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1 THERAPEUTICS DOI /j x The efficacy of aloe vera gel in the treatment of oral lichen planus: a randomized controlled trial C. Choonhakarn, P. Busaracome, B. Sripanidkulchai* and P. Sarakarn Division of Dermatology, Department of Medicine, Srinagarind Hospital Medical School, Faculty of Medicine, *Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences and Department of Biostatistics and Demography, Faculty of Public Health, Khon Kaen University, Khon Kaen 40002, Thailand Summary Correspondence Charoen Choonhakarn. c_choonhakarn_dermatologist@ hotmail.com Accepted for publication 6 October 2007 Key words aloe vera, lichen planus, oral cavity, randomized controlled trial Conflicts of interest None declared. Background Oral lichen planus (OLP) is a chronic inflammatory disease that can be painful especially in the atrophic and erosive forms. Several therapies have been tried, with varying results. There is one case report in which aloe vera (AV) was used successfully in the treatment of lichen planus. Objectives To compare the efficacy of AV and placebo in the topical management of OLP. Methods A randomized, double-blind, placebo-controlled trial was designed. Fiftyfour patients were randomized into two groups to receive AV gel or placebo for 8 weeks. Results Fifty-four consecutive patients (34 women and 20 men) participated in the study. We found erosive and ulcerative lesions in 83% and 17%, respectively. The most common site of OLP was the lower lip. Twenty-two of 27 patients treated with AV (81%) had a good response after 8 weeks of treatment, while one of 27 placebo-treated patients (4%) had a similar response (P < 0Æ001). Furthermore, two patients treated with AV (7%) had a complete clinical remission. Burning pain completely disappeared in nine patients treated with AV (33%) and in one treated with placebo (4%) (P = 0Æ005). Symptomatology improved by at least 50% (good response) in 17 patients treated with AV (63%) and in two treated with placebo (7%) (P < 0Æ001). No serious side-effects were found in both groups. Conclusions AV gel is statistically significantly more effective than placebo in inducing clinical and symptomatological improvement of OLP. Therefore, AV gel can be considered a safe alternative treatment for patients with OLP. Oral lichen planus (OLP) is a chronic inflammatory disorder of mucosal surfaces; spontaneous remissions are rarely seen. The disease is quite common, affecting approximately 1 2% of the population. 1,2 OLP, unlike cutaneous lichen planus (LP), is usually recalcitrant to treatment. OLP can be classified into three clinical types: white reticular, atrophic erosive and ulcerative. The erosive lesions hardly ever remit spontaneously and may lead to confusion with other vesiculobullous or autoimmune mucosal diseases which share similar clinical manifestations. The posterior buccal mucosa is the most common site of involvement, followed by the tongue, gingiva, labial mucosa and vermilion of the lower lip. 2 5 In general, all treatments aim at eliminating atrophic and ulcerative lesions and alleviating symptoms. Several topical and systemic treatments are available for patients with OLP but therapeutic responsiveness may differ between patients. 3 8 Aloe vera (AV) is a cactus-like plant that belongs to the Liliaceae family. Some cosmetic and medicinal products are made from the mucilaginous tissue in the centre of the AV leaf, which is called AV gel. AV gel contains no anthraquinones, which are responsible for the strong laxative effects of aloes The pharmacological actions of AV include antiinflammatory, antibacterial, antiviral and antifungal properties, and hypoglycaemic effects. 10,12,13 AV has been used for skin conditions including radiodermatitis, psoriasis and genital herpes infection, with good results. 12,14 To the best of our knowledge, there has been only one case report of LP that successfully responded to topical and systemic AV. 15 There has been no study comparing AV gel and placebo in the treatment of OLP. Therefore, the objective of our study was to compare the efficacy of topically applied AV gel and placebo for the treatment of OLP in a double-blind, randomized protocol. 573

2 574 Aloe vera in oral lichen planus, C. Choonhakarn et al. Materials and methods Patients with OLP attending the Division of Dermatology, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University were asked to participate in our study. The inclusion criteria were as follows: (i) clinical and histopathological diagnosis of OLP; (ii) age at least 18 years. The exclusion criteria were: (i) pregnant women; (ii) lesions in contact with dental amalgam; (iii) the use of drugs possibly causing a lichenoid reaction; (iv) any treatment for OLP or immunosuppressive drugs for pre-existing diseases within the 4 weeks prior to the study; and (v) a history of hypersensitivity to AV. A randomized, double-blind, placebo-controlled study was designed. Local ethical committee approval was obtained before the trial started and all patients gave written informed consent. The AV gel was prepared by the Faculty of Pharmaceutical Sciences, Khon Kaen University from AV grown in Khon Kaen province, Thailand. It consisted of 70% AV mucilage, sorbitol, potassium sorbate, sodium metabisulphite and hydroxyethylcellulose. The placebo gel contained the same ingredients except AV mucilage. The study medications were packed in identical containers and the code was kept at the Faculty of Pharmaceutical Sciences until completion of the study. Study design A randomized controlled trial was performed. Patients were randomly divided into two groups. Randomization was performed by using a simple random numbers table. The first group of patients received AV gel, whereas the second group of patients received placebo. Which medication was used was unknown to patients or physicians. The patients were instructed to apply the medication twice daily and were prohibited from using any emollient during the applications of study medication. Each patient was examined at the beginning of treament, and then after 2, 4, 6 and 8 weeks of therapy. The clinical data were scored according to the criteria used by Thongprasom et al.: 16 0, no lesion; 1, mild white striae, no erythematous area; 2, white striae with atrophic area <1cm 2 ; 3, white striae with atrophic area > 1 cm 2 ; 4, white striae with erosive area < 1 cm 2 ; 5, white striae with erosive area > 1 cm 2 or ulcerative lesion. The pain was scored by visual analogue scale (VAS). 17 Patients were asked to score their intensity of pain at each visit. Pain scores ranged from 0 (no pain) to 10 (extreme pain). Treatment response was graded as complete when the scores according to Thongprasom et al. were either 0 or 1, good when scores decreased by 50% from baseline, poor when scores decreased by < 50% from baseline, and as no response when the lesions were unchanged. Complete resolution of the symptoms was defined as the absence of pain (VAS score of 0). Good, poor or no response of the symptomatology was defined as a decrease of 50%, a decrease of < 50%, or no change, respectively, in the VAS scores. Statistical analysis A search of the relevant published articles gave no information on sample size calculation because only one case report was found. Therefore, we used the PASS program with the following indicators: mean difference = 50%, SD = 25%, type I error =0Æ05, type II error =0Æ10, and determined that 27 patients were needed for each group. Z-test for twoway hypothesis testing was used to compare the responses between the groups. P < 0Æ05 was considered to be statistically significant. Results Fifty-four consecutive patients (34 women and 20 men) were enrolled in the study. No patient dropped out from the study. Demographics and clinical characteristics are shown in Table 1. There were no significant differences between the two groups with regard to age, sex, clinical and pain scores at baseline. The mean duration of the disease before participating in the study was 25Æ1 months in the AV-treated group and 28Æ6 months in the placebo-treated group. We found atrophic and erosive lesions in 45 patients (83%) (24 in AV group and 21 in placebo group), ulcerative lesions in nine patients (17%) (four in AV group and five in placebo group) and reticular lesions in all patients. All patients complained of pain within the lesions. The mean pain scores were 6Æ78 and 6Æ91 in the AV and placebo groups, respectively. The most common site of involvement in our study was the lip (76%), especially the lower lip (72%), followed by the buccal mucosa (44%), gingiva (4%) and tongue (4%), respectively (Table 2). Two of 54 patients also had cutaneous LP. Regarding clinical signs at the end of therapy, two of the 27 patients treated with AV had complete response (7%), Table 1 Demographics and clinical features of the patients Aloe vera Placebo Age (years), mean ± SD 52Æ81 ± 12Æ16 52Æ44 ± 14Æ85 Gender (male female) Symptoms (VAS), mean ± SD 6Æ78 ± 0Æ71 6Æ91 ± 0Æ67 Clinical score, mean ± SD 4Æ18 ± 0Æ42 4Æ10 ± 0Æ47 VAS, visual analogue scale. Table 2 Location of the lesions Location of the lesions, Agent Lip Buccal mucosa Tongue Gingiva Aloe vera (n = 27) 18 (33) 15 (28) 2 (4) 2 (4) Placebo (n = 27) 23 (43) 9 (17) 0 0 Total (n = 54) 41 (76) 24 (44) 2 (4) 2 (4)

3 Aloe vera in oral lichen planus, C. Choonhakarn et al. 575 Table 3 Comparison of clinical response and pain symptoms Clinical response Pain symptoms Response Aloe vera Placebo Aloe vera Placebo Complete response 2 (7) 0 9 (33) 1 (4)** Good response 22 (81) 1 (4)* 17 (63) 2 (7)* Poor response 2 (7) 13 (48)* 1 (4) 14 (52)* No response 1 (4) 13 (48)* 0 10 (37) *P <0Æ001, **P =0Æ005. while none of the placebo-treated patients had complete remission. Improvement of the lesions by a decrease of the clinical scores by 50% (good response) was noted in 22 patients (81%) in the AV group and in only one patient (4%) in the placebo group. The difference was statistically significant (P <0Æ001). Thirteen patients (48%) in the placebo group had poor response (improvement of < 50% from baseline) whereas two patients (7%) in the AV group exhibited such a response. No change of the lesions after 8 weeks of therapy was observed in one patient (4%) receiving AV and in 13 patients (48%) receiving placebo. The difference was statistically significant (P < 0Æ001) (Table 3; Figs 1 3). Complete remission of symptomatology occurred in nine patients (33%) in the AV group and in one patient (4%) in the placebo group. The difference was statistically significant (P =0Æ005). Seventeen patients (63%) had a decrease of 50% in pain score from baseline (good response) with AV treatment, while two patients (7%) had a similar response with placebo. Poor response of pain relief was noted in 14 placebo-treated patients (52%), and there was no change in pain score from the beginning to the end of treatment in 10 patients (37%) of the same group (Table 3). No serious side-effects and no withdrawals owing to adverse effects of AV gel or placebo were recorded. Two Fig 1. Ulcerative lichen planus on the lower lip; complete remission after an 8-week treatment with aloe vera gel. Fig 2. Erosive lesion on the lower lip; complete remission after an 8-week treatment with aloe vera gel.

4 576 Aloe vera in oral lichen planus, C. Choonhakarn et al. Fig 3. Erosive lesions on the tongue; clinical improvement after an 8-week treatment with aloe vera gel. patients receiving AV gel reported stinging and mild itching at the lesions within the first week but the symptoms spontaneously disappeared when the patients continued to use the gel. No significant complaint was reported in the placebo group. Discussion Current treatments for OLP are aimed at alleviating pain and eliminating the lesions. Many treatments have been tried but there is a lack of strong evidence supporting their efficacy. 18 Even though no therapy of OLP is curative, pain relief can be achieved in the majority of patients with topical treatment such as corticosteroids, 3 6,16 ciclosporin, 2,6 retinoic acid 2,3,7 or tacrolimus. 8 Some recalcitrant lesions require systemic medications. Various systemic agents have been reported to be beneficial in the treatment of OLP, e.g. acitretin, azathioprine and systemic corticosteroids. 2 4 OLP is a T cell-mediated disease in which cytotoxic CD8+ T cells trigger apoptosis of oral epithelial cells. Upregulation of intercellular adhesion molecules and cytokines secreted by activated lymphocytes and keratinocytes such as interleukin (IL)-2, IL-4, IL-10 and tumour necrosis factor (TNF)-a can play a role in the pathogenesis of LP. 1,2 AV can inhibit the inflammatory process by its interfering action on the arachidonic acid pathway via cyclooxygenase. 10,11 Recent data suggest that AV also has anti-inflammatory effects by the reduction of leucocyte adhesion and TNF-a level. 19,20 After a review of the literature, only one report about AV in the treatment of LP was found. Hayes 15 described a 52-year-old woman who developed LP in the oral cavity and on her hands. The treatment commenced with drinking 2 oz of stabilized AV juice daily and applying 75% AV cream on the lip and hands. No other dietary supplement, antimicrobial or steroid agent was used. After 4 weeks, the OLP had disappeared and the hand lesions showed slight improvement. Symptomatology of itching and burning also subsided. Then, the dose was doubled to 4 oz of AV daily. Six months after starting treatment, the skin lesions had resolved. In our study, OLP was common in women (female male ratio 1Æ7 : 1). We found white reticular lesions in every patient, atrophic and erosive lesions in 45 patients and ulcerative lesions in nine patients. The lower lip was the most common site of involvement. All patients had pain within the lesions. In the present study, AV gel was effective in the treatment of OLP when compared with placebo. We found 89% of the AV-treated patients significantly improved (improvement of at least 50% from baseline) after 8 weeks of therapy whereas only 4% of placebo-treated patients had a similar response (P <0Æ001). In particular, 7% of the AV-treated patients had complete remission of the lesions (score 0 or 1 according to the criteria of Thongprasom et al. 16 ), while none of the placebo group had such a response. The lesions in most of the patients (96%) receiving placebo showed changes in sign scores indicating either poor or no response. Pain relief in the AV group was also statistically significantly greater than in the placebo group. Pain scores decreased by 50% from baseline in 96% of the AV-treated patients compared with 11% of the placebo-treated patients (P < 0Æ001). However, no formal quality of life assessments were used in this study. Existing evidence demonstrates that AV used in a variety of concentrations might be effective in shortening the duration of wound healing. The amount of active ingredient in AV varies depending on the age of plants, growing and harvesting conditions, parts of plants, and extraction methods. 21 The AV gel that we were able to prepare from AV plants grown in Khon Kaen province was at 70% concentration. The antiinflammatory properties of this gel were previously studied in rats: gastric ulcers induced by indomethacin showed significant improvement after administration of AV. 22 We therefore decided to use 70% AV gel for the treatment of OLP in our study. In conclusion, the effect of 70% AV gel on OLP was significantly better than that of placebo. The results showed decreases both in clinical signs and in pain scores. Mild adverse effects were reversible and AV was generally well tolerated. Thus, AV gel is a safe and effective treatment for OLP. Acknowledgments This work was supported by a grant from Khon Kaen University. We thank Mr Anun Riewthong for technical assistance.

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