Lichenoid reactions (LRs) are a set of disorders with similar clinical presentations but various causes. These reactions are divided into such subtypes as lichen planus, drug-induced lichen planus, contact LRs, and LRs due to graft-versus-host disease. Oral lichen planus (OLP) is a rather common and chronic oral disease that mostly affects the oral mucosa. ¹

LRs are common oral mucosal lesions, which the most significant factor to distinguish from OLP is their atypical location and unilaterality. Although the primary cause of this disease is unknown, recent studies have shown different immune complexes along with responding cells for inflammatory structures and chronic lesions. ²

Most of the patients with lichen planus are middle-aged women. ³ The prevalence of lichen planus has been reported to be 1%–1.5%, and in 80%–90% of cases, it affects buccal mucosa. ⁴ , ⁵

OLP has six different subtypes but is mainly seen as reticular and erosive forms, the most common of which is reticular form. ⁶

Oral LRs also can be induced by drugs such as thiazides, nonsteroidal anti-inflammatory drugs, and angiotensin-converting enzyme inhibitors; systemic diseases like diabetes; and allergic reactions to metals such as amalgam and food supplies. ⁷ , ⁸ , ⁹

The discomfort and pain associated with these lesions can affect the normal function of the mouth, increase the risk of infection, and to some extent, reduce the patients' quality of life. ¹⁰

The management of such lesions first requires the identification of the triggering factors. ¹¹ The main treatment for LRs is the administration of systemic and local corticosteroids. Its local and potent type such as triamcinolone has increasingly been used for the treatment of LR. ¹² Adverse effects of using corticosteroids include secondary candidiasis, adrenal suppression, increased blood pressure, and becoming prone to infections. ¹³ , ¹⁴

Another treatment for lichen planus is medicinal plants such as Melissa officinalis which its extract is used in Melissa gel. Melissa gel, offered by Goldaru Pharmacy Co. in Iran, includes 1% gel-based balm mint (M. officinalis) dried extract, standardized by 0.23% tannic acid. ¹⁵ Melissa is used for local treatment of gingival inflammatory, microbial and painful complications, and oral lesions. It includes antimicrobial, antifungal, antivirus, anticancer, and anti-inflammatory properties and can reduce salivary and sweat secretion. ¹⁶ , ¹⁷ , ¹⁸

As long as LRs are currently one of the common oral lesions and using prolonged corticosteroids as main treatment have shown various complications, this study was conducted to analyze the effect of Melissa gel comparing to triamcinolone paste among the patients with LRs.

In this randomized clinical trial, 60 patients (29 females and 31 males) aged between 20 and 60 years (59.8 ± 14.3) who referred to the department of oral and maxillofacial medicine with at least one clinically and histopathologically proven erosive oral LR in buccal mucosa and having Thongprasom score ¹⁹ more than 1 were included. The exclusion criteria were as follows: patients with allergy to botanical products, the presence of any malignant or viral involvements in the mouth, history of receiving topical therapy for oral LRs in the last 2 weeks or systemic therapy in the last 4 weeks, histopathological sign of dysplasia, history of allergy to corticosteroids, life-threatening and systemic diseases such as increased blood pressure and diabetes, pregnancy, and lactation. Informed consent was obtained from the patients before the study initiation. This study was approved by the Isfahan University of Medical Sciences Ethics Committee and conducted according to the Declaration of Helsinki.

Patients were randomly divided into two groups either take Melissa or triamcinolone 0.1% according to a list made by block randomization. Group A was instructed to apply and spread a 1-cm layer of Melissa gel (Melissan 5gr gel, Goldaru Corporation, Isfahan, Iran), and Group B was instructed to apply and spread a 1-cm layer of triamcinolone acetonide 0.1% paste (Teriadent 0.1%, Raha Pharmaceutical Corporations, Isfahan, Iran) on the oral lesions, three times a day, for 4 weeks. The patients were asked to use the medication after eating and washing their mouth and not to eat, drink, or smoke for at least 30 min. The assessment was performed at weeks 0, 2, and 4 by a clinician who was blind to patients' allocated groups.

The lesion size was measured by a scaled tongue blade and the recovery rate was evaluated in each visit according to the Thongprasom criteria ¹⁹ Table 1.{Table 1}

Patients ranked the severity of pain and burning sensation on a 10-cm Visual Analog Scale (VAS) from 0 (no pain) to 10 (extreme pain) at the beginning and each visit. The patients were asked to draw a vertical line on the VAS horizontal ruler and score their intensity of pain.

In each visit, patients were asked about any side effects such as ulcer, burning sensation or pain during eating and drinking, dry mouth, and numbness after taking the prescribed drugs. Any use of products such as caffeine, tobacco, and alcohol was also recorded in the patients' questionnaires.

The obtained data were analyzed by SPSS software (version 20, IBM Corp., Armonk, NY, USA). Repeated measures ANCOVA test was used to compare the analyzed data between groups at different intervals and the Mann–Whitney test was administered to compare two groups. Chi-square test, paired t-test, and survival analysis were performed as well.

Enrollment into the study began in March 2016 and ended in April 2017. Sixty patients, 29 females and 31 males with the age range of 20–60 years and a mean age of 59 years, referred to the Department of Oral and Maxillofacial Medicine, Isfahan University of Medical Sciences, were included in this study. There were thirty patients in each group. The demographic characteristics are listed in Table 2.{Table 2}

There were no significant differences between the two groups for baseline characteristics including age, sex, baseline lesion size, and pain intensity (VAS) (P > 0.05).

In the first visit (week 2), the mean and standard deviation of VAS among the Melissa group were 2.4 and 1.35 and 3.4 and 1.31 for the triamcinolone group. VAS index between the two groups showed significant differences in the 2 ^ndand 4 ^thweeks (P = 0.018, P = 0.001).

As demonstrated in Table 3, comparing VAS values at different visits revealed a significant difference for Melissa before treatment and in 2 and 4 weeks after treatment. In the triamcinolone group, the same results were reported based on the paired sample t-test.{Table 3}

To compare the clinical index of LR in the study groups, findings showed no significant difference between the groups in terms of the lesion extension before and 1 weeks after treatment, but there was a significant difference between the two groups after 4 weeks and triamcinolone was better in reducing lesion size (P = 0.003) Table 4.{Table 4}

LRs are common oral lesions caused by numerous factors. ²⁰ , ²¹ Therefore, it seems necessary to make an effort to treat and eliminate the factors associated with the disease to prevent the following complications such as possible malignant changes. Corticosteroids like triamcinolone are effective to treat LRs, but medicinal plants have also shown to be effective with minimum adverse effects. ¹⁰ , ²² , ²³ , ²⁴

This study was carried out to evaluate the effect of Melissa gel compared to triamcinolone paste on patients with LRs, and it demonstrated that Melissa gel was more effective than triamcinolone in terms of reducing pain in 4 weeks. Birdane et al. also investigated the effect of Melissa in rodents, and similarly, it indicated antinociceptive effects. ²⁵ Evaluating the effect of Melissa in recurrent herpes labialis, Ahadian et al. concluded that Melissa gel is more able to decrease the pain than acyclovir. ¹⁵ Melissa contains flavonoids, polyphenolic ingredients, and essences such as limonene, citral, and citronella. Since flavonoids and limonene have shown analgesic and anti-inflammatory effects, it is appropriate to use Melissa gel to decrease the pain. ²⁶ , ²⁷

Although Melissa gel was more effective than triamcinolone in reducing pain in 4 weeks, the short-term effect of triamcinolone was more than Melissa gel between 2 and 4 weeks. Similar to our study, Hasanein and Riahi et al. in an animal model of diabetic hyperalgesia demonstrated that long-term oral administration of M. officinalis has antinociceptive effects on painful diabetic neuropathy. The possible cause of these results may be rosmarinic acid which is the major phenol constituent of M. officinalis and possesses a strong antinociceptive and antioxidant effect. ²⁸ , ²⁹

The results of our study also showed that Melissa gel decreased the size of the lesion at each visit compared to baseline. The results of Koytchev et al. were similar to ours and established that M. officinalis can significantly reduce the intensity of symptoms of herpes labialis such as the number and size of the affected area. ³⁰ These results may be due to the inflammatory effect in phenolic compounds such as flavonoids and rosmarinic acid and essential oil in M. officinalis. ³¹

The results also indicated that although there was no significant difference between the two groups before and 2 weeks after treatment, triamcinolone was significantly more effective in reducing lesion size in 4 weeks. In contrast to our results, an in vivo study in rats demonstrated that M. officinalis causes a significant reduction and inhibition of paw edema induced by carrageenan and experimental trauma in rats. ²⁴

Medicinal plants have been used successfully to treat oral diseases. For instance, Das et al. reported the positive effects of licorice biofilm in the treatment of radiotherapy-induced mucositis. ³² Furthermore, Sookto et al. showed that M. officinalis had anti-Candida properties and prevented the connection of this fungus. ³³

Moreover, Martin et al. investigated the effect of oral patches containing licorice extract in the treatment of aphthous ulcers and reported positive effects in the size of the lesion and patient's pain. ³⁴ Another nonpharmacologic and nonsteroidal therapy used for the treatment of lichenoid diseases was the use of topical retinoic acid in comparison with topical fluocinolone acetonide, and the topical fluocinolone acetonide was more effective to reduce the severity of lichen planus. ¹²

The limitations of this study included a lack of comprehensive control over the use of drugs and small sample size. Future studies are recommended to recruit a larger study sample, compare different herbal compounds, use herbal complexes, and make use of topical corticosteroids and herbal medicines alternatively to obtain more accurate results.

Melissa gel performed better than triamcinolone in decreasing pain intensity, however, triamcinolone was more effective in reducing lesion size.

Financial support and sponsorship

This study was supported by the Deputy of Research of Isfahan University of Medical Sciences.

Conflicts of interest

The authors of this manuscript declare that they have no conflicts of interest, real or perceived, financial or non-financial in this article.