INTRODUCTION:

Aphthous stomatitis is also termed as mouth ulcer, canker sore or aphthous ulcer. Recurrent aphthous stomatitis (RAS) is a condition with repeated occurrences of ulcers in the mouth.¹ Mouth ulcers can be extremely painful when they occur in the area that moves during eating or talking. Thereby affecting the quality of daily life badly. Molecular necrosis of mucosa causes the break in the continuity of the epithelium which creates an ulcerative condition including sores, lesions, abrasions, and lacerations in any part of the oral cavity usually inside of the lips and cheeks or on the tongue.²

RAS has an indefinite etiology and therefore, there are no specific treatments available for this condition.^[3] It may occur in association with various mild to serious diseases. The causative factors for aphthous stomatitis are Trauma (physical, chemical, or thermal), infections (bacterial and viral), several deficiencies such as nutritional, vitamin, immune, or hematic deficiency, mental stress, hormonal changes, genetic predisposition, SLS and food additives, allergies and sensitivities, radiation therapy, chemotherapy, cessation of smoking, uremic stomatitis, Crohn’s disease, diabetes mellitus, Sjogren syndrome, squamous cell carcinoma, tuberculous ulcers, syphilitic ulcers, etc.⁴ Recent studies have reported that aphthous stomatitis is observed to be frequent in covid-19 patients.⁵

The treatment given is mostly symptomatic. The main inconvenience to the patient is due to the pain which is because of the ulcer. Therefore, the treatment strategy comprises pain relief and ulcer healing. For pain relief, mostly local anesthetics are applied topically. These agents temporarily block the pain sensation and do not contribute to ulcer healing. Several anti-infectives like chlorhexidine, levamisole, sucralfate, tetracycline, etc are used to prevent and treat the infection.⁶ In some cases, steroids or immunosuppressants like cyclosporine are also used which alter the reaction of the body to external stimuli and thus control some of the causative factors. Additionally, supplements like vitamin B complex, folic acid, and vitamin C are also advised for the treatment.⁷ There is no Western medicine available that can take care of all aspects of RAS⁸. Therefore, attention is given to herbal drugs having strong treatment claims as folklore medicine.⁹ There are several herbal products available in the market containing a combination of herbs or herb extracts however, there are no studies available that report their efficacy. At the same time, clinical studies for some herbal products are reported to exhibit varying efficacy in comparison to placebo or other comparator products. However, products described in literature as successful, are not available in the market. Thus an effective product for the treatment of RAS is still lacking. The present work attempts to critically review all the clinical studies reported for plant extracts or herbal products with respect to their clinical usefulness. This review goes on to look at the key reasons for the success or failure of a study based on the dose, nature of phytoconstituents, mode of use, etc. Finally, we expect the readers to get knowledge about the utility of different plant extracts in RAS for designing and developing a clinically useful product for making it available in the market.

METHODOLOGY:

For this work, we collected the literature mentioning the clinical studies of plant-based medicines for the treatment of RAS, aphthous stomatitis, and mouth ulcers. Clinical studies following different criteria for the study design like, randomized, single-blind, double-blind or parallel studies were included. Upon searching the databases like Clinical trials.gov, Google Scholar, PubMed, and Springer, a total of 42 searches were selected excluding the repeated searches. Only the studies where clinical intervention was applied by topical route (gel, mouth rinse, patch, or spray) were considered. The studies not following any criteria for the study design were excluded from this review. The collective data of such selected studies, related to study design, methodology, and results were tabulated and analyzed in various aspects. All those aspects are discussed in this review. Further, the plant extracts or the herbal interventions studied were categorized based on the effectiveness of the intervention in reducing the pain and size of the ulcer. Reports mentioning complete healing and absence of pain of ulcers in shorter duration were categorized as showing promising anti-mouth ulcer activity. Plant-based medicines showing comparatively longer duration for healing of ulcers due to certain shortcomings in the study design or the mode of application were categorized as Plant Extracts Showing Potential for Activity in RAS. The rest of the clinical trials were categorized as Plant Extracts Not Showing Convincing Activity in RAS.

Plant Extracts Showing promising activity in RAS

The plant extracts that showed a significant reduction in the pain and ulcer size on the third day and either complete healing or substantial recovery from the symptoms of the subjects within 5-7 days, are discussed in this section. The details of the study design and efficacy data of such extracts are given in Table 1.

There are several plants native to Europe, the Mediterranean region, and southwest Asia that are mainly known for their essential oils and are used in traditional medicine systems as a treatment for RAS. Myrtus communis, Zataria multiflora, Satureja khuzistanica, Anthemis nobelis (Roman Chamomile) and Matricaria chamomilla (German Chamomile) are some of those plants. The anti-inflammatory, antioxidant, chemoprotective and antimicrobial properties of many of these plants are already proved. The presence of these properties forms a strong basis for studying their activity in RAS.

A 5% paste of M. communis was evaluated for its efficacy in RAS in a double blind, placebo controlled clinical trial in 45 patients. The study was conducted at two centers. The leaf extract was prepared and lyophilized. The paste of this extract was applied four times a day for six days. It was found to be quite effective in RAS. On day 2, about 25% and on day 4, about 51%, and on day 6, about 80% of patients were without any erythema or exudation. The corresponding values in the placebo group were 0%, 2% and 7%. Thus, 5% paste of Myrtus communis may have potential in the treatment of RAS. The aqueous leaf extract of M. communis has been found to contain flavonoids, polyphenolic compounds, etc.¹⁰ These compounds are known for their anti-oxidant activity. The other favorable factor was the use of lyophilized extracts. The lyophilized extracts are the concentrated composition of therapeutically active phytoconstituents. The speed of healing and reduction in pain at each visit was more prominent in the treatment group. This product can find a useful application in the clinical treatment of RAS. The dosage form is easy to manufacture, and its application is patient friendly. The frequency of application may pose a hurdle in treatment adherence. Otherwise, it seems to fit well into the requirements of a good drug product.

In another study, however, it was found that the hydroalcoholic extract of Z. multiflora was better than the M. communis mouth rinse. Z. multiflora is a thyme-like plant found in southwestern Asia. In this study, the efficacy of A. nobelis extract and its mixture with Z. multiflora in RAS was also studied. The studies were conducted on 101 patients. The mouth rinse preparation of M. communis that is available on the market in Iran was used for the study. There were four groups, and each group consisted of about 25 patients. The Z. multiflora extract performed best amongst all groups and complete healing of ulcers was observed on day 6 and no pain was experienced after day 3 of the treatment. For M. communis mouth rinse, complete healing was observed after 7 days and pain elimination happened after 4 days.¹¹

Considering the better activity shown by the lyophilized extract of M. communis in the study conducted by Babaee et al, it can be concluded that the lyophilized extract is better than the mouth rinse. The nature of phytoconstituents present in M. communis and Z. multiflora extract is similar.¹² Z. multiflora additionally contains thymol which might impart an edge to this due to its antiseptic, anti-inflammatory and antibacterial properties. A comparative study is required to find out a better treatment option.

Tadbir et al used chamomile extract in orabase and compared its efficacy with triamcinolone and plain orabase.¹³ On day 6 both the pain intensity and ulcer size were significantly reduced, confirming the promising activity of this extract. Thus, chamomile both as extract as well as its essential oil has been found to be effective in the treatment of RAS. There is an urgent need to standardize the dose and formulate it in the suitable dosage form to have a clinical agent with more than ever promising activity. Psidium guajava (Guava) is an evergreen shrub native to Asia, Africa, Central America, and South America. It is popular for its properties like, wound healing, anti-inflammatory, analgesic, antidiabetic, anticaries, etc. in folklores. Despite the easy availability of the leaves and rich claims from traditional knowledge about its mouth ulcer healing activity, not many studies are published in this regard. Guintu and Chua studied the activity of water extract of guava leaves in patients suffering from minor aphthous ulcers and compared it with a normal saline solution. Both the treatments were used as mouth wash for three minutes, thrice a day, for one week, distributed randomly to two groups (n=16) of patients. The visual analogue scale (VAS) and ulcer size were the monitored parameters. From the third day onwards, a significant difference in the VAS in guava group was seen compared to the normal saline group. On day 6, the VAS in the guava group was 0.38±0.72 and in the saline group, it was 3.12±1.36 indicating better efficacy of guava extract. Further, on day 7, 75% of patients showed no ulcers in the guava group and only 25% of patients showed no ulcers in the normal saline group.¹⁴ It also has been proposed as a prophylactic agent in oral care in another study conducted in about 60 subjects by Nayak et al.¹⁵ The water extract of P. gujava contains tannins, flavonoids, polyphenolic compounds and saponins along with other constituents. The studies are required to determine the phytoconstituents that are responsible for the activity.

After the promising activity shown by flavonoids, polyphenols, tannins and essential oils in the treatment of RAS, oils were also found to be effective in RAS. Pumpkin seed oil mainly contains protein, fibers and fats.¹⁶ It has been found useful in benign prostatic hyperplasia, prostate cancer.¹⁷There are not many references of pumpkin seed oil that can hint at its use in RAS, nevertheless, it was studied clinically for its effectiveness in the treatment and prevention of RAS based on the presence of vitamins, minerals and other antioxidants in it. The studies were conducted on 25 patients of varying severity of mouth ulcers and only those patients were included in the study who did not benefit from the existing therapies. Surprisingly, significant results were obtained on day 4 and day 8. A specifically designed index called “Oral clinical manifestation index (OCMI)” that included number & types of ulcers, frequency and duration of occurrences, pain intensity etc., was used for monitoring the efficacy. A whooping reduction in OCMI from 12.96±1.42 (Day 0) to 2.76±1.5 (Day 4) and to 0.72±1.48 (Day 8) was observed. The study further reported the efficacy of preventing reoccurrence of aphthous stomatitis during the study period of three months. Thus, this was one of its own kinds of study proving pumpkin seed oil as a very effective treatment option in RAS.¹⁸ Pumpkin seed oil can work in two ways. First, by providing essential building material like fatty acids, sterols, tryptophan, antioxidants, etc. that are required for the formation of new cells at the ulcer site and second, by forming a barrier between the contents of, the oral cavity and the ulcer site. The barrier will protect it from the attacks of pathogenic bacteria. This seems to be a very simple product not requiring any special preparation. It can be a very promising candidate for large-scale clinical studies. In fact, the authors of this article suggest conducting large scale comparative trials for the interventions mentioned so far in this section.

Plant extracts showing potential for activity in RAS

Among the various reported clinical studies, some plant extracts or their phytoconstituents didn’t show very promising activities. However, if the results of published clinical trials are analyzed critically, we can notice their potential. Turmeric, licorice, aloe vera, Rhizophera mangle, Berberine, marine algae are among such natural products.

Turmeric is well-known for its anti-inflammatory, antiseptic and analgesic properties, which are mainly due to its major constituent, curcumin. It has been studied extensively for its medicinal properties. There are four studies reported on the activity of curcumin in RAS. In a placebo-controlled study, turmeric gel was applied twice a day (n=28) but there was no complete recovery after 7 days. Reduction in ulcer diameter was from 4.71±0.81 mm to 0.75±0.58 mm with curcumin gel and from 5.00±0.75 mm to 1.06±0.59 mm in placebo. Similar results were observed with pain scores. Thus, it can be concluded that the curcumin gel was not significantly different in efficacy when compared with placebo. The reason for this unimpressive effect can be the dose of curcumin in the gel. It was only 2%.¹⁹ In another study, the turmeric powder as a whole was compared with triamcinolone in the two groups of 10 patients each suffering from minor RAS. No complete recovery of the ulcers in terms of pain and ulcer size was reported after five days in both the groups. A pain score of 1.1±1.2 and 0.8±2.5 was reported in the turmeric and triamcinolone groups respectively, at the end of five days. While the ulcer sizes of 6.5±9.8 mm and 4.12±3.9 mm were reported in both groups at the end of five days. Although the turmeric group showed greater reduction in the pain score, it can’t be concluded to be used as a drug product as it didn’t cure the pain and ulcers completely in five days.²⁰ The patients experience great inconvenience and poor quality of life due to RAS. The product which relieves pain in hours and cures ulcer in 3-5 days will be highly welcome. In our opinion, the whole turmeric powder may not be a good agent for this purpose. Instead, curcumin in a suitable dosage form should be preferred for this purpose.

Curcumin was also compared with honey and Orabase® gel in 105 patients. All the treatments were applied three times a day for seven days and curcumin performed significantly better than honey and Orabase® gel in relieving pain and reducing ulcer size. However, none of the treatment was found to result in complete recovery at the end of seven days.²¹ Considering the anti-inflammatory and analgesic activity of curcumin, one may think that increasing the frequency of application might result in faster recovery, however, even in the study where curcumin was used as mouth wash five times a day, did not result in complete recovery of RAS. These studies were conducted in 74 patients, and it was compared with Sage mouth wash.²²

All the above-mentioned studies didn’t result in the complete recovery of RAS in 5-7 days. As the antiseptic and anti-inflammatory properties of curcumin are proven, therefore, it’s expected that curcumin preparations should be efficacious in the treatment of RAS. The undesirable efficacy in the above-mentioned studies may be due to low dosage of curcumin and inappropriate dosage form. The curcumin, being highly lipophilic, may require some treatment so that it can penetrate the ulcer cells to show activity. We are of the opinion that curcumin needs some strategic improvements in terms of formulation development before it can show desired clinical efficacy in RAS.

As per traditional knowledge, licorice root can be used in throat malaise, mouth ulcers, asthma, etc.²³ There are many products containing licorice available in the market for the treatment of mouth ulcers. Yet, there are no published reports on the clinical efficacy of those products. Hassan and Khalil²⁴used water extract of licorice as a mouth wash 3 times a day for 3 days in patients suffering from superficial mouth ulcers as well as deep mouth ulcers (n=6). Improvement in ulcer condition was observed from the first day in patients having superficial ulcers, leading to complete healing on the third day. Patients with deep ulcers take a long time to heal. Yet these studies can’t be taken as an indicator of efficacy as the sample size was small and results were not compared with placebo or any standard treatment.

Galal et. al, compared the efficacy of Liquorice with Acacia nilotica extract in the management of RAS in a placebo controlled trial.²⁵ The lyophilized extracts of these herbs were converted into 2% mucoadhesive pastes for topical application. Forty human volunteers with minor mouth ulcers were divided into four groups. First and second groups received pastes of liquorice and A. nilotica extracts. The third group was given a paste containing a mixture of both the extracts (1% of each extract). The fourth group was given placebo. Treatment of minor aphthae using a mixture of Liquorice and Acacia nilotica extracts showed greatly improved pain reduction and ulcer healing than each extract alone. The pain score of the mixture was reduced from 5±0 to 1.1±1.7 in five days. Similar results were observed for reduction in ulcer size. Thus, the mixture of licorice was found to be a better treatment option than liquorice alone. Further, it can be hypothesized that increasing the dose may also help in enhancing the efficacy.

In one more study, the combination of liquorice and A. nilotica was compared with Amlexanox and the diode laser method.²⁶The study was randomized and placebo controlled. The patients with RAS were divided into four groups (n=15 in each group). A 2% mucoadhesive paste of the mixture of liquorice and A. nilotica was prepared in the same way that Galal et al used and it was given to one group. The second group received mucoadhesive tablets of 2 mg Amlexanox. The ulcers of the third group were given treatment with diode laser radiation. The fourth group (control) received placebo mucoadhesive tablets. The duration of treatment was 5 days. It was observed that the reduction in both pain scores and ulcer size in the herb mixture group was better than the placebo but less than that of the diode laser and Amlexanox groups. As mentioned earlier, there is a need to optimise the dose of these extracts to see the real potential of this combination as a treatment option for mouth ulcers.

Moghadamnia AA et.al., evaluated the efficacy of 1% liquorice bioadhesive in an observer blind, placebo controlled trial in RAS.²⁷In this study the treatment group was compared with the placebo-bioadhesive patches group and no treatment group. Though the liquorice patches showed more considerable pain relief than the placebo patches, still, the overall efficacy was not significantly superior to the placebo patch. The dose used in this study was too low. We are of the strong opinion that liquorice products must be first tested at higher dosages before rejecting them as a medicine for RAS. The potential of liquorice was proved in the study done by Galal et al. Now there is a need to further study the synergistic effect of liquorice along with other agents with promising activity in RAS.

Aloe vera is another herb with very strong endorsement by the traditional systems of medicine for wound healing. It contains a variety of phytoconstituents including vitamins, enzymes, minerals, sugars, anthraquinone, fatty acids, hormones etc. The wound healing property is attributed to the mucopolysaccharides and hormones present in it.²⁸ A 2% Aloe vera gel was evaluated in minor RAS in a double blind placebo controlled trial by Babaee et al. ²⁹The gel was prepared using freshly purified leaf juice extract. The subjects (n=40) were instructed to apply the formulations 3 times a day for 10 days. The reduction in pain severity was more prominent in aloe vera gel than in placebo gel. However, with respect to overall cure, this treatment was not better than the placebo.

In another study, Ghada Mansour et al³⁰ compared the clinical efficacy of aloe vera against myrrh in the management of minor RAS using 0.5% w/w mucoadhesive gels for both the natural compounds. The patients (n=90) were advised to apply the gels 4 times a day for 5 days. Both the treatments were compared with a placebo gel. On day 6, ulcer sizes in the aloe vera group were lesser (2.5 mm²) than myrrh (3.3 mm²) and placebo (4.2 mm²). However, on day 6, the mean pain scores were the least in the myrrh group (0.72), then in the aloe vera (1.1) or placebo group (1.7). Aloe vera happened to be superior in decreasing ulcer size, erythema, and exudation whereas myrrh resulted in more pain reduction.

Shi et al combined aloe vera with Lactobacillus plantarum in the form of 5% (of aloe vera) gel. The patients (n=35) were instructed to apply gel on the site of the ulcer three times each day until the ulcer disappeared. Another group was given chitosan gel as a placebo (n=16). There was no significant difference between the treatment and the placebo group with respect to mean healing time. For aloe vera probiotic gel, it was 7.40 ± 1.85 days whereas for chitosan gel, it was 7.93 ± 1.84 days. However, about 35% and 65% of patients recovered in 4-6 days and 7–10 days respectively with the treatment. And obviously, the corresponding numbers for chitosan gel were 20% and 80% of patients were recovered by 7–10 days. This study confirms the healing potential of aloe vera.³¹

All the clinical studies carried out to assess the utility of aloe vera in RAS indicate that aloe vera do have a potential for mouth ulcer healing but it may not do so as a lone agent. As there are several other studies where it has shown promising wound healing activity, we recommend the use of aloe vera as a wound healing agent in a combination formulation. ^32,33We also suggest increasing the dose before arriving at any conclusion.

Berberine is an alkaloid obtained from roots, rhizomes, stems and bark of a variety of plants belonging to the genus Berberis. This alkaloid has shown activities that an ideal anti-mouth ulcer agent should possess, like anti-inflammatory, anti-oxidant antimicrobial etc. Its role in RAS was evaluated in a randomized double blind, placebo controlled clinical trial (n=87).³⁴ A 0.5% berberine containing gel was given to treatment group and placebo gel to control group. The drug was applied on the ulcer, 4 times a day for 5 days. Pain intensity and healing rate of ulcers were used as indicators of the effectivity of berberine. The Berberine group showed significant reduction in both the parameters. However, healing was not complete after five days of treatment. It behaved definitely better than placebo, but it may not be acceptable as a clinical agent for the treatment of mouth ulcers. Further studies with higher doses and/or using berberine in combination with other more effective agents are needed to establish its relevance in the treatment of RAS.

Marine algae or seaweeds are species of interest to many researchers. Bechir et al compared the antiulcerogenic effect of various marine algae extracts in collagen gel in 186 patients (97 women and 89 men) to treat Apthous stomatitis.³⁵ Three varieties of algae (Cystoria barbata; Ulvae lactuvea; Ceramium rubrum) in two different concentrations ((5%, 10%) in collagenic gel were studied in patients with RAS conditions (n=31). Gel was applied 4 times daily for 7 days. The reduction in the symptoms in patients treated with the collagenic gel containing 10% The C. rubrum extract was found to be notably better than in patients treated with the other gels. The species C. barbata has high antioxidant activity and contains polyphenols, flavonoids, phospholipids, vitamins, heavy metals, etc that could be used in the therapy of degenerative diseases. Further, the presence of collagen may also boost tissue recovery in ulcers. As the treatment with 10% concentration could result in complete recovery in all the 31 patients after five days of treatment, therefore, to speed up the recovery, this formulation should be enriched with additional effective compounds and a clinically useful product can be developed.

Plant extracts not showing convincing activity in RAS

There are few more reports available where the treatment composed of products of natural origin didn’t show any convincing therapeutic activity. The probability of developing clinically viable medicines looks faint for these products. Honey, ginger, and traditional Chinese medicine (TCM) belong to this category.

The efficacy of honey was compared with salicylate gel by Halim et.al to treat minor RAS. A randomized clinical trial involving 20 outpatients from a dental clinic was planned. Patients were instructed to apply the medicaments three times a day for five days. Pain score and ulcer size difference (between day 1 and day 5) were analyzed using the Mann-Whitney test. No significant relief was observed from honey (Mean pain score 5.7 on Day 1 and 1.1 on Day 5) as compared to salicylic acid gel (Mean pain score 4.40 on Day 1 and 0.80 on Day 5). Salicylate gel is widely prescribed to cure mouth ulcers, yet it is not a very effective medicine. As pure honey was not found to be better than salicylate gel, therefore, there is no reason to study this product further.³⁹

Ginger has been traditionally used for its anti-inflammatory, sedative, and pain regulatory properties. A double-blinded, placebo controlled clinical trial (n=15) was planned by Haghpanah et al, to evaluate ginger for its mouth ulcer healing activity.⁴⁰ The alcoholic extract of ginger in a mucoadhesive base, was compared with a placebo mucoadhesive base. There was a third group who was not given any treatment. Both the treatment and placebo were applied for 20 minutes four times a day for 7 days. Both the ginger and placebo behaved almost in a similar manner in reducing the pain and ulcer size. The efficacy of ginger was not significantly different compared to the placebo group. Although this study rules out the role played by ginger in healing the ulcers, it hints at the role of a barrier that adheres to mucosa, protects it from the external pain-inducing stimuli and also provides with the building material for new cells.

TCM system is a very well researched system and is well engaged in verifying its own claims. TCM considers RAS as the outcome of GI disorders. Therefore, the methods of treatment are based on correcting the GI functioning. We couldn’t find any specific medicines being prescribed specifically by topical route for the treatment of RAS. Yet, there were two published reports exploring the role of TCM in this disease. Yunnan Baiyao powder and Pudilan Xiaoyan Oral Liquid are the two TCMs which are currently used for anti-hemorrhagic and antiviral properties respectively. Both are formulations containing a mixture of herbs out of which the composition of Yunnan Baiyao powder is protected by patent and trade secrets.

In a double blind, randomized clinical trial study by Liu et al, the efficacy of a toothpaste containing 0.65% of Yunnan Baiyao was reported in comparison to a placebo toothpaste.⁴¹ The study was carried out in 227 patients and patients were instructed to brush their teeth twice in a day using 1 g of toothpaste. The mean ulcer size was reduced from 4.5 mm to 3.4 mm and 2.1 mm on day 3 and day 5 respectively. Further, in the treatment group, 66.4% of patients and in the placebo group, 50% of patients showed significant healing on day 5. Considering the substantial rate of healing, it can be said that though Yunnan Baiyao toothpaste has better efficacy than placebo, it still needs more improvement before it can be used in clinics for treating RAS. As the composition of this powder is secret and is not disclosed, therefore, the reason for its activity and ways to improve that, can’t be scientifically discussed.

Pudilan Xiaoyan Oral Liquid is a TCM preparation composed of Indigowoad Root (Isatis Indigotica), Bunge Corydalis (Corydalis Bungeana), Mongolian Dandelion (Taraxacum Mongolicum), Scutellaria Amoena (Scutellaria Baicalensis). In a study aimed at exploring the efficacy of this preparation, the treatment group (n=177) received 10 ml of Pudilan oral liquid, and the control group (n=57) received placebo. The studies were run for 8 days, and it was observed that the mean healing time required for the treatment group was 5.28 days, while for the control group, it was 6.1 days. Although the p value is significant (0.03), this preparation is not useful for clinical purposes. If, without treatment, the patient can be cured in 6 days, he would not like to take treatment to get cured in 5.28 days. The reason for similarity in both the results may be the additional treatment of vitamin B2 tablets 20 mg, that was given three times a day to both the groups.⁴² Vitamin B2 is clinically used for the treatment of mouth ulcers, therefore, the design of this study was not such that the efficacy of Pudilan oral liquid could be determined.

Watermelon frost spray is another traditional Chinese medicine which is a combination of 14 Chinese herbs and is claimed to be useful for the treatment of mouth ulcers. However, details of published clinical studies in favor of its efficacy are not available in the literature.⁴³

DISCUSSION:

Though RAS is very prevalent worldwide, its etiology is still to be understood clearly. Thus, several therapeutic options available for the symptomatic relief from the lesions, pain, and inflammation including use of corticosteroids, antibiotics, and analgesics. These are not the good treatment options for RAS due to their limitations. The use of plant-based products in the treatment of RAS finds strong support in traditional medicine. Yet, promising herbal treatment options giving rapid relief and preventing recurrence are not available till date. Due to the lack of interest in this area by pharma companies, not many high-quality clinical studies are available. There is a great need for well-planned clinical trial protocols to get meaningful outcomes which could be further translated as effective therapy. For effective therapy, the product should alleviate pain and reduce the ulcer size quickly. The formulation should take care of all the symptoms and its components should act at cellular levels for quick relief. In short, the product should possess anti-inflammatory, analgesic as well as wound healing properties to prove to be an effective herbal product for the treatment of RAS. In the present review, plant extracts used in the clinical studies for topical application have been categorized based on time taken to reduce pain intensity, time required for reduction in size of ulcer and complete healing. Extracts of M. communis, Z. multiflora, Satureja khusistanica, chamomile essential oil, cinnamaldehyde, Rue, pomegranate flowers and peels, as well as guava leaves showed promising activity for the treatment of RAS. In almost all the studies aqueous or hydroalcoholic extracts in the form of mouth washes, mouth rinses, pastes, gels, tablets were applied topically for 5-7 days with varying frequency of application. Reduction in size of ulcer and significant decrease in pain intensity along with complete healing was observed in considerably less time for all these plant extracts. The efficacy of these plant-based medicines can be credited to the presence of phytoconstituents like flavonoids and polyphenols. These extracts and essential oils can be made more effective by following an effective formulation strategy to improve contact time with the ulcerous area and to decrease frequency of application. Eventually, there can be good patient adherence to the medication for quick relief from RAS. Addition of some functional excipients like mucoadhesives, collagens, gums may increase adherence at the site of action and collagen like excipients may contribute to the regeneration of mucosal linings. ^{44, 45}

Turmeric, licorice extract, aloe vera leaf extract, berberine extract are categorized as plant extracts showing potential for therapeutic activity for RAS, as these take a longer duration for reduction in pain and healing of ulcers. This might be due to low dose of extract and improper formulation strategy. For example, licorice extract in combination with acacia nilotica in the form of bioadhesive patches showed better efficacy. Collagen based gel of marine algae showed faster healing of ulcers. Addition of plant extracts like licorice, and turmeric to such a formulation may further reduce healing time and can contribute to reduction of pain. In some studies, the activity was not compared with placebo. Thus, the design of a clinical study also needs to be given importance for better outcome of the study, which may contribute to availability of an effective plant-based formulation for treating RAS^46,47,48.

Clinical studies performed on honey, ginger and many Chinese medicines did not show convincing activity for the treatment of RAS, though these agents claimed to have tissue regeneration activity in the literature.^49,50,51 Absence of proper formulation and sufficient content of extract in the base proved these agents ineffective for the treatment of RAS. In case of traditional Chinese Medicine, Yunnan Baiyao, the formulated toothpaste did not show promising results when compared with placebo toothpaste. TCM preparation, Pudilan Xiaoyan Oral Liquid did not show convincing improvement in the ulcer pain and healing as compared to control, suggesting lack of functionality towards reduction in pain and healing of ulcers^52,53,54.

There may be scope for improvement of its efficacy by combining it with other promising plant extracts. Though claimed to be effective, no details of the clinical studies are available for the efficacy of watermelon frost spray along with 14 Chinese herbs for the treatment of RAS^55,56.

Thus, more scientific clinical study design, proper formulation strategy, and use of a combination of extracts might result in an effective plant-based formulation for the treatment of RAS without any adverse effects^57,58.

CONCLUSION:

The critical analysis of the published clinical studies on herbal products revealed that extracts of plants like M. communis, Z. multiflora, S. khuzistanica, chamomile, rue, pomegranate and guava have promising activity as anti-aphthous agents. Similarly, cinnamaldehyde and pumpkin seed oil also belong to the category of effective agents. These are required to be converted into suitable dosage forms to get clinically useful products. We also found that plants like turmeric, licorice, aloe vera, R. mangle, Berberis, and some marine algae have potential for activity, and it is possible to convert them into good products with the use of an appropriate formulation approach. Of course, a good quality study design will be needed to prove its usefulness. Further, it was also noted that although very popular in folklore, honey, ginger and some TCM didn’t show any convincing activity in the treatment of RAS. This review will be helpful to the product development scientists working in this area.

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Name of Herbal Intervention	Placebo/ Control Group	No. of Subjects	Mode and Frequency of Application	Efficay in placebo/ control Group	Efficacy in Treatment Group
5% paste of lyophilized extract of M. communis	Placebo	45	To apply on the ulcers, four times a day for six days	Day 2: 0% of healed patients Day 4: 2% of healed patients Day 6: 7% of healed patients	Day 2: 25% of healed patients Day 4: 51% of healed patients Day 6: 80% of healed patients
Hydroalcoholic extracts of Z. multiflora	M. Communis Mouthrinse Anthemis nobelis Extract Mixture of Z. multiflora and A. nobelis extracts	101	To apply 10 drops of each extract on the affected area for one minute, five times a day	M. communis mouth rinse Complete pain disappearance: 4.25 days Complete ulcer healing: 8 days A. nobelis mouth rinse Complete pain disappearance: 5.2 days Complete ulcer healing: 9 days Mixture of Extracts Complete pain disappearance: 3 days Complete ulcer healing: 7 days	Complete pain disappearance: 3 days Complete ulcer healing: 6 days
30 drops in 100 ml Chamomile essential oil as Mouth rinse	Placebo	50	Mouth rinse for 1-2 minutes, three times a day until complete resolution of the ulcers	Day 3 Mean Pain intensity: 6.37 Ulcer Diameter: 5.2 mm Day 5 Mean Pain intensity: 3.83 Ulcer Diameter: 4 mm	Day 3-Mean Pain intensity: 5.04 Ulcer Diameter: 4.2 mm Day 5-Mean Pain intensity: 2.19 Ulcer Diameter: 2.1 mm
1. Dental paste of Ruta graveolens (Rue) extract in Sesame oil 2. Dental paste of Ruta graveolens (Rue) extract in Olive oil	Placebo	101		Percentage of patients with no pain on Day 1: 0% Percentage of patients with complete ulcer healing in >1 week: 3.7%	"Rue base with Sesame Oil Percentage of patients with no pain on Day 1: 47.37% Percentage of patients with complete ulcer healing in >1 week: 65.79% Rue base with Olive Oil Percentage of patients with no pain on Day 1: 74.99% Percentage of patients with complete ulcer healing in >1 week: 88.89%"
Water extract of Psidium gujava leaves	Placebo	32	mouth wash for three minutes, thrice a day	Day 3-Mean Pain intensity: 4.75 Day 5-Mean Pain intensity: 3.18 Percentage of patients with complete ulcer healing at day 7: 25%	Day 3-Mean Pain intensity: 3.62 Day 5-Mean Pain intensity: 1.31 Percentage of patients with complete ulcer healing at day 7: 75%
Pumpkin seed oil 100%	NA	25	To apply on ulcers twice a day	NA	Day 0-Mean ulcer size: 6.20 mm OCMI Score: 12.96 Day 4 -Mean ulcer size: 0.72 mm OCMI Score: 2.76