., 2015 (60) | SR (2 RCT) | 70 | Low-level laser therapy (LLLT); diode/GaAlAs lasers; wavelength ~809–810 nm; variable power (60 mW–0.5 W), energy density, application mode, and frequency | Sham laser / placebo | Pain reduction, lesion size, and healing time | *The LLLT group showed a statistically significant reduction in pain compared with the control group (p < .001) *Compared with the sham group, authors found the complete healing time for the LLLT group to be highly significant, with a P value less than 0.001 | NA | Critically low |
| Wahyuni et al., 2021 (61) | SR (2 RCT) | 240 | Plant-based products *Acemannan 0.5% (extracted from Aloe vera) in Carbopol *Curcuma longa extract 10 mg/g | Standard treatment or a positive/negative control group | Pain (VAS) Size Number of ulcers Duration of ulcer period | No different effectiveness compared to a positive control, but the acemannan oral gel was reported to be safe through blood and dermatitis tests | Oxford Quality Scoring System | Critically low |
| Wang et al., 2025 (42) | SR & MA (16 RCT) | 620 | Diode laser therapy (low-level laser therapy) wavelengths ranged from 660–980 nm; treatment delivered as single, two, or multiple sessions. | Sham/placebo laser or topical treatments | Pain reduction and ulcer healing | DL therapy was more effective than medication or placebo in reducing Visual Analog Scale, shrinking ulcer size and accelerating healing time. Moreover, subgroup analyses demonstrated that DL therapy effectively alleviated immediate pain in patients, and a single exposure significantly shortened the healing time of RAU. DL therapy is an effective treatment for RAU without any adverse effects. | Cochrane RoB (version 1) | High |
| Wu et al., 2024 (41) | SR & MA (9 RCT) | 1469 | Fire needle therapy alone or combined with acupuncture-based modalities; 3–14 day courses | Oral vitamins, transfer factor injections, chlorhexidine gargle, acupoint injection | Total effective rate Ulcer pain, Healing time, recurrence rate, symptom volume score | Fire needle therapy significantly improved the total effective rate, reduced the visual analogue scale score, diminished the Traditional Chinese Medicine symptom score, and shortened the healing time of RAS | Cochrane RoB 2 | High |
| Zhou et al., 2017 (62) | SR (12 RCT and CCTs) | 1246 | Oral Chinese medicine with or without vitamin tablets | Vitamin tablets or a placebo | Episode duration, Episode frequency, Reducing pain and ulcer size, ulcer number | Results showed that Chinese patent medicines were beneficial for patients with RAS in relieving ulcer pain and reducing the duration and frequency of attacks | Cochrane RoB (version 1) | Critically low |
| Zúñiga-López et al., 2024 (63) | SR (3 RCT) | 120 | Chitosan Biogel | Triamcinolone or polyvinyl alcohol or Aloe vera or placebo | Ulcer size reduction / healing time | *The ulcer size reduction was statistically similar in both groups during six days of follow-up. * Healing time was statistically similar in both groups (Chitosan and Aloe vera) | Cochrane RoB 2 | Moderate |
| Note: AMSTAR 2: A Measurement Tool to Assess Systematic Reviews; LLLT: low-level laser therapy; DL: diode laser; NMA: network meta-analysis; MA: meta-analysis; SR: systematic review; RCT: randomized controlled trial; OCT: open clinical trial; NS: not assessed; VAS: Visual Analogue Scale. | ||||||||
Table 2. Continued.
| | 0% | 10% | 20% | 30% | 40% | 50% | 60% | 70% | 80% | 90% | 100% |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Q16 | 95% | 5% |
| Q15 | 22% | 17% | 61% |
| Q14 | 73% | 27% |
| Q13 | 80% | 20% |
| Q12 | 32% | 7% | 61% |
| Q11 | 39% | 61% |
| Q10 | 5% | 95% |
| AMSTAR-2 | | | | | | | | | | | |
| Q9 | 59% | 32% | 10% |
| Q8 | 71% | 29% |
| Q7 | 76% | 5% | 20% |
| Q6 | 83% | 17% |
| Q5 | 83% | 17% |
| Q4 | 15% | 85% |
| Q3 | 95% | 5% |
| Q2 | 34% | 7% | 59% |
| Q1 | 90% | 10% |
**Yes** **Partial Yes** **No** **Not Applicable**
Figure 2. Quality assessment of included studies following Assessment of Multiple Systematic Reviews (AMSTAR) 2 tool guidelines.
administered topically as a single application, either as a crushed tablet (100–150mg) incorporated into adhesive pastes or as low-concentration hydrogels (0.05–0.15%). Comparators included placebo or no treatment. The meta-analysis demonstrated that topical doxycycline was associated with a statistically significant reduction in ulcer healing time, whereas no consistent benefit was observed for pain reduction. Considerable methodological heterogeneity was noted, particularly in outcome definitions, delivery vehicles, and blinding procedures, resulting in an overall low-to-moderate certainty of evidence.
In a Cochrane systematic review of systemic and topical interventions for RAS, Brocklehurst et al. (10) evaluated tetracycline mouth rinses and sub-antimicrobial-dose doxycycline (SDD) as part of a broader assessment of systemic therapies. The review
**Colchicine**
One SR by Cabras et al. (46) evaluated the effectiveness and safety of systemic colchicine for the management of recurrent oral ulcers, including idiopathic RAS. The review synthesized evidence from two randomized controlled trials (RCTs) and three open clinical trials (OCTs) involving patients with RAS, alongside studies in Behçet’s disease and PFAPA, and reported substantial clinical and methodological heterogeneity, which precluded quantitative pooling. Across RAS-focused studies summarized in the review, colchicine was administered systemically at daily doses ranging from 0.5 to 1.5 mg, with treatment durations varying from eight weeks to six months. Outcomes assessed included ulcer frequency, pain intensity, lesion size, duration of episodes, and recurrence intervals. Overall, the evidence supporting colchicine in idiopathic RAS was mixed and of low certainty. Comparative data suggested that colchicine was less effective than other systemic agents such as clofazimine, thalidomide, and dapsone, while demonstrating similar efficacy to low-dose systemic corticosteroids. However, randomized placebo-controlled evidence was limited and inconsistent: one RCT found no statistically significant difference between colchicine and placebo, whereas open clinical trials reported symptomatic improvement compared with no treatment. Overall, Cabras et al. concluded that the role of colchicine in idiopathic RAS remains controversial, with insufficient high-quality randomized evidence to support routine use. The review highlighted that heterogeneity in study design, dosing regimens, outcome definitions, and follow-up duration substantially limits confidence in the observed effects. Consequently, colchicine may be considered a second-line systemic option in selected refractory cases, but its use should be individualized, closely monitored, and weighed against alternative systemic therapies with more favorable benefit–risk profiles.
**Thalidomide**
Evidence on thalidomide for RAS was synthesized in one NMA (32), one conventional MA (38), and two SRs (10,59). Across these secondary syntheses, thalidomide was consistently evaluated as a systemic immunomodulatory agent, primarily in patients with severe, frequent, or refractory RAS. In the network meta-analysis by Cheng et al. (32), which compared systemic and topical interventions across randomized trials, thalidomide demonstrated therapeutic benefit for ulcer reduction and prolongation of ulcer-free intervals, particularly in severe disease. However, despite favorable effect estimates, thalidomide did not achieve a high ranking in cumulative efficacy (SUCRA), largely due to safety-related penalties and limited comparative advantage over other systemic agents. Findings from the meta-analysis by Jian et al. (38) further indicated that thalidomide was associated with improvements in clinical response rates, ulcer number and size, and healing time, as well as reductions in inflammatory biomarkers such as tumor necrosis factor (TNF-α). Importantly, pain reduction was inconsistent, and pooled analyses did not demonstrate a statistically significant analgesic benefit. Notably, its use was associated with a significantly higher incidence of adverse effects, notably peripheral neuropathy, thromboembolic events, sedation, and gastrointestinal disturbances (68). The quality of included trials was variable, with many studies exhibiting high risk of bias due to limitations in blinding, allocation concealment, and sample size heterogeneity. The overall certainty of evidence was rated as low to moderate. The Cochrane review by Brocklehurst et al. (10) acknowledged thalidomide as a potentially effective agent in managing severe RAS but cautioned against its routine use due to insufficient high-quality evidence and substantial safety risks. In a more recent synthesis, Skučas et al. (59) highlighted the drug’s ability to extend the RAS-free interval and reduce lesion recurrence but reaffirmed that its clinical utility is constrained by its adverse effect profile.
**Physical or energy-based therapies**
**Laser therapy (LLLT)**
Three NMA (32–34), one MA (15), and eight SRs (10,16,48,50,53,55,59,60) evaluated the effectiveness of laser therapy in RAS. Across these evidence syntheses, low-level laser therapy—particularly diode and GaAlAs lasers operating in the near-infrared spectrum, was consistently associated with significant short-term pain reduction and accelerated ulcer healing compared with placebo or conventional topical agents. Cheng et al. (32) and Liu et al. (33) ranked LLLT among the most effective interventions for reducing pain and ulcer size in RAS, outperforming several conventional pharmacological treatments in short-term outcomes. Similarly, Mashrah et al. (34) identified laser therapy as one of the most effective non-pharmacological modalities but emphasized substantial clinical and methodological heterogeneity, particularly regarding laser wavelength, power density, and treatment duration. A recent MA by Radithia et al. (15) further confirmed that LLLT significantly reduced pain scores, ulcer size, and healing time, with subgroup analyses favoring diode lasers. Nonetheless, across all reviews, the certainty of evidence was rated as low to moderate, primarily due to small sample sizes, unclear blinding, inconsistent reporting of laser parameters, and lack of long-term follow-up. Importantly, laser therapy was consistently reported as well tolerated, with no serious adverse events, supporting its safety profile as a symptomatic treatment option. Other systematic reviews provided similar findings. For instance, Khaleel Ahmed et al. (50) reported superior clinical outcomes, including faster epithelization and pain relief, following Nd:YAG and InGaAlP laser application. Brocklehurst et al. (10) and Han et al. (48) acknowledged the therapeutic potential of LLLT but
emphasized methodological limitations and inconsistent reporting across trials. Pavlić et al. (55), Najeeb et al. (53), and Skučas et al. (59) described laser therapy as beneficial in reducing lesion duration and severity. Suter et al. (16). The systematic review by Vale et al. (60) critically evaluated the LLLT literature and identified 22 publications, of which only two randomized controlled trials met strict eligibility criteria. Both trials demonstrated statistically significant reductions in pain intensity and healing time following LLLT compared with sham treatment. Despite marked heterogeneity in laser application parameters—including power output, energy density, mode of application (contact vs non-contact), and irradiation frequency—the two trials employed very similar wavelengths (809–810 nm), suggesting wavelength as a key determinant of clinical efficacy. However, the review concluded that no standardized clinical protocol could be recommended due to the limited number of eligible trials and variability in laser parameters
**Fire needle therapy**
One recent systematic review with meta-analysis by Wu et al. (41) synthesized evidence from nine randomized controlled trials (RCTs) involving 1469 participants diagnosed with RAS. All included trials were conducted in China and evaluated fire needle therapy, either as a standalone intervention or combined with other acupuncture-based modalities (e.g., acupoint injection, manual acupuncture, or acupoint application), compared with conventional non–fire-needle treatments.
Across pooled analyses, fire needle therapy demonstrated statistically significant improvements in several short-term clinical outcomes. Compared with control interventions, most commonly oral vitamins (vitamin B complex and vitamin C), injectable transfer factors, compound chlorhexidine gargles, or acupoint injections, fire needle therapy significantly increased the total effective rate (RR = 1.25, 95% CI 1.14–1.36), reduced pain intensity measured by the visual analogue scale (VAS) (MD = −1.68, 95% CI −1.82 to −1.53), and shortened ulcer healing time (MD = −1.66 days, 95% CI −2.73 to −0.59). Improvements were also observed in Traditional Chinese Medicine (TCM) symptom volume scores.
No statistically significant reduction in recurrence rate was observed when all control groups were pooled (RR = −0.18, 95% CI −0.36 to 0.01), although subgroup analyses excluding TCM-based controls suggested a possible reduction compared with conventional Western treatments alone. Reported adverse events were rare and mild (e.g., transient bleeding or hematoma), but systematic safety reporting was limited, with most trials providing no explicit adverse-event data.
Despite consistent direction of benefit for pain relief and healing acceleration, the overall certainty of evidence was rated as very low using GRADE methodology. This downgrading was driven by methodological limitations (unclear or high risk of bias, lack of blinding), substantial clinical heterogeneity (variation in fire needle technique, combination therapies, treatment duration, and control interventions), and imprecision. Accordingly, fire needle therapy may be considered a potential adjunctive or alternative non-pharmacological option for short-term symptom relief in RAS, but robust conclusions regarding long-term efficacy and recurrence prevention cannot be drawn.
**Herbal and natural product-based interventions**
The therapeutic efficacy of herbal products, including Chinese medicines, for the management of RAS has been extensively evaluated in all three NMAs (32–34) and 13 SRs (20,24,35,39,40,45,49,52,57,59,61–63); two of these SRs included quantitative meta-analyses (35,39). Across all NMAs, topical and systemic traditional Chinese medicine (TCM) formulations consistently ranked among the most effective treatments for short-term pain relief, ulcer size reduction, and healing acceleration. In an NMA of 26 RCTs, Liu et al. (33) identified Kangfuxin solution and Yunnan Baiyao as superior to conventional therapies for pain and ulcer size, with Kangfuxin achieving the highest SUCRA ranking for pain reduction. These findings were corroborated by Cheng et al. (32) who reported that Kangfuxin, compound licorice rinse, and Yunnan Baiyao consistently ranked highly across pain intensity, healing duration, and lesion size outcomes. Similarly, Mashrah et al. (34) demonstrated that integrated TCM regimens (topical plus systemic) significantly reduced pain and healing time and were associated with lower recurrence compared with standard care. Evidence from conventional herbal therapies paralleled these findings. A meta-analysis by Abdulrahman et al. (35) (9 RCTs, 844 participants) showed that herbal agents significantly reduced ulcer size at days 3–5, pain intensity, and healing duration, although effects were not sustained at day 7. *Punica granatum*, *Aloe vera*, and camel thorn distillate demonstrated the most consistent benefits. Qualitative SRs reported comparable effects for topical licorice (1–5%), curcumin formulations (1–5%), *Aloe vera*, chamomile, honey, and *Curcuma longa*, with several trials reporting clinical equivalence to 1% triamcinolone acetonide for pain and ulcer size reduction. However, the review noted considerable heterogeneity and a generally unclear risk of bias across studies, and no formal grading of evidence certainty was provided. Dorsareh et al. (20), in a qualitative review of six RCTs, reported that topical licorice (1–5%) significantly improved clinical outcomes - including pain, ulcer size, and healing time - typically within four to eight days, and with no adverse effects. The risk of bias in these studies was primarily rated as unclear due to insufficient details on allocation concealment and blinding procedures. Al-Maweri et al. (45) reviewed eight RCTs evaluating curcumin in various formulations (e.g., 1–5% gels, pastes, and powders) and concluded that curcumin significantly reduced both pain and ulcer size, with four trials demonstrating clinical equivalence to 1% triamcinolone acetonide. However, the methodological quality of the included trials was limited, with Jadad scores ranging from 2 to 4, and the overall level of evidence was judged to be low.
Further SRs provided evidence for the potential utility of herbal and Chinese medicinal agents in RAS management. Liu et al. (39) and Zhou et al. (62) evaluated a wide range of Chinese herbal formulations and identified promising effects associated with heat-clearing and detoxifying prescriptions such as *Rhizoma coptidis* and Yunnan Baiyao. Nonetheless, both reviews highlighted low methodological quality and high clinical heterogeneity across included studies. Skucas et al. (59) synthesized data from trials evaluating botanical therapies and noted that *Aloe vera*, curcumin, licorice, and honey were consistently associated with favorable outcomes, although limitations in trial design and lack of adverse effect reporting were noted. Reviews by Wahyuni et al. (61), Hasanah and Hidayat (49), and Pratiwi et al. (57) consistently emphasized the beneficial effects of *Aloe vera*, chamomile, honey, and *Curcuma longa* in pain management and mucosal healing. Nair et al. (52) further confirmed the clinical value of *Aloe vera* in treating oral mucosal lesions, including RAS. Shavakhi et al. (24) provided mechanistic insights, summarizing that various herbal agents exert therapeutic effects through anti-inflammatory, antioxidant, and immunomodulatory pathways—such as inhibition of pro-inflammatory cytokines (e.g., TNF-α, IL-1β), downregulation of COX-2, and promotion of epithelial healing.
**Nutritional and systemic supplements**
Micronutrients
Parra-Moreno et al. (54) conducted a systematic review assessing a broad spectrum of therapeutic interventions for RAS, including vitamin and mineral supplementation. The review highlighted that deficiencies in micronutrients - particularly vitamin B12, iron, and folate - are commonly associated with RAS, and that supplementation in patients with confirmed deficiencies may yield clinical benefits such as reduced recurrence and enhanced ulcer healing. However, the authors emphasized that the current body of evidence supporting the use of nutritional supplements remains limited by methodological shortcomings, including inadequate blinding, small sample sizes, and lack of standardized outcome measures. As a result, they concluded that while targeted supplementation may be appropriate in individuals with documented nutritional deficiencies, there is insufficient high-quality evidence to support the routine use of vitamin or mineral supplements in RAS patients with normal serum nutrient levels.
Zinc supplementation
One SR by Halboub et al. (47) included seven clinical trials (n=482) and found that zinc significantly reduced RAS recurrence rates in five studies and improved pain and healing time in three of four studies assessing symptom outcomes. Various forms and doses of zinc (sulfate, gluconate, glutamate) were used, with treatment durations ranging from 7 days to 12 months. While six studies reported no adverse events, one study noted mild gastrointestinal symptoms in a few participants. Nonetheless, inconsistencies in the dose, outcome measures, and risk of bias assessments limit the generalizability of the findings.
In another recent SR (59), the authors of the review highlighted zinc as an essential trace element with potential therapeutic benefits in RAS due to its anti-inflammatory, antimicrobial, and mucosal healing properties. Various formulations were discussed, including zinc citrate in oral care products and systemic preparations such as mucoadhesive tablets and dispersible oral tablets. The included RCTs in the review reported reductions in ulcer pain, size, and recurrence rates among patients receiving zinc supplementation compared to placebo. However, while the review noted positive clinical trends, it did not offer a formal assessment of methodological quality or grade the strength of evidence.
Probiotics
One MA (23) & one NMA (34) reported the efficacy of probiotics in the management of RAS. In a systematic review and meta-analysis by Cheng et al. (23), which included seven randomized controlled trials (RCTs), three of which were incorporated into the meta-analysis. The review investigated the effects of probiotics, either as monotherapy or as adjunctive treatment, on pain and ulcer severity. Among five trials comparing probiotics alone to placebo or standard treatment, three reported significant reductions in pain outcome, while two found no notable differences. Only one study observed a significant improvement in ulcer severity with probiotics alone. In contrast, two studies demonstrated that probiotics combined with corticosteroids or anesthetic-antiseptic gels significantly enhanced outcomes, including pain relief and lesion healing, compared to standard treatments alone. The pooled analysis revealed a statistically significant reduction in pain favoring probiotic use, though effects on ulcer severity remained inconsistent.
Additionally, an NMA by Mashrah et al. (34) identified probiotics as effective in prolonging ulcer-free intervals and reducing recurrence rates, supporting their utility as a long-term management strategy. However, their short-term benefits in promoting ulcer healing or reducing size were limited, and most studies included in the synthesis showed low methodological quality with inconsistent reporting on blinding and outcome measurement. Despite promising results, the evidence base remains constrained by small sample sizes, heterogeneity in probiotic strains and dosing, and the absence of standardized protocols.
Miscellaneous interventions
One MA (37) evaluated the effects of sodium lauryl sulfate (SLS)-containing versus SLS-free dentifrices in patients with RAS. The review included four double-blind, randomized crossover trials involving 124 participants. Results consistently favored SLS-free dentifrices, which significantly reduced the number of ulcers, ulcer duration, frequency of episodes, and pain intensity compared to SLS-containing formulations. Meta-analyses of two studies demonstrated a statistically significant reduction in the number of ulcers and ulcer duration. However, the included studies exhibited a high risk of bias, mainly due to inadequate randomization and incomplete outcome reporting, alongside notable heterogeneity in study designs.
Safety outcomes
Reported adverse effects varied across interventions and were generally dependent on the route of administration. Topical therapies,
16 N. A. AL-AIZARI ET AL.
including, hyaluronic acid, and laser-based interventions, were consistently associated with favorable safety profiles, with only minimal or no reported adverse events across included reviews. Specifically, topical corticosteroids were generally well tolerated across included reviews. Common adverse events were mild and localized, including transient burning sensation, mucosal thinning, and secondary oral candidiasis, particularly with prolonged or high-potency use. Serious systemic adverse effects were rare, reflecting the limited systemic absorption associated with topical administration.
In contrast, the findings demonstrate that systemic agents were more frequently associated with adverse effects. Common events included gastrointestinal discomfort, particularly with colchicine, while serious or less frequently risks such as peripheral neuropathy, sedation, and thromboembolic complications, were primarily reported with thalidomide. These agents were also associated with well-recognized contraindications and typically require clinical monitoring, including assessment for gastrointestinal intolerance, neurologic symptoms, and, in the case of thalidomide, strict pregnancy prevention measures. Systemic corticosteroids were infrequently evaluated and are not routinely recommended for idiopathic RAS due to the risk of adrenal suppression, mucosal atrophy, glucose intolerance, and opportunistic infections. When topical corticosteroids are prescribed repeatedly or at high potency (e.g., clobetasol propionate), periodic clinical monitoring for candidiasis is advisable, and prolonged continuous use should be avoided.
Overall, while systemic therapies may offer benefit in selected refractory cases, their safety profiles ensure that they should be interpreted cautiously and weighed against potential risks, particularly when compared with topical or adjunctive interventions that demonstrated more favorable tolerability.
**Discussion**
The present umbrella review comprehensively analyzed and synthesized the available evidence of systematic reviews, meta-analyses, and network meta-analyses regarding the effectiveness of diverse therapeutic interventions for RAS. A total of 41 reviews were included, encompassing a broad range of pharmacological, non-pharmacological (e.g., laser therapy, fire needle therapy), and complementary therapies. This triangulation provides clinicians with a balanced understanding of where consensus exists and where caution is needed. The findings suggest that a wide range of interventions offer symptomatic relief and promote ulcer healing in RAS. However, the strength and certainty of evidence varied considerably across the included reviews. Herbal and traditional Chinese medicines, particularly Kangfuxin, Yunnan Baiyao, compound licorice, *Aloe vera*, and curcumin, demonstrated the most consistent efficacy for pain reduction and ulcer healing across both network meta-analyses (32–34) and individual systematic reviews. Laser therapies, especially diode and low-level laser types, were also frequently reported to yield beneficial outcomes in pain relief and tissue repair, although substantial variability in treatment parameters and protocols limits the generalizability of findings.
Other interventions, such as hyaluronic acid, propolis, and zinc supplements, demonstrated moderate efficacy with favorable safety profiles, aligning with prior evidence supporting their wound-healing and anti-inflammatory properties. Meanwhile, commonly used agents like topical corticosteroids and doxycycline showed mixed outcomes, with limited or inconclusive evidence regarding their impact on recurrence reduction (69).
Despite the broad scope of evidence, several methodological limitations weaken the strength of the conclusions. The methodological quality of the included reviews, as evaluated using the AMSTAR 2 tool, was highly variable. Only 22% of the reviews were rated as high quality, while 25% were rated critically low, reflecting inconsistencies in reporting, data synthesis, and protocol registration (28). Furthermore, many of the underlying randomized controlled trials (RCTs) were assessed as having high or unclear risk of bias, particularly in terms of allocation concealment, blinding, and selective outcome reporting factors known to compromise internal validity (70).
Although laser therapy and herbal agents showed favorable efficacy, their real-world accessibility remains limited by equipment availability and regional drug registration. For example, Kangfuxin and Yunnan Baiyao are not widely distributed outside Asia, and laser devices may be cost-prohibitive in primary care settings. In addition, overlap analysis of primary studies using corrected covered area (CCA) analysis revealed substantial redundancy among laser intervention studies (CCA = 17.68%), which may have artificially inflated pooled effect sizes and compromised the independence of findings (71). Despite consistent short-term benefits observed across several interventions, the certainty with which these findings can be translated into clinical recommendations is limited by the methodological quality of the underlying evidence. A substantial proportion of included reviews were rated as low or critically low confidence using AMSTAR 2, indicating that conclusions, particularly for adjunctive and complementary therapies should be interpreted cautiously. Accordingly, this umbrella review does not propose a prescriptive treatment algorithm but rather provides an evidence-informed synthesis to support individualized clinical decision-making.
Clinical heterogeneity represents another important limitation. Interventions were delivered using diverse formulations (e.g., gels, tablets, rinses, sprays), dosages, and treatment durations, thereby limiting the feasibility of direct comparisons across studies. Outcome reporting was also inconsistent with pain, lesion size, or healing time, and recurrence assessed using heterogenous definitions, measurement scales, and time points, often without standardized or validated assessment tools. Unlike primary systematic reviews, umbrella reviews depend on secondary synthesis that often differ in outcome timing, measurement scales, and analytic approaches. In the present review, pain outcomes were assessed at heterogenous time points, healing was reported as either complete resolution or mean days to closure, and recurrence was variably defined. Under these circumstances, reporting pooled or comparative quantitative estimates would not be methodologically defensible.
This umbrella review has several strengths. To the best of our knowledge, it is the most comprehensive synthesis to date examining the comparative effectiveness of a wide range of interventions for RAS. It was conducted following stringent methodologies: in accordance with Cochrane and PRISMA guidelines, employed AMSTAR 2 for critical appraisal, and utilized the GROOVE method to evaluate primary study overlap, thus enhancing transparency and methodological rigor (26,72). Future research should prioritize well-designed, head-to-head trials with long-term follow-up, standardized outcome reporting, and practical evaluations of real-world accessibility and cost. Such efforts are essential to inform treatment guidelines and optimize patient outcomes.
**Conclusion**
This umbrella review provides a high-level synthesis of current evidence on treatment interventions for RAS, addressing both the strengths and limitations of various therapeutic options. Topical
corticosteroids, hyaluronic acid, and laser therapy consistently demonstrated short-term efficacy in reducing pain and healing duration. Herbal agents such as curcumin, Kangfuxin, and licorice showed promising results, with favorable safety profiles but moderate certainty of evidence. Systemic treatments like thalidomide and colchicine may benefit refractory cases but are limited by their adverse effect profiles and accessibility.
Importantly, discrepancies among recent network meta-analyses underscore a marked methodological heterogeneity in outcome definitions, population characteristics, and analytical models, highlighting the need for harmonized research standards. Furthermore, while many interventions demonstrate clinical potential, their long-term impact on recurrence prevention, cost-effectiveness, and accessibility remains poorly understood.
By incorporating both efficacy and safety data, and by proposing a decision-making framework based on ulcer severity, this review aims to support personalized and evidence-informed management of RAS. Future research should prioritize well-designed, head-to-head trials with long-term follow-up, standardized outcome reporting, and practical evaluations of real-world accessibility and cost. Such efforts are essential to inform treatment guidelines and optimize patient outcomes.
**Acknowledgments**
Open Access funding provided by the Qatar National Library.
**Author contributions**
Nader Al-Aizari: Conceptualization, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing.
Hashem Al-Shamiri: Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing—original draft, Writing—review & editing.
Bayan AlShehri: Investigation, Methodology, Resources, Writing—review & editing.
Khalid Alhomood: Investigation, Methodology, Resources, Writing—review & editing.
Saeed Alzahrani: Investigation, Methodology, Resources, Writing—review & editing.
Waad Abuhasna: Investigation, Methodology, Resources, Writing—review & editing.
Sadeq Al-Maweri: Investigation, Methodology, Resources, Writing—review & editing
**Disclosure statement**
No potential conflict of interest was reported by the author(s).
**Funding**
The authors declare that no funds, grants, or other support were received to conduct this review.
**ORCID**
Sadeq Ali Al-Maweri [](http://orcid.org/0000-0003-4932-1377) http://orcid.org/0000-0003-4932-1377
**Data availability statement**
Data sharing is not applicable to this article as no data were created or analyzed in this study.
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