The Shilajit Mouthwash Effect Versus Conventional Treatment on Pain and Healing of Oral Lichen Planus: A Randomized Clinical Trial

doi:10.21203/rs.3.rs-5031354/v1

Download PDF

Article

The Shilajit Mouthwash Effect Versus Conventional Treatment on Pain and Healing of Oral Lichen Planus: A Randomized Clinical Trial

https://doi.org/10.21203/rs.3.rs-5031354/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background: Oral lichen planus is an inflammatory chronic disease affecting oral mucosa mainly managed by corticosteroids. However, corticosteroids’ adverse effects necessitate the exploration of alternative remedies. This study aims to assess the potential of Shilajit, natural material with healing properties, in treating oral lichen planus.

Methods: This randomized clinical trial (pilot study) involved fifty-six confirmed ulcerative, erosive, or atrophic non-dysplastic oral lichen planus lesions. Thirty lesions received Shilajit, Nystatin, and Triamcinolone acetonide0.1% mouthwash and twenty-five, Triamcinolone acetonide0.1% and Nystatin. Lesion size, Visual Analogue Scale, and Thongprasom were monitored over sixty days. Data was analyzed by SPSS 23.0. Independent samples t-test, Chi-squared test, repeated measures ANOVA, paired T-tests, and T-tests were performed.

Results: Lesion size reduction, pain alleviation, and healing rates (Thongprasom) were improved in both groups. There was no significant difference between the two groups in Visual Analogue Scale reduction. Thongprasom reduced significantly, more prominently, and was persistent in the case compared to the control group. Minimal side effects were reported in the Shilajit group.

Conclusions: This study shows the promising role of Shilajit in managing oral lichen planus and calls for further research to validate its efficacy and safety profile as a corticosteroid substitute.

Trial registration: The trial was registered in the Iranian Registry of Clinical Trials (IRCT20120101008585N9).

Biological sciences/Drug discovery/Diagnostics

Biological sciences/Drug discovery/Drug regulation

Biological sciences/Drug discovery/Drug safety

Biological sciences/Drug discovery/Drug screening

Lichen Planus

Oral

Mumie

Steroids

Ulcer

Lichen planus is a long-term inflammatory T-cell-mediated condition with an unknown etiology that affects mucosa and cutaneous layers (1). Oral lichen planus (OLP) lesions can manifest in different types, such as reticular, plaque, papular, atrophic, and erosive types, which may coexist simultaneously. These lesions are predominantly found on the buccal mucosa, gingiva, and tongue and can involve the mucosa bilaterally (2). While OLP may present with mild or no symptoms, the erosive form can cause severe pain and significantly influence the quality of life of individuals (3). Although a potential association between OLP and oral cancer has been suggested, it remains a topic of debate.

The occurrence rate of OLP is from 0.5–2.6%, with a higher incidence in females compared to males. There is no discernible preference based on race or ethnicity (4). Although OLP commonly affects middle-aged individuals (thirty to sixty years old), there have been rare instances of children being diagnosed with the condition (5, 6).

Histopathologically, OLP is characterized by features such as hyperkeratosis, acanthosis, "saw-toothed" rete pegs, mononuclear subepithelial infiltration of T-cells and histiocytes in a band-like pattern, and colloid, Civatte, cytoid, and hyaline bodies (7, 8).

Various treatment modalities and medications are available for OLP; however, some may be associated with side effects and limited safety profile (3). Corticosteroids, either topically or systemically, are the most commonly used agents for managing OLP. Topical corticosteroids are typically prescribed for mild cases, while systemic corticosteroids may be indicated for severe presentations. Nonetheless, the use of systemic corticosteroids is contentious as a result of their probable adverse effects. In addition to corticosteroids, Triamcinolone acetonide injections have shown efficacy in treating OLP (9). Long-term corticosteroid use can lead to complications, such as secondary candidiasis, hypothalamic-pituitary-adrenal suppression, telangiectasia, increased systemic absorption, mucocutaneous atrophy, elevated blood pressure and glucose levels, and psychiatric symptoms (10–13).

Given the various clinical forms and severity of OLP lesions in individuals, treatment approaches must be tailored to each case's specific characteristics. To mitigate the risks associated with long-term corticosteroid use, alternative treatments have been proposed for OLP management. These include retinoids, laser therapy, as well as herbal and traditional remedies like Curcumin, Aloe vera, Licorice, Calendula, honey, etc. (14–20).

Shilajit (Mumijo) is a viscous brown-black organic substance extracted from steep rock mountains in several countries (21)(Fig. 1). When administered internally, Shilajit exhibits tonic, laxative, expectorant, diuretic, anti-bilious, immuno-modulatory, lithotriptic, and anti-hypertensive properties. Externally, it possesses antiseptic, analgesic, de-obstruent, and germicidal effects (22, 23). Shilajit has anti-oxidant, immuno-modulatory, anti-inflammatory, anti-allergic, anti-anxiety, anti-stress, and tissue repair-regenerative properties (24, 25). Its bacteriostatic and anti-inflammatory attributes promote faster epithelization and clearance of necrotic tissues and granulations from ulcers (26).

Considering Shilajit's therapeutic characteristics in promoting ulcer healing, its potential benefits for gastric and intestinal ulcers, and lower or no side effects compared to the severe side effects associated with corticosteroid therapy (the conventional treatment for severe OLP) (28), our study aims to evaluate Shilajit's efficacy in alleviating pain, inflammation, and ulcer size in erosive and atrophic OLP lesions compared to corticosteroids. We also seek to explore whether Shilajit could enhance the positive effects of corticosteroids on OLP or serve as a standalone alternative therapy.

Shilajit’s preparation and analyzation

Initially, the solubility test was carried out on the sample, revealing that 15% of the collected sample was impure. To prepare 100 cc of mouthwash, 1.15 grams of Shilajit was added to lukewarm water and vigorously stirred for thirty minutes using a stirrer until all active ingredients dissolved. The mixture was left to settle, and the resulting solution was filtered to remove impurities. Due to the high risk of microbial contamination in natural materials, the Shilajit used in the mouthwash preparation underwent microbial contamination testing. To minimize contamination, the best method that caused the most minor damage to the effective ingredients in Shilajit was employed. This method was pasteurization at 53°C for 25 minutes. Following microbial load assessment (in terms of pharmacopeia), if within acceptable limits, the process continued. Subsequently, Mumijo extraction concentrations were tested for cell toxicity, germ-free material was left to get cold, and was added to the mouthwash formulation at a 0.5% dosage. In a separate sterilized container, water was poured, then propylene glycol and anti-fungal and anti-bacterial preservatives (methyl paraben and propyl paraben) were added and stirred until completely dissolved. The two solutions were mixed and poured into clean 250 cc brown glasses under aseptic conditions. The mouthwash was refrigerated until use. Post-production of Mumijo extraction and isolation, chemical analysis, and standardization of ingredient percentages for repeatable future studies according to the precise date were planned. Chemical analysis was conducted using GC-MS following the method proposed by Reiter et al. (29).

Patient selection

Patients clinically and/or pathologically diagnosed with atrophic or erosive and ulcerative oral lichen planus (OLP) at the Oral and Maxillofacial Medicine Department of Shiraz Dental School were selected for the study. Individuals with pregnancy, history of inflammatory diseases, malignancies, dysplastic lesions, or currently undergoing OLP treatment (except those resistant to treatment) were excluded. Informed consent was taken from all patients before intervention.

Ethical aspects

The clinical trial protocol adhered to Helsinki ethical principles (2002 version) and was approved by the ethics committee of Shiraz University of Medical Sciences (IR.SUMS.DENTAL.REC.1400.011). The trial was registered in the Iranian Registry of Clinical Trials this is the registration number of IRCT20120101008585N9. The registration date was 28/09/2020.

Study design and intervention

This clinical trial, conducted as a single-blinded (examiner blinded) randomized pilot study from 2022 to 2023, involved initially a sample size of 27 lesions in case and 24 lesions in control group. The study aimed for a 95% confidence interval and 80% power, with a minimum of 2 units difference between the Visual Analogue scale (VAS) (30) of the two groups.

Allocation of fifty-one lesions into control (24 lesions) and intervention groups (27 lesions) was achieved through block randomization. Each block consisted of four allocations, with two for the intervention group and two for the control group. Within each block, six possible treatment allocation sequences were listed on cards, and one sequence was randomly chosen for each participant until all allocations were completed (13 blocks). The randomization process was conducted by a methodologist, while the allocation concealment was managed by the principal researcher. On every 51 cards, a sequence was written and sealed. Envelopes were put in a box. Based on the order of registration an envelope was allocated for each participant. This trial was blinded to the outcome assessor.

Patients in the intervention group were prescribed Triamcinolone acetonide 0.1% (Triadent oral paste by Raha Pharma Co., Isfahan, Iran) to be used twice daily for two weeks, followed by once daily for the subsequent two weeks alongside routine treatment (Triamcinolone mouthwash 0.02%, with instructions for gargling 10 ml three times daily). Additionally, a newly designed Shilajit mouthwash from the Pharmacokinetic Department of Shiraz Pharmacy Department was prescribed for gargling three times a day for four minutes (10 ml each time), with a recommendation to avoid eating or drinking for 30 minutes post-use. This mouthwash was to be used after each meal.

In the control group, patients were similarly prescribed Triamcinolone acetonide 0.1% (Triadent oral paste by Raha Pharma Co., Isfahan, Iran) to be used twice daily for two weeks, followed by once daily for the next two weeks, with the same mouthwash preparation and usage instructions as the intervention group. After the evaluation period, patients (from both groups) requiring further treatment received Triamcinolone mouthwash 0.02% for complete healing. To prevent oral candidiasis in both groups, all participants were prescribed oral suspension of Nystatin (100,000 U manufactured by Jaber-ibn-Haian) to gargle 40 drops for four minutes twice daily, 30 minutes after steroid application.

Measurements

In this study, we assessed the effectiveness of the intervention by measuring changes in lesion size, pain levels, and clinical significance using a graded tongue blade, VAS, and Thongprasom scale. The evaluation was conducted by an investigator who was unaware of the type of treatment given to each group.

The Thongprasom scale (31) was utilized to evaluate OLP lesions clinically, with scores ranging from 0 to 5 based on the characteristics of the lesions: five (white striae + erosive area > 1 cm2), four (white striae + erosive area < 1 cm2), three (white striae + atrophic area > 1 cm2), two (white striae + atrophic area < 1 cm2), one (mild white striae only), and zero (no lesions or normal mucosa). Lesion size was evaluated with a graded tongue blade, while pain levels were assessed using a VAS ranging from 0 to 10. These measurements were taken before the intervention (day 0), and on the 7th, 14th, 30th, and 60th days post-intervention, with photographs captured during each follow-up session.

Statistics analysis

Statistical analysis was performed using SPSS version 23.0. The mean ± deviation comparison of age and sex distribution between the two groups was done using independent samples t-test and Chi-squared test, respectively. Changes in mean ± deviation of lesion size, VAS, and Thongprasom scores over time were analyzed using repeated measures ANOVA for intragroup comparisons. Pairwise comparisons between different time points within and between groups were conducted using paired T-tests and T-tests, respectively. Statistical significance was determined by a p-value < 0.05.

In total, 56 lesions (27 lesions in case and 24 lesions in control group) met the inclusion criteria during 2022 to 2023. Five patients in the Shilajit group did not attend follow-up sessions and as a result, were excluded from the study. Follow-up sessions were days 7, 14, 30, 60 after initiation of the treatment. The mean age of participants was 57.25 ± 6.74 and 56.45 ± 12.02 years old in the case and the control group, respectively. Due to the independent samples t-test, there was no significant difference in the age means between the two groups (P = 0.76).

Sex distribution between the two groups is presented in Table 1. Due to the Chi-squared test, there was no significant difference in sex distribution between the two groups (P = 0.70).

Table 1

sex distribution.
			Group		Total
			Female	Male	Total
Sex	case	Count	22	21	43
		% within sex	51.2%	48.8%	100.0%
		% within group	81.5%	87.5%	84.3%
	control	Count	5	3	8
		% within sex	62.5%	37.5%	100.0%
		% within group	18.5%	12.5%	15.7%
Total		Count	27	24	51
		% within sex	52.9%	47.1%	100.0%
		% within group	100.0%	100.0%	100.0%

The descriptive data of VAS, size, and Thongprasom score (thon) of the lesions in the case and the control groups in different days are presented in Tables 2, 3, and 4, respectively. Repeated measures ANOVA was utilized to analyze intragroup comparison of mean ± SD deviation of VAS, size, and thon score of the lesions. According to this test, the passing of time showed a significant VAS mean decrease in both groups (p-value < 0.001), while no significant interaction effect was reported (p-value = 0.24) for VAS of groups and time. No difference was observed between the VAS mean of the two groups over time (p-value = 0.39) (Fig. 2). Moreover, the analysis showed that no significant interaction effect was reported (P = 0.16) between time and the size of the lesions, time was not significantly effective in the reduction of this variable for both case and control groups (p-value = 0.06), and no difference was observed between the size of the lesions of the two groups over time (p-value = 0.61) (Fig. 3). Also, the result showed a significant interaction effect between time and Thongprasom score, which was because of a significant difference between the means of the two groups in Thongprasom 0. So, Thongprasom was controlled and re-analyzed, and finally, no significant interaction effect was reported between time and Thongprasom score. However, a significant difference was observed between the Thongprasom mean of the two groups over time (p-value = 0.02) (Fig. 4); the Thongprasom mean decreased more prominently in patients who had used Shilajit mouthwash.

Table 2

descriptive data of VAS.
	Group	Mean	Standard Deviation	Number
VAS0	case	5.70	2.68	27
	control	5.25	2.93	24
	Total	5.49	2.78	51
VAS7	case	2.03	1.95	27
	control	2.95	2.67	24
	Total	2.47	2.34	51
VAS14	case	1.51	2.20	27
	control	2.20	2.48	24
	Total	1.84	2.34	51
VAS30	case	1.37	2.28	27
	control	1.87	2.17	24
	Total	1.60	2.22	51
VAS60	case	.96	1.67	27
	control	1.54	2.10	24
	Total	1.23	1.89	51
VAS: visual analysis scale

Table 3

descriptive data of the size of the lesions.
	Group	Mean	Standard Deviation	Number
size0	case	10.55	20.45	27
	control	3.64	1.53	14
	Total	8.19	16.84	41
size7	case	4.62	11.39	27
	control	3.35	1.33	14
	Total	4.18	9.23	41
size14	case	2.44	4.36	27
	control	2.50	1.00	14
	Total	2.46	3.56	41
size30	case	.59	1.12	27
	control	2.50	1.00	14
	Total	1.24	1.40	41
size60	case	.28	.69	27
	control	2.50	1.00	14
	Total	1.04	1.32	41

Table 4

descriptive data of Thongprasom score.
	Group	Mean	Standard Deviation	Number
thon0	case control Total	4.40 3.12 3.80	.97 1.29 1.29	27 24 51
thon7	case	3.00	1.61	27
	control	2.50	1.47	24
	Total	2.76	1.55	51
thon14	case	2.48	1.47	27
	control	2.25	1.56	24
	Total	2.37	1.50	51
thon30	case	2.22	1.47	27
	control	2.41	1.47	24
	Total	2.31	1.46	51
thon60	case	1.55	1.52	27
	control	2.45	1.44	24
	Total	1.98	1.54	51

thon: Thongprasom score

Intragroup comparison of VAS, Thongprasom, and size changes of the lesions between different time intervals are represented in Tables 5, 6, and 7, respectively. Paired T-test was used to analyze these comparisons.

Table 5

intragroup changes of VAS between different days.
Group		Paired Differences				P-value
		Mean	Standard Deviation	95% Confidence Interval of the Difference
		Mean	Standard Deviation	Lower	Upper
case	VAS0 - VAS7	3.66	2.41	2.71	4.62	.000*
	VAS0 - VAS14	4.18	2.90	3.03	5.33	.000*
	VAS0 - VAS30	4.33	3.21	3.06	5.60	.000*
	VAS0 - VAS60	4.74	2.94	3.57	5.90	.000*
	VAS7 - VAS14	.51	1.42	− .04	1.08	.070
	VAS7 - VAS30	.66	1.27	.16	1.16	.011*
	VAS7 - VAS60	1.07	1.17	.60	1.53	.000*
	VAS14 - VAS30	.14	.81	− .17	.47	.355
	VAS14 - VAS60	.55	.97	.17	.94	.006*
	VAS30 - VAS60	.40	.74	.11	.70	.009*
control	VAS0 - VAS7	2.29	2.25	1.33	3.24	.000*
	VAS0 - VAS14	3.04	2.85	1.83	4.24	.000*
	VAS0 - VAS30	3.37	3.32	1.97	4.77	.000*
	VAS0 - VAS60	3.70	3.36	2.28	5.13	.000*
	VAS7 - VAS14	.75	1.79	− .00	1.50	.053
	VAS7 - VAS30	1.08	2.61	− .02	2.18	.055
	VAS7 - VAS60	1.41	2.28	.45	2.38	.006*
	VAS14 - VAS30	.33	2.11	− .56	1.22	.449
	VAS14 - VAS60	.66	1.49	.03	1.29	.039*
	VAS30 - VAS60	.33	1.78	− .42	1.08	.370

VAS: visual analysis scale, *: p-value < 0.05

Table 6

**intragroup changes of Thongprasom between different days.**
Group		Paired Differences				P-value
		Mean	Standard Deviation	95% Confidence Interval of the Difference
		Mean	Standard Deviation	Lower	Upper
case	thon0 - thon7	1.40	1.62	.76	2.04	.000*
	thon0 - thon14	1.92	1.68	1.25	2.59	.000*
	thon0 - thon30	2.18	1.49	1.59	2.77	.000*
	thon0 - thon60	2.85	1.63	2.20	3.49	.000*
	thon7 - thon14	.51	1.39	− .03	1.07	.065
	thon7 - thon30	.77	1.25	.28	1.27	.003*
	thon7 - thon60	1.44	1.94	.67	2.21	.001*
	thon14 - thon30	.25	1.37	− .28	.80	.336
	thon14 - thon60	.92	1.49	.33	1.51	.003*
	thon30 - thon60	.66	1.27	.16	1.16	.011*
control	thon0 - thon7	.62	.71	.32	.92	.000*
	thon0 - thon14	.87	1.15	.38	1.36	.001*
	thon0 - thon30	.70	1.30	.15	1.25	.014*
	thon0 - thon60	.66	1.30	.11	1.21	.020*
	thon7 - thon14	.25	.89	− .12	.62	.185
	thon7 - thon30	.08	1.01	− .34	.51	.692
	thon7 - thon60	.04	1.04	− .39	.48	.846
	thon14 - thon30	− .16	.76	− .48	.15	.295
	thon14 - thon60	− .20	.77	− .53	.12	.203
	thon30 - thon60	− .04	.20	− .12	.04	.328

thon: Thongprasom score, *: p-value < 0.05

Table 7

intragroup changes in the size of the lesions between different days.
Group		Paired Differences				P-value
		Mean	Standard Deviation	95% Confidence Interval of the Difference
		Mean	Standard Deviation	Lower	Upper
case	size0 - size7	5.93	16.79	− .70	12.57	.078
	size0 - size14	8.10	20.95	− .18	16.39	.055
	size0 - size30	9.96	20.52	1.84	18.08	.018*
	size0 - size60	10.26	20.50	2.15	18.38	.015*
	size7 - size14	2.17	11.38	-2.33	6.67	.331
	size7 - size30	4.02	11.42	− .49	8.54	.078
	size7 - size60	4.33	11.39	− .17	8.84	.059
	size14 - size30	1.85	4.20	.19	3.51	.030*
	size14 - size60	2.16	4.23	.48	3.83	.013*
	size30 - size60	.30	.73	.01	.59	.041*
control	size0 - size7	.28	.42	.03	.53	.026*
	size0 - size14	1.14	1.29	.39	1.88	.006*
	size0 - size30	1.14	1.29	.39	1.88	.006*
	size0 - size60	1.14	1.29	.39	1.88	.006*
	size7 - size14	.85	1.08	.23	1.48	.011*
	size7 - size30	.85	1.15	.19	1.52	.015*
	size7 - size60	.85	1.15	.19	1.52	.015*
	size14 - size30	.00	.39	− .22	.22	1.000
	size14 - size60	.00	.39	− .22	.22	1.000

*: p-value < 0.05

The intergroup comparison of VAS score, thon, and the size of the lesions’ changes between different time intervals was analyzed with T-test and is represented in Table 8. Although the Thongprasom of the case group was significantly higher than the control group on day 0 (p-value < 0.001), it became significantly lower on day 60 in comparison with the control group (p-value = 0.03). Moreover, as indicated in Table 8, the size of the case and the control groups were significantly different from each other on days 30 and 60 (P < 0.001).

Table 8

intergroup changes in the size of the lesions, VAS, and Thongprasom score between different days.
Days		VAS					Thongprasom					Size of the lesions
Days		0	7	14	30	60	0	7	14	30	60	0	7	14	30	60
P-value	Equal variances assumed	.56	.16	.29	.42	.28	.000*	.25	.59	.64	.03*	.21	.68	.96	.000*	.000*
P-value	Equal variances not assumed	.56	.17	.30	.42	.28	.000	.25	.59	.64	.03	.09	.57	.95	.000	.000
Mean Difference	Equal variances assumed	.45	− .92	− .68	− .50	− .57	1.28	.50	.23	− .19	− .90	6.91	1.26	− .05	-1.90	-2.21
Mean Difference	Equal variances not assumed	.45	− .92	− .68	− .50	− .57	1.28	.50	.23	− .19	− .90	6.91	1.26	− .05	-1.90	-2.21

VAS: visual analysis scale, *: p < 0.05

The location of OLP varied in different patients. Most patients’ OLP were located on left, right, or both buccal mucosae. However, gingiva, edentulous ridge, tongue, and palate were also locations that OLP was observed in patients.

Regarding the type of lesions, at first, most of them were ulcerative, several, erosive, and few cases, atrophic. Lesions that were keratotic at first were excluded from the study.

According to the results of this study, VAS continued decreasing during 60 days of follow-ups in both evaluated groups. Still, there were no significant differences in this reduction between the two groups (p-value > 0.05). The Thongprasom and the inflammation of the OLP lesions of individuals who had used Shilajit and corticosteroid mouthwash continuously, decreased during these 60 days. Still, this result achieved in patients who had used only corticosteroid mouthwash up to only seven days. Therefore, the inflammation reduction by using Shilajit mouthwash was more persistent and prominent compared to the usage of corticosteroid mouthwash solely (p-value < 0.05). The size of the OLP lesions started decreasing from day 14 and continued until day 60 in the intervention group; however, in the control group, this reduction started sooner (day 7) but stopped on the 14th day. The intergroup comparison of VAS between the two evaluated groups during different days was not statistically different (p-value > 0.05). The OLP size and inflammation reduction were successful and almost similar in both evaluated groups, however the positive effects of the Shilajit mouthwash continued and stayed longer than the corticosteroids mouthwash. The clinical improvement of several OLP lesions with Shilajit mouthwash is presented in Figs. 5, 6, 7, and 8.

To our knowledge, no study was conducted using Shilajit mouthwash on OLP lesions. However, several studies used Shilajit on gastric or intestinal ulcers (28, 32–35). The most important differences between these studies and the present study are that we studied erosive, atrophic, and ulcerative OLP lesions. In contrast, other studies focused only on gastric or intestinal ulcers. Moreover, the presenting study assessed multiple scores such as size, VAS, and Thongprasom, while other studies did not evaluate diverse scores (28, 32–35). Also, just one study (35) studied the effect of Shilajit on a human trial, other studies were animal experimentations.

Shahrokhi et al. conducted a study in 2015. They assessed Shilajit aqueous extract (100 mg/kg/daily) on gastric ulcers in rats for four days. Their results showed that as the same as our study, Shilajit had a protective effect on ulcerative mucosa and reduced the incidence of ulcerative lesions. This protection is due to its anti-oxidant ingredients, repairing, regenerative, and anti-inflammatory activity (28).

Moghadari et al. evaluated normal saline and routine wound dressing on pressure ulcers of skin compared with 20% Shilajit water solution, normal saline, and routine wound dressing in 28 days in a clinical trial in 2018. Their study confirmed the same results as our study. Size and skin ulcers healing processes improved in both groups (groups with usage of conventional treatment and conventional treatment companied by Shilajit solution) but the reduction was significantly more in the group using Shilajit solution. In the presenting study as the same as Moghadari et al.’s findings, OLP lesion healing process (size and OLP inflammation) was improved by using Shilajit mouthwash. However, in contrast to Moghadari et al.’s study, the reduction in the size of the lesions was not significantly different between the case and the control group. Also, similar to our study, they show that usage of Shilajit accompanied by conventional treatment decreases ulcerative characteristics more than the usage of conventional treatment solely (35).

In another study by Shahrokhi et al. in 2018, the protective effect of Shilajit (250 mg/kg) was assessed against acetic acid-induced ulcerative colitis in rats. They confirmed that Shilajit reduced the severity of inflammation, improved the ulcer index, lowered oxidative stress, and showed regenerative and healing processes (34).

Ghasemkhani et al. assessed the influence of Shilajit (250 mg/kg) on gastric ulcers induced by aspirin in rats for four days in 2020. They, similar to our study, confirmed the reduction in the size and number of ulcers. However, as mentioned before, the size reduction of our case group was not different in comparison with the control group. Their study suggested a reduction in mucosal damage, edema severity, and leukocyte infiltration in tissue due to the usage of Shilajit (33), which is in line with the presenting evaluation in which Thongprasom index has been decreased by Shilajit mouthwash. This mouthwash decreased this score by reducing the OLP lesions’ inflammation and size.

In a 2023 study, Shilajit was used for a four-day period with a 250 mg/kg dosage. They used gavage and rectal routes. Their study assessed the effectiveness of Shilajit on damaging liver as a result of colitis with ulcer due to acetic acid usage in male rats. Eight days after colitis with ulcer was induced, they evaluated the influences by the assessment of the liver enzymes (SGPT, SGOT, ALP), direct bilirubin, total, and serum albumin amounts. They showed that the usage of Shilajit by both gavage and rectal administration reduces the liver damage caused by ulcerative colitis by reducing liver enzymes. They also concluded that the therapeutic influences of Shilajit are almost same as sulfasalazine, that is the most used substance in treating colitis. Also, the gavage route for Shilajit usage had higher protective influences on damaged liver due to colitis with ulcer in comparison with the rectal path (32).

As mentioned before, there is no human clinical trial about the influence of Shilajit on healing processes of OLP lesions. There are limited researches in animal models with non-oral mucosa ulcers in which all of them confirmed the anti-inflammatory activity of Shilajit administration. Shilajit reduced the inflammation and size of ulcers similar to the findings of the presenting study. Although the location of mucosal ulcers and the route of Shilajit administration were differed between these studies, the systemic effect of Shilajit was utterly predictable.

Fortunately, no side effect has been reported for Shilajit mouthwash in this study; only one of the patients declared a burning sensation in their mouth after using Shilajit mouthwash. Patients showed no side effects regarding Shilajit mouthwash in the follow-up session that was conducted one year after the first day Shilajit mouthwash was used.

Shilajit has several characteristics and components (such as benzoic acid, humus (sixty to eighty percent), hippuric acid, ichthyol, fatty acids, dibenzo-a-pyrones, albuminoids, various vitamins and minerals like B1 and B2, and essential oils (36)) that makes it a candidate to replace or used additionally to conventional treatments of mucosal ulcers. Most of its biological influences are due to the existence of humic acid, dibenzo-a-pyrones, and fulvic acid. These three components act as carrier molecules for active parts (37). Shilajit’s anti-oxidant, repairing, and regenerative activities are due to polyphenol complexes like 4-methoxy‐6‐carbomethoxybi‐phenyl, fulvic acids (FAs), benzoic acid, and tirucallane‐type triterpenoids (23, 28). Moreover, Shilajit can escalate the scavenging activities of antioxidant enzymes. Thus, it reduces oxidative stress and mucosal damage (33). The anti-inflammatory activities of Shilajit are due to the level reduction of IL-10,6, and 1β (interleukin) and TNF-α (tumor necrosis factor), the existence of dibenzo-α-pyrones with fluvic and humic acid in it (38, 39). As a result of Shilajit’s bacteriostatic and anti‐inflammatory influences, the process of eliminating necrotic tissues and granulations from the ulcers and ulcer epithelization became easier and faster (40). Shilajit also has some anti-allergic influences. This characteristic is due to its effects on histamine release; thus, mast cell degranulation (41).

The clinical trial protocol adhered to Helsinki ethical principles (2002 version) and was approved by the ethics committee of Shiraz University of Medical Sciences (IR.SUMS.DENTAL.REC.1400.011). The trial was registered in the Iranian Registry of Clinical Trials (IRCT20120101008585N9). This clinical trial was registered in 28/09/2020 with the registration number of 99-01-99-22130 .

This pilot study for the effect of Shilajit on the treatment of atrophic, erosive, and ulcerative oral lichen planus had several limitations. According to the findings of this human clinical trial on the OLP healing process, it is better to consider further investigations on a greater sample size of participants for more accurate and comprehensive results. Also, a raw material like Shilajit is not sterile in itself. Considering this fact, the process of making its mouthwash and eliminating impurities and any kind of contaminations is complex and time-consuming.

This study is the first evaluation of the influence of Shilajit on OLP. In addition, the use of corticosteroid (topical, systemic administration, and intra-lesion injection), the conventional treatment for OLP, has several disadvantages. The long-term usage of topical steroids may cause the thinning of mucosa and oral candidiasis; thus, an anti-fungal is probably needed simultaneously with the treatment. Moreover, this treatment may be absorbed systemically via thin mucosa and cause adrenal suppression and other serious complications (42). Also, intralesional injections are painful and can cause localized tissue atrophy and secondary candidiasis (43).

Furthermore, even short-term use of systemic steroids could result in insomnia, anxiety, edema, diarrhea, generalized muscle weakness, and susceptibility to infection (44). Due to the wide range of corticosteroid’s side effects, it is better to find another treatment with fewer side effects and the same healing results in comparison with corticosteroids. As this study demonstrated, Shilajit is an herbal medicine with the lowest side effects and high healing effects on OLP, and it could be considered an alternative to corticosteroids while conducting more investigations.

The current study revealed that the patient’s pain, inflammation, and the size of the lesions continued decreasing with the use of Shilajit in 60 days of follow-ups. In addition, the effects of Shilajit are more prominent and persistent; also, Shilajit has an auxiliary effect in the durability of the conventional treatment. Due to Shilajit’s wide range of positive characteristics because of its components and lower amount of side effects in comparison with corticosteroid (the OLP conventional treatment), it might contain a promising role in the treatment of OLP.

Oral lichen planus (OLP)

Visual Analogue scale (VAS)

Degree Celsius (°C)

Milliliter (ml)

cubic centimeter (cc)

Gas chromatography–mass spectrometry (GC-MS)

Thongprasom score (thon)

Alkaline Phosphatase (ALP)

Serum glutamic oxaloacetic transaminase (SGOT)

Alanine transaminase (SGPT)

fulvic acids (FAs)

Ethics approval and consent to participate

The clinical trial protocol adhered to Helsinki ethical principles (2002 version) and was approved by the ethics committee of Shiraz University of Medical Sciences (IR.SUMS.DENTAL.REC.1400.011). The trial was registered in the Iranian Registry of Clinical Trials with the registration number of IRCT20120101008585N9. All participants signed a consent form in regards of participation.

Consent for publication

Consent form was taken from patients before the initiation of therapy.

Competing interests

The authors did not have any conflicts of interest.

Funding

This research was supported by the Vice-Chancellor of Shiraz University of Medical Science with the grant number of 20795.

Author Contribution

ShA: analyzed and interpreted the patient data, drafted the workAA: analyzed and interpreted the patient data, drafted the work, and revised itFL: designed the work, analyzed and interpreted the patient data, drafted the work, and revised itMShS: designed the work

Acknowledgements

This study was based on the thesis of Aylar Afshari and was funded by Shiraz University of Medical Sciences (grant no. 20795).

Data Availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Al-Hashimi I, Schifter M, Lockhart PB, Wray D, Brennan M, Migliorati CA, et al. Oral lichen planus and oral lichenoid lesions: diagnostic and therapeutic considerations. Oral Surgery, Oral Med Oral Pathol Oral Radiol Endodontology. 2007 Mar 1;103(SUPPL.):S25.e1-S25.e12.
Bennardo F, Liborio F, Barone S, Antonelli A, Buffone C, Fortunato L, et al. Efficacy of platelet-rich fibrin compared with triamcinolone acetonide as injective therapy in the treatment of symptomatic oral lichen planus: A pilot study. Clin Oral Investig. 2021;25(6):3747–55.
Husein‐ElAhmed H, Gieler U, Steinhoff M. Lichen planus: a comprehensive evidence‐based analysis of medical treatment. J Eur Acad Dermatology Venereol. 2019;33(10):1847–62.
Rotaru D, Chisnoiu R, Picos AM, Picos A, Chisnoiu A. Treatment trends in oral lichen planus and oral lichenoid lesions. Exp Ther Med. 2020;20(6):1.
Sugerman PB, Savage NW, Walsh LJ, Zhao ZZ, Zhou XJ, Khan A, et al. The pathogenesis of oral lichen planus. Crit Rev Oral Biol Med [Internet]. 2002 Jul 1 [cited 2023 Aug 29];13(4):350–65. Available from: https://journals.sagepub.com/doi/full/10.1177/154411130201300405
Laeijendecker R, Van Joost T, Tank B, Oranje AP, Neumann HAM. Oral lichen planus in childhood. Pediatr Dermatol [Internet]. 2005 Jul 1 [cited 2023 Aug 29];22(4):299–304. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1525-1470.2005.22403.x
Payne AGT, Walton TR, Walton JN, Solomons YF. The Outcome of Implant Overdentures from a Prosthodontic Perspective: Proposal for a Classification Protocol. Int J Prosthodont [Internet]. 2001 [cited 2021 Sep 27];14(1):27–32. Available from: http://www.quintpub.com/userhome/ijp/ijp_14_1_payne4.pdf
Lodolo M, Gobbo M, Bussani R, Torelli L, Rupel K, Ottaviani G, et al. Histopathology of oral lichen planus and oral lichenoid lesions: An exploratory cross-sectional study. Oral Dis [Internet]. 2023 Apr 1 [cited 2023 Aug 29];29(3):1259–68. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/odi.14112
Fantozzi PJ, Treister N, Shekar R, Woo S-B, Villa A. Intralesional triamcinolone acetonide therapy for inflammatory oral ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol. 2019;128(5):485–90.
Gorouhi F, Solhpour A, Beitollahi JM, Afshar S, Davari P, Hashemi P, et al. Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus. J Am Acad Dermatol. 2007;57(5):806–13.
Passeron T, Lacour J-P, Fontas E, Ortonne J-P. Treatment of oral erosive lichen planus with 1% pimecrolimus cream: a double-blind, randomized, prospective trial with measurement of pimecrolimus levels in the blood. Arch Dermatol. 2007;143(4):472–6.
Rhodus NL, Myers S, Kaimal S. Diagnosis and management of oral lichen planus. Northwest Dent. 2003;82(2):17–9.
Becker JC, Houben R, Vetter CS, Bröcker EB. The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report. BMC Cancer. 2006;6:1–6.
Ebner H, Mischer P, Raff M. LOKALBEHANDLUNG DES LICHEN RUBER PLANUS DER MUNDSCHLEIMHAUT MIT VITAMIN A SAURE. H+G Zeitschrift fur Hautkrankheiten [Internet]. 1973 Sep 1 [cited 2023 Aug 29];48(18):735–40. Available from: https://europepmc.org/article/med/4765567
Desiate A, Cantore S, Tullo D, Profeta G, Grassi FR, Ballini A. 980 nm diode lasers in oral and facial practice: Current state of the science and art. Int J Med Sci [Internet]. 2009 Nov 24 [cited 2023 Aug 29];6(6):358–64. Available from: /pmc/articles/PMC2786991/
Namratha, K., Shenai, P., Chatra, L., Rao, P. K.,... - Google Scholar [Internet]. [cited 2023 Aug 30]. Available from: https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Namratha%2C+K.%2C+Shenai%2C+P.%2C+Chatra%2C+L.%2C+Rao%2C+P.+K.%2C+Veena%2C+K.%2C+%26+Prabhu%2C+R.+V.+%282013%29.+Antioxidant+and+Anticancer+effects+&btnG=
Nair GR, Naidu GS, Jain S, Nagi R, Makkad RS, Jha A. Clinical effectiveness of aloe vera in the management of oral mucosal diseases-a systematic review [Internet]. Vol. 10, Journal of Clinical and Diagnostic Research. JCDR Research & Publications Private Limited; 2016 [cited 2023 Aug 30]. p. ZE01–7. Available from: /pmc/articles/PMC5028429/
Vibha JB, Choudhary K, Singh M, Rathore MS, Shekhawat NS. A Study on Pharmacokinetics and Therapeutic Efficacy of Glycyrrhiza glabra : A Miracle Medicinal Herb Department of Biotechnology , Lachoo Memorial College of Science and Technology ,. Bot Res Int [Internet]. 2009 [cited 2023 Aug 30];2(3):157–63. Available from: https://www.researchgate.net/publication/255660807
Machado MAN, Contar CMM, Brustolim JA, Candido L, Azevedo-Alanis LR, Gregio AMT, et al. Management of two cases of desquamative gingivitis with clobetasol and calendula officinalis gel. Biomed Pap [Internet]. 2010 Dec 1 [cited 2023 Aug 30];154(4):335–8. Available from: https://europepmc.org/article/med/21293545
Sanatkhani M, Mozafari PM, Amirchaghmaghi M, Fathi MN, Sanatkhani M, Sarjami N, et al. Effect of cedar honey in the treatment of oral lichen planus. Iran J Otorhinolaryngol [Internet]. 2014 [cited 2023 Aug 30];26(76):151–61. Available from: /pmc/articles/PMC4087854/
Garedew A, Feist M, Schmolz E, Lamprecht I. Thermal analysis of mumiyo, the legendary folk remedy from the Himalaya region. Thermochim Acta. 2004 Jul 30;417(2):301–9.
Thiyagarajan R, Sunderrajan A. Gunapadam Thathu jeeva vaguppu. Gunapadam thatu jeeva vagupp. 1992;474–8.
Agarwal SP, Khanna R, Karmarkar R, Anwer MK, Khar RK. Shilajit: A review [Internet]. Vol. 21, Phytotherapy Research. John Wiley & Sons, Ltd; 2007 [cited 2023 Aug 31]. p. 401–5. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ptr.2100
Schepetkin I, Khlebnikov A, Kwon BS. Medical drugs from humus matter: Focus on mumie [Internet]. Vol. 57, Drug Development Research. John Wiley & Sons, Ltd; 2002 [cited 2023 Aug 31]. p. 140–59. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ddr.10058
Ghosal S. Free radicals, oxidative stress and antioxidant defense. Phytomedica. 2000;21(182):1–8.
DSh S. mumie asil’. Eksp Khirurgiia I Anesteziol [Eksp Khir Anesteziol]. 1969;14(6):36–9.
Rahmani Barouji S, Saber A, Torbati M, Fazljou SMB, Yari Khosroushahi A. Health Beneficial Effects of Moomiaii in Traditional Medicine. Galen Med J [Internet]. 2020 Aug 27 [cited 2024 Mar 1];9:e1743. Available from: /pmc/articles/PMC8343599/
Shahrokhi N, Keshavarzi Z, Khaksari M. Ulcer healing activity of Mumijo aqueous extract against acetic acid induced gastric ulcer in rats. J Pharm Bioallied Sci [Internet]. 2015 Jan 1 [cited 2023 Aug 31];7(1):56. Available from: /pmc/articles/PMC4333629/
Reiter B, Lechner M, Lorbeer E, Aichholz R. Isolation and characterization of wax esters in fennel and caraway seed oils by SPE‐GC. J High Resolut Chromatogr. 1999;22(9):514–20.
Crichton N. Visual analogue scale (VAS). J Clin Nurs. 2001;10(5):706.
Thongprasom K, Luangjarmekorn L, Sererat T, Taweesap W. Relative efficacy of fluocinolone acetonide compared with triamcinolone acetonide in treatment of oral lichen planus. J Oral Pathol Med [Internet]. 1992 Nov 1 [cited 2023 Aug 29];21(10):456–8. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1600-0714.1992.tb00974.x
Shahrokhi N, Amiresmaili S, Afshar RM, Shahrokhi M. Comparing the Effects of Sulfasalazine and Shilajit on Liver Damage Caused by Acetic Acid-Induced Ulcerative Colitis in Male Rats. J Babol Univ Med Sci. 2023;25(1).
Ghasemkhani N, Tabrizi AS, Namazi F, Nazifi S. Treatment effects of Shilajit on aspirin‐induced gastric lesions in rats. Physiol Rep. 2021;9(7):e14822.
Shahrokhi N, Keshavarzi Z, Haddad MK, Amirafzali F, Dabiri S, Shahrokhi N. Protective effect of Mumiju against acetic acid-induced ulcerative colitis in rats. Avicenna J Phytomedicine [Internet]. 2018 [cited 2023 Aug 31];8(5):457. Available from: /pmc/articles/PMC6190247/
Moghadari M, Rezvanipour M, Mehrabani M, Ahmadinejad M, Tajadini H, Hashempur MH. Efficacy of mummy on healing of pressure ulcers: A randomized controlled clinical trial on hospitalized patients in intensive care unit. Electron physician. 2018;10(1):6140.
Ghosal S, Lal J, Singh SK. The core structure of shilajit humus. Soil Biol Biochem. 1991 Jan 1;23(7):673–80.
Al-Himaidi AR, Mohammed U. Safe use of salajeet during the pregnancy of Female mice. Online J Biol Sci. 2003;3(8):681–4.
Ghaaazi Firozsalari F, Shahrokhi N, Khaksari Hadad M, Asadikaram G, Atashbar J. Effect of Shilajit on the levels of pro-inflammatory and anti-inflammation cytokines in hepatic injury in male rats. J Maz Univ Med Sci. 2018;28(159):1–13.
Van Rensburg CEJ. The antiinflammatory properties of humic substances: a mini review. Phyther Res. 2015;29(6):791–5.
Shakirov DS. Treatment of infected wounds with Mumie asil in experiment. Exp Surg Anesth. 1969;6:36–9.
Ghosal S, Lal J, Singh SK, Dasgupta G, Bhaduri J, Mukhopadhyay M, et al. Mast cell protecting effects of shilajit and its constituents. Phyther Res [Internet]. 1989 Jan 1 [cited 2023 Aug 31];3(6):249–52. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ptr.2650030606
Sousa FACG de, Rosa LEB. Oral lichen planus: clinical and histopathological considerations. Rev Bras Otorrinolaringol. 2008;74:284–92.
Goel RK, Banerjee RS, Acharya SB. Antiulcerogenic and antiinflammatory studies with shilajit. J Ethnopharmacol. 1990;29(1):95–103.
Bhattacharya SK, Sen AP, Ghosal S. Effects of shilajit on biogenic free radicals. Phyther Res [Internet]. 1995 Feb 1 [cited 2023 Aug 31];9(1):56–9. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ptr.2650090113

No competing interests reported.

Download PDF

Editorial decision: Revision requested
07 Oct, 2024
Reviews received at journal
05 Oct, 2024
Reviews received at journal
03 Oct, 2024
Reviewers agreed at journal
22 Sep, 2024
Reviewers agreed at journal
21 Sep, 2024
Reviewers agreed at journal
21 Sep, 2024
Reviewers invited by journal
19 Sep, 2024
Editor assigned by journal
18 Sep, 2024
Editor invited by journal
10 Sep, 2024
Submission checks completed at journal
09 Sep, 2024
First submitted to journal
04 Sep, 2024

You are reading this latest preprint version

The Shilajit Mouthwash Effect Versus Conventional Treatment on Pain and Healing of Oral Lichen Planus: A Randomized Clinical Trial

Status:

Version 1

Abstract

Figures

Background

Methods

Shilajit’s preparation and analyzation

Patient selection

Ethical aspects

Study design and intervention

Measurements

Statistics analysis

Results

Discussion

Conclusions

Abbreviations

Declarations

Competing interests

Funding

Author Contribution

Acknowledgements

Data Availability

References

Additional Declarations

Status:

Version 1