Efficacy and safety of adjuvant topical application of botanicals in the treatment of melasma: A systematic review and meta-analysis

Abstract

Objective

To systematically evaluate the efficacy and safety of topical application of botanical (TAB) adjuvants in the treatment of melasma and provide evidence-based medical evidence for their clinical application.

Methods

Medline, Web of Science, EMBASE, Cochrane Library, CNKI, VIP, Wanfang Data, and SinoMed, databases were searched to identify all randomized controlled clinical trials on TAB adjuvant treatment for melasma from inception to May 2023. The primary outcomes included clinical efficacy, adverse effects, recurrence rate, and melanin index. Subgroup analyses were performed using the Melasma Area Severity Index (MASI) scores.

Results

This study included 16 randomized trials with 1386 participants. Eligible trials demonstrated that topical phytomedicine adjuvant treatment for melasma increased clinical effectiveness (RR = 1.14, 95% CI (1.10, 1.19), P ＜0.00001), decreased recurrence rate (RR = 0.28, 95% CI (0.13, 0.59), P = 0.0009), and decreased melanin index (MI) (MD = −22.2,95% CI (−31.79, −12.61), P < 0.00001). In addition, subgroup analysis showed that topical phytomedicines reduced MASI scores (I² = 0%, MDI = −0.95, 95% CI (−1.23,0.67), P < 0.00001), but when scored as the rate of decrease in MASI, topical phytomedicines had high MASI scores (I² = 15%, MD = 0.3, 95% CI (0, 0.59), P = 0.05), indicating a slower rate of melasma mitigation when botanicals were applied topically. Although burning pain, redness and other mild adverse reactions may occur during the treatment period, they can be recovered on their own, and there is no statistical significance in the comparison of the two groups (RR = 0.95, 95% CI (0.42, 2.51), P = 0.91).

Conclusion

TAB for melasma has a clear adjuvant clinical efficacy, a low recurrence rate, and does not cause serious adverse effects. An appropriate administration method may achieve better efficacy; however, this requires further verification.

Highlights

• •Melasma is a common chronic acquired skin disease becoming a topic of great concern.
• •Botanicals are favored by patients with melasma because of their low side effects and cost effectiveness.
• •This study confirmed the efficacy and safety of the topical application of botanical adjuvants in the treatment of melasma.
• •This study provided evidence-based medical evidence for their clinical application.

1. Introduction

Melasma is a common chronic acquired skin disease characterized by increased facial pigmentation with an incidence of 8.8%–40% [1]. This disease occurs in women of childbearing age and in dark-skinned populations, especially those with Fitzpatrick skin photoreactivity types III–IV [2], and manifests as reticular or flaky patches or patches of light brown or dark brown on both sides of the cheeks [3]. The pathogenesis of this disease is complex, involving melanocytes, keratin-forming cells [4], fibroblasts, endothelial cells, and basement membrane alterations [5]. Exposure to ultraviolet and visible light [6], alterations in hormone levels [7], and genetic susceptibility [8], are risk factors for melasma development. Due to its impact on facial appearance, it seriously affects patients' life and psychology. Particularly for women, melasma removal has become a great concern. Melasma is a common disfiguring skin disease. Although not life threatening, this condition greatly affects the patient's emotional and mental health, increasing psychological pressure; this may lead to anxiety, depression, and other psychological disorders.

Currently, there is no standard treatment plan for melasma. Common solutions include sun protection, topical creams such as hydroquinone, niacinamide, vitamins A and C, oral medications such as, chemical exfoliation laser therapy, acupuncture, and acupoint injections. However, these treatments are prone to chemical irritation, inflammatory reactions and hyperpigmentation; other drawbacks include the potential for recurrence and unstable efficacy [9]. Therefore, patients often seek complementary and alternative medicines to supplement or replace conventional treatments. TAB as a nursing intervention promotes a positive self-concept and quality of life in patients.

Botanicals are favored by patients with melasma due to low side effects, safety, and cost effectiveness. However, there is insufficient evidence regarding the effectiveness of topical application of natural botanicals for the clinical adjuvant management of melasma. Therefore, this study aimed to systematically evaluate evidence from randomized controlled trials (RCTs) on topical interventions with botanicals for melasma, to provide evidence for their safety and efficacy, to improve the treatment of melasma.

2. Materials and methods

To perform this meta-analysis, which included all published trials, we used the PRISMA 2020 27-item checklist [10]. This study was registered with PROSPERO (ID:CRD42023474077).

2.1. Inclusion criteria

The study inclusion criteria were as follows: 1) participants diagnosed with melasma; 2) patients in the control group were treated with conventional treatments, patients in the test group were selected to use TAB alone or as an adjunct to conventional treatment, and the frequency and duration of the treatment were not limited; 3) evaluation included physicians’ assessment of the MASI or modified MASI (mMASI) scores before and after treatment, MI, and other testing indices. Other validated methods include physician assessment of efficacy, physician follow-up of recurrence, and adverse effects reported during and after treatment. Other outcomes included participants' subjective self-assessments, participant-reported outcomes, and satisfaction; and 4) study was a randomized controlled trial. In the absence of randomized trials, well-designed non-randomized controlled trials and prospective self-controlled pre- and post-studies were considered narrative representations of current facts.

2.2. Exclusion criteria

The exclusion criteria were as follows: 1) studies that did not provide detailed information on patient selection, allocation, study design, and outcomes were excluded; 2) studies with pregnant or lactating patients were excluded; 3) studies analyzing other causes of melasma; 4) only one published study was included; 5) non-RCT literature such as summaries of clinical experience, patents, and reviews; and 6) unpublished literature or conference papers.

2.3. Literature screening and data extraction

Two independent authors searched the Medline, EMBASE, Web of Science, Cochrane Library, ClinicalTrials.gov, CNKI, Wanfang Data, VIP, and SinoMed databases for core journals, conference abstracts, tracking references, and conducted a comprehensive medical literature search. Studies published in all languages were included and the search strategy followed the PRESS guidelines [11]. First, duplicates were excluded and titles were read to screen out irrelevant literature. Second, the full text was read to exclude literature that did not meet the nadir criteria, and content including the following was extracted: (1) basic information about the literature (e.g., authors and chronology, etc.); (2) basic information about the patients (e.g. sex, age, type of disease, etc.); (3) intervention methods; and (4) outcome indicators (including total clinical efficiency [12], incidence of adverse effects, recurrence rate, MASI, MI, etc.).

2.4. Quality evaluation of included studies

The results were assessed independently by two investigators according to the risk of bias assessment tool for RCTs recommended by the Cochrane Handbook and cross-checked. The evaluation included reject, data integrity, random sequence generation, etc, Disagreements were resolved via discussion with a third investigator.

2.5. Statistical methods

A meta-analysis was performed using RevMan 5.3 software provided by the Cochrane Collaboration Network. Continuous variables are presented as standardized mean difference (SMD) or mean difference (MD) and odds ratio (OR) are presented as discontinuous variables. Each effect size was expressed as a 95% confidence interval (CI). When I² was >50%, the studies were considered heterogeneous, and subgroup analysis was performed. If the subgroup analysis was inappropriate, a descriptive analysis was performed. No heterogeneity was observed. A funnel plot was used to analyze publication bias for the number of papers with ≥10 combined outcome indicators. Differences were considered statistically significant at P < 0.05. Publication bias was evaluated using the Egger's test.

3. Results

3.1. Literature search results and basic characteristics

A total of 2951 relevant studies were retrieved, and 16 RCTs with a total of 1386 patients were finally screened and included. The literature screening process is shown in Fig. 1, and the literature characteristics are shown in Table 1.

Fig. 1.

Literature screening flowchart.

Table 1.

Basic characteristics of the included literature.

Author and Year	County	n (T/C)	Age (T/C)	Sex	Disease duration/year (T/C)	Interventions(C/T)		Treatment/week	Adverse reactions/n (T/C)	Ending indicators	Randomization method	Types of melasma	Active ingredients or botanical drugs
Bavarsad 2020 [13]	IRAN	11/11	34.7 ± 10.2/33.5 ± 7. 8	Female	5.31 ± 2.92/3.46 ± 1.44	CT	TAB	12	0	②⑥	shuffled cards	Epidermal, Dermal, Combination	Lycopene and Wheat bran extract
Chang2022 [14]	China	21/21	36.81 ± 4.69/34.90 ± 5.39	Female	0.17 ± 0.033/0.17 ± 0.0325	CT	CT + TAB	16	0/1	①②④	random number table approach	Pigmented combined vascular type	Polygonatum odoratum (Mill.) Druce, Glycyrrhiza uralensis Fisch., Polygonatum sibiricum Delar. ex Redoute, Carthamus tinctorius L.
Guo2012 [15]	China	30/35	25-49/28-48	Female	0.25–9/0.5–7	CT	CT + TAB	12	45293	①②③	randomization	–	Angelica sinensis (Oliv.) Diels, Carthamus tinctorius L., San Qi, Typhonium giganteum Engl., Poria cocos (Fr.) Wolf., White silkworm, Root of Sinkiang Arnebia, Angelica dahurica (Fisch. ex Hoffm.) Benth. & Hook. f. ex Franch. & Sav., Bletilla striata (Thunb. ex Murray) Rchb. F.
Huang2001 [16]	China	80/68	35	Male:2,Female:146	3.2	CT	TAB	12	0	①②	randomization	–	Angelica dahurica (Fisch. ex Hoffm.) Benth. & Hook. f. ex Franch. & Sav, Lithargite, Typhonium giganteum Engl., Poria cocos (Fr.) Wolf., Bletilla striata (Thunb. ex Murray) Rchb. F., Salvia miltiorrhiza Bunge, Root of Sinkiang Arnebia
Li2018 [17]	China	25/25	30.72 ± 10.57/30.58 ± 10.36	–	–	CT	CT + TAB	12	–	①	randomization	–	Glycyrrhiza uralensis Fisch., Saposhnikovia divaricata (Turcz.) Schischk., San Qi, Carthamus tinctorius L., Salvia miltiorrhiza Bunge, Angelica sinensis (Oliv.) Diels, Dioscorea polystachya Turczaninow, Cynanchum otophyllum Schneid., Atractylodes macrocephala Koidz., Poria cocos (Schw.) Wolf.
Lin2016 [18]	China	30/30	31.40 ± 11.34	Female	6.73 ± 4.36	CT;	CT + TAB	12	45292	①②③	randomization	Epidermal, Dermal, Combination	Poria cocos (Schw.) Wolf, Atractylodes macrocephala Koidz., Cynanchum otophyllum Schneid., Dioscorea polystachya Turczaninow, Angelica sinensis (Oliv.) Diels, Salvia miltiorrhiza Bunge, Carthamus tinctorius L., San Qi, Saposhnikovia divaricata (Turcz.) Schischk., Glycyrrhiza uralensis Fisch.
Liu2008 [19]	China	86/62	19–45	Female	0.25–17	CT	CT + TAB	12	–	①⑤	randomization	–	Angelica sinensis (Oliv.) Diels, sichuan lovage rhizome, White silkworm, Angelica dahurica (Fisch. ex Hoffm.) Benth. & Hook. f. ex Franch. & Sav.
Liu2017 [20]	China	150/150	38.0 ± 7.9/38.3 ± 8.4	–	2.1 ± 0.8/1.9 ± 0.7	CT	CT + TAB	12	–	①④	randomization	–	Ampelopsis japonica (Thunb.) Makino, Cynanchum otophyllum Schneid., Typhonium giganteum Engl., White silkworm, Atractylodes macrocephala Koidz., Angelica dahurica (Fisch. ex Hoffm.) Benth. & Hook. f. ex Franch. & Sav., Cissusrepens Lamk.
Luo2012 [21]	China	90/30	30.6 ± 3.5/32.2 ± 4.8	Female	3.7 ± 1.1/4.2 ± 1.8	Distilled water	TAB	12	–	①	randomization	–	Oyster Shell, Japanese Snakegourd Root, Almond, Chinese Waxgourd Seed, Peach Seed, Angelica dahurica (Fisch. ex Hoffm.) Benth. & Hook. f. ex Franch. & Sav., Ampelopsis japonica (Thunb.) Makino, White silkworm, Liquorice Root., Nardostachyos Root and Rhizome, Borneol
Mendoza2014 [22]	Philippines	15/15	29.04 ± 7.8	Male:12	–	CT	TAB	8	1/0	②⑥	Randomized and double-blind,	Epidermal, Mixed	R. occidentalis cream
Tao2022 [23]	China	51/51	50.85 ± 6.16/50.25 ± 6.65	Female	5.25 ± 1.78/5.28 ± 1.79	CT	CT + TAB	12	45325	①②③⑥⑦⑧	random number method	Epidermal, Mixed	Almond, Angelica sinensis (Oliv.) Diels, White silkworm, Angelica dahurica (Fisch. ex Hoffm.) Benth. & Hook. f. ex Franch. & Sav., Sichuan lovage rhizome
Wang2007 [24]	China	31/31	31/30	Female	45448	CT	CT + TAB	4	–	①	randomization	–	Angelica sinensis (Oliv.) Diels, sichuan lovage rhizome, Peach Seed, Angelica dahurica (Fisch. ex Hoffm.) Benth. & Hook. f. ex Franch. & Sav., Typhonium giganteum Engl., White silkworm, White Lablab Seed, Bletilla striata (Thunb. ex Murray) Rchb. F., Ampelopsis japonica (Thunb.) Makino, Manchurian Wildginger, Lithargite, Borneol
Yu2012 [25]	China	30/35	26-47/24-45	Male:2,Female:63	0.25–9/0.5–7	CT	CT + TAB	12	45323	①②	randomization	–	San Qi, Typhonium giganteum Engl.,Poria cocos (Fr.) Wolf., Angelica sinensis (Oliv.) Diels, Carthamus tinctorius L., White silkworm, Root of Sinkiang Arnebia, Angelica dahurica (Fisch. ex Hoffm.) Benth. & Hook. f. ex Franch. & Sav., Peach Seed
Zhang2019 [26]	China	30/30	40.37 ± 7.22/40.4 ± 5.67	Males and Females	5.45 ± 3.53/5.47 ± 4.00	CT	TAB	12	0/2	②⑥⑦	Randomized and double‐blind,	Fitzpatrick skin types III,IV	China camellia, Sanchi, Prinsepia utilis oil, Portulaca oleracea
Zhang2023 [27]	China	30/30	33.07 ± 9.43/37.38 ± 9.02	Female	6.51 ± 1.67/6.84 ± 1.74	CT	CT + TAB	12	–	①③④	randomization	–	Smoked Plum, Pomegranate Rind, Angelica dahurica (Fisch. ex Hoffm.) Benth. & Hook. f. ex Franch. & Sav., Honeysuckle Stem
Zhao2020 [28]	China	30/30	37.67 ± 5.51/37.57 ± 5.92	Female	4.18 ± 1.80/4.27 ± 2.15	CT	CT + TAB	8	45292	①⑥	random number method	–	Pearl powder, Curcuma aromatica Salisb., Cyperus rotundus L., Angelica sinensis (Oliv.) Diels, Salvia miltiorrhiza Bunge, sichuan lovage rhizome, Poria cocos (Fr.) Wolf., Typhonium giganteum Engl., Puncturevine Caltrop Fruit, White silkworm

Conventional therapies include topical non-botanical creams, oral medications, and lasers. CT indicates conventional therapies; T indicates test group; C indicates control group; -- indicates not mentioned; ①Total clinical efficiency; ②Adverse effects; ③Recurrence rate; ④Degree of lesion score; ⑤Serum sex hormone levels (FSH, LH, E2, P); ⑥Melasma lesion area and severity index (MASI or MASI decline rate); ⑦MI; ⑧Dermatological quality of life index.

3.2. Total clinical effective rate

The 13 included papers [[14], [15], [16], [17], [18], [19], [20], [21],[23], [24], [25],27,28] mentioned the total clinical effective rate, with 684 cases in the test group, and 597 cases in the control group, and no statistical heterogeneity between studies (I² = 0%). Meta-analysis using the fixed-effects mode showed that the clinical effective rate of the experimental group was higher than that of the control group, and the difference was statistically significant (RR = 1.41, 95% CI (1.10, 1.19), P < 0.00001). This indicated that TAB can significantly improve the clinical efficacy of treating melasma (Fig. 2).

Fig. 2.

Forest plot for comparison of total clinical efficiency.

3.3. Adverse reactions

Eight out of 16 included RCTs, recorded the number of adverse reactions in 237 patients in the test group and 247 patients in the control group [14,15,18,22,23,25,26,28]. Common adverse reactions included burning pain, redness [15,18,22,25,26], hyperpigmentation [14,28], and itching [23]; however, all of these reactions gradually resolved spontaneously. There was no statistical heterogeneity between studies (I² = 0%), which were analyzed using the fixed effects model. Results of the meta-analysis showed that the diamond-shaped portion was located on the null line. Therefore, the incidence of adverse reactions was compared between the two groups, but was not found to differ significantly [RR = 0.95, 95% CI (0.42, 2.15), P = 0.91] (Fig. 3).

Fig. 3.

Forest plot for comparison of adverse reactions.

3.4. Recurrence rate

The number of recurrences was recorded in four RCTs out of 16 included studies [15,18,23,27]. In terms of disease recurrence, the follow-up time was three months in two cases [23,27], six months in one case [18] and one year in one case [15]. A total of 133 and 127 patients were included in the test and control groups, respectively. There was no heterogeneity between the studies (I² = 0%), and the analysis was performed using the fixed effects model, as shown in Fig. 6. Meta-analysis results showed that the diamond-shaped portion was located on the left side of the null line; therefore, the incidence of relapse rate was compared between the two groups, and the difference was statistically significant [RR = 0.28, 95% CI (0.13, 0.59), P = 0.0009]. This indicated that the recurrence rate after topical application of phytomedicines was lower than that of the control group (Fig. 4).

Fig. 6.

Forest plot for MASI subgroup analysis.

Fig. 4.

Forest plot for recurrence rate comparison.

3.5. MASI

In all, five studies [13,22,23,26,28] mentioned MASI or MASI decline rate (_△MASI), 137 cases in the test and control groups, respectively. Meta-analysis was performed using the random effects model and showed no statistical significance between studies (P = 0.30), with statistical heterogeneity I² = 91% (Fig. 5). Heterogeneity in the test and control groups was high, therefore, a subgroup analysis was performed. MASI is one of the common indexes that responds to the severity of melasma and lesion area, can indicate the development of melasma and has important clinical significance for melasma. The subgroup analysis was performed according to the degree of _△MASI and MASI of patients. The results showed that when patients were scored by MASI, the MASI score of TAB was low, indicating a good clinical effect [I² = 0%, MD = −0.95, 95% CI (−1.23, 0.67), P < 0.00001]; however, when patients were scored by the _△MASI, the MASI score of TAB was high [I² = 15%, MD = 0.3, 95% CI (0, 0.59), P = 0.05] (Fig. 6), indicating a slow rate of melasma mitigation when botanicals were used topically. Comprehensively, the rate of MASI decline may be a factor influencing the heterogeneity among the literature; that is, while TAB for melasma is effective, the results are slow.

Fig. 5.

Forest plot for MASI comparison.

3.6. MI

Two papers [23,26] referred to MI, 81 cases in the test and control groups, respectively, with statistical heterogeneity and statistical significance between studies [I² = 0%, P < 0.00001], analyzed using the fixed-effects model (Fig. 7). The results lie to the left of the null line [MD = −22.2, 95% CI (−31.79, −12.61)], indicating that TAB has a lower MI than conventional treatments and reduces melanin levels in patients. However, this index was included in only two trials and did not fully reflect the true nature of the topical application of phytomedicines.

Fig. 7.

MI analysis forest diagram.

3.7. Publication bias

The funnel plot of the number of studies with ≥10 combined outcome indicators is illustrated in Fig. 8. The funnel plot of the total effective rate of topical treatment of melasma with botanicals shows that most of the studies are in the middle of the "inverted funnel,” and the left and right sides are basically symmetrical, suggesting and obvious publication bias. Egger's test also showed publication bias (P = 0.001). Therefore, a larger number of samples is required. Notably, drawing funnel plots was challenging owing to the insufficient number of studies available to test the efficacy of the treatment.

Fig. 8.

Total efficiency publication bias funnel plot.

4. Discussion

Melasma is a common clinical facial pigment metabolism disorder. Oxidative stress in the damaged skin environment is an important factor in skin aging and deterioration and natural drugs have a strong antioxidant capacity. In addition, topical drugs such as hydroquinone cream and retinoic acid cream for treating melasma can exfoliate and irritate the skin barrier, resulting in itching and redness, which in turn aggravates skin inflammation. Botanicals, on the other hand, are gentle and non-irritating, repairing inflammation and remodeling the skin barrier. Simultaneously, laser surgery therapy is costly and cannot be self-administered. Therefore, low-cost, easy-to-use therapies with less adverse effects are required. Phytomedicines are derived from green plants and are natural, inexpensive, easily available, easy to self-administer, and highly acceptable; therefore, they are considered as alternative therapies worthy of research.

Traditional Chinese medicine believes that the liver, spleen, and kidney are the key organs in the development of chloasma; Depressed liver qi can transform into fire, resulting in a loss of harmony between qi and blood on the face. The kidney governs water, and water deficiency can make the hyperactivity of fire, which leads to the inability to moisturize the skin. If the spleen is deficient, there will be insufficient qi and blood, so the face will not be able to emit glory and produce chloasma. This study found that the blood activation is the main effect in TAB, so as resulting in activation of blood circulation and removing blood stasis. Although chemical extracts focus on the whitening effect, most botanicals are herbal formulas; thus, their relative mechanisms are less known, and the corresponding research on herbal formulas should be strengthened. The results of our analysis showed that the clinical efficiency of phytomedicinal topical treatment of melasma was significantly better, with no significant adverse reactions compared to existing chemical treatments. According to the results of the study with the single largest sample size (n = 150) included in this review [20], the use of topical botanicals combined with oral Chinese medicine improved the overall clinical efficiency compared with conventional Chinese medicine treatment. The results of our meta-analysis were consistent with this study, indicating the superior efficacy and safety of topical botanicals in the adjunctive conventional treatment of melasma.

Although this study confirmed the efficacy of topical botanicals in the treatment of melasma, there were certain limitations. For example, the occurrence of adverse reactions in topical botanicals compared with conventional treatment was comparable but not significantly superior, which may be because the trials included in this study did not strictly control the medication dose in the intervention and control groups. Second, due to the history of pharmaceutical development, the use of therapeutic drugs and other reasons, TAB in China is higher compared to other countries. Therefore, this study mostly included studies from China. Therefore, the our results may not be relevant in other populations. Other limitations include the lack of uniformity in the type of melasma between studies, variation in the type of botanicals used between studies, and the inconsistency in the duration of treatment and post-treatment follow-up between studies. Therefore, these limitations need to be considered when interpreting the results of the studies for clinical decision making. Consequently, further multicenter, large-sample, high-quality RCT studies are warranted to obtain more reliable clinical evidence to confirm the validity of our findings.

5. Conclusions

In conclusion, based on currently available evidence, this analysis suggests that topical adjunctive treatment with botanicals may enhance clinical efficacy, without no adverse effects, have a relatively low recurrence rate in melasma. Additionally, it may reduce MASI and MI scores, suggesting that it may be effective and safe. However, appropriate treatment duration, dispensing application of prescribed medications, and proper administration may yield better efficacy, which requires further validation. Although topical application of botanicals as adjuvant therapy has a better future in the treatment of melasma, multicenter, large-sample, well-designed RCT trials are required to increase clinicians' confidence in the use of TAB as an adjuvant therapy for melasma.

Disclosures

Lin Guo,Shuo Tian, Yuanxin Zhang, Siqing Wu,Ming Bai and Mingsan Miao declare that they have no competing interests.

Compliance with ethics guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Funding

This work was supported by the “National Natural Science Foundation of China” (No. 82074038), “Major public welfare special project in Henan Province” (No. 201300310100), “Henan Province Key R&D Special Project (INTERNATIONAL COOPERATION Category)” (No. 231111521200) and “Postdoctoral research project in Henan Province” (No. 202001053).

Data availability statement

The data and support information used for this research are available at the following link:https://data.mendeley.com/datasets/w4wgjbn9fd/2.

CRediT authorship contribution statement

Lin Guo: Writing – review & editing, Writing – original draft, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Yuanxin Zhang: Visualization, Validation, Data curation. Siqing Wu: Formal analysis. Ming Bai: Validation. Shuo Tian: Validation. Mingsan Miao: Visualization, Validation, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.