Effect of Aloe vera as a local drug delivery agent in the management of periodontal diseases: A systematic review and meta-analysis.

BACKGROUND: Aim of the present meta-analysis was to evaluate the effect of Aloe vera in various forms such as gel, mouthwash, and dentifrice on gingival and plaque index (PI) in comparison to various allopathic products such as chlorhexidine, metformin, chlorine dioxide, fluoridated toothpaste, and alendronate.
MATERIALS AND METHODS: A comprehensive electronic search was conducted on PubMed/MEDLINE, GOOGLE SCHOLAR, and HAND SEARCH of reference list of archived articles published till January 2020. Randomized controlled trials were searched comparing the Aloe vera product with other products which used PI and gingival index (GI) to evaluate the outcomes. Finally, nine studies assessing PI and four studies evaluating GI were considered for the meta-analysis. After extracting the information, a risk of bias was estimated. The standardized mean differences (SMDs) and fixed and random effect models were obtained from the mean treatment differences.
RESULTS: The estimates of SMD of PI from fixed effects (SMD = 0.271, 95% confidence interval [CI] = 0.00134-0.407, P < 0.001) and random effects (SMD = 0.288, 95% CI = 0.048-0.529, P = 0.019) were found slightly different, the models showed consistent results yielding positive and significant treatment effects. For GI fixed effects (SMD = 0.27, 95% CI = -0.035-0.575, P = 0.0803, not significant) and random effects (SMD = 0.259, 95% CI = 0.049-0.469, P = 0.016, significant) were found slightly different and positive. However, one model showed significant and another model showed nonsignificant treatment effects.
CONCLUSION: Results from our meta-analyses confirmed the beneficial effects of A. vera in improving the periodontal parameters and hence may be considered as a safe alternative drug delivery agent for the management of periodontal diseases in future. Copyright:

INTRODUCTION

Periodontal diseases include a collection of ailments that may be acquired or hereditary diseases of the gingiva, cementum, periodontal ligament, and alveolar bone. Periodontal illnesses, according to some experts, are chronic infectious illnesses caused mostly by bacteria.[1] Periodontal diseases are extremely complex to treat as the infection is caused by bacterial biofilm, which is very resistant to antimicrobials and human defenses.[2] The removal of microorganisms from the periodontal cavity is arduous and the bacteria persist in the oral cavity. Surgical intervention, mechanical therapy, and the use of pharmaceutical medications are all available treatment options for periodontal disease.[3]

Controlling supragingival plaque using topical antimicrobial agents such as dentifrices, mouthwash, and gels is a successful approach. Irrigation systems or devices can deliver agents into deep pockets, but they are not clinically effective in avoiding periodontal attachment loss. The use of topical delivery and controlled release systems at the target site to administer antimicrobial drugs has become a popular new trend, resulting in more consistent and extended concentration profiles.[4] Ayurvedic and herbal medicines have recently gained popularity as a means of overcoming the side effects of allopathic medicine. The comparatively safe nature of plant extracts has encouraged the usage of herbal products. In the form of local drug delivery, several herbal products and their elements are used to treat periodontitis.[5] Neem,[6] Aloe vera,[7] Lemon grass,[8] Tea tree oil,[9] Curcumin,[10] Oak,[11] Coriander,[12] and Pomegranate[13] are some of the herbal products that are popularly used as an adjunct to scaling and root planing.

A. vera among these herbal products is known to be extremely helpful in treating periodontal diseases. Its soothing and healing characteristics help to minimize gingival bleeding as well as swelling and soft tissue edema.[14]

Different authors have utilized A. vera in various forms such as mouthwash, gel, dentifrice, and chip in contrast to multiple allopathic medications and found it useful in improving periodontal parameters.[7151617] Penmetsa GS et al.[18] compared A. vera mouthwash to chlorhexidine mouthwash. A. vera was shown to be just as efficient as chlorhexidine in reducing gingival inflammation and bleeding. As a result, in line with all of these researches on A. vera, the goal of this meta-analysis was to compare the effects of A. vera in various forms such as gel, mouthwash, and dentifrice on gingival and plaque index (PI) to allopathic medications such as chlorhexidine, metformin, chlorine dioxide, fluoridated toothpaste, and alendronate.

MATERIALS AND METHODS

Reporting format

Preferred reporting items for systematic review and meta-analyses developed by Moher et al. in 2009[19] and Cochrane collaboration[20] was used as a guide for reporting the present analysis. Moreover, the protocol of this study was registered at the national institute for health research PROSPERO, International Prospective Register of Systematic Review (ID: CRD42020164233) link.

Focused question

The research question for This systematic review and meta-analysis analysis was specifically framed focusing on the PICO criteria.[2122] We wanted to evaluate the effect of A. vera as a Local drug delivery agent in the management of periodontal diseases using PI and gingival index (GI).

Search protocol

A comprehensive electronic search was conducted on PubMed/MEDLINE, GOOGLE SCHOLAR, and HAND SEARCH of reference list of archived articles. The research search strategy used the key words and Medical Subject Headings terms and a combination for the effective search results. The search terms used were “Periodontitis” OR “Periodontal diseases” OR “Gingivitis” OR “Aloe vera” OR “Periodontal parameters” OR “Gingival Index” OR “Plaque Index” AND “Aloe Vera mouthwash” OR “Toothpaste” OR “Dentifrice” OR “Gel” AND randomized controlled trials” OR “RCT” OR “Clinical Trials.” A combination of all these terms was used for the exhaustive search purpose.

Screening and study selection

Three reviewers (AJ, SR, and PB) independently screened the articles based on titles and abstracts in consonance with inclusion and exclusion criteria. Abstract of all the relevant studies and its possible significance were obtained and independently reviewed by the reviewers. To resolve any discrepancies a reviewer (SU) was consented. The concordance of option and interpretation amongst the authors was analyzed by Kappa statistics. Further, full text papers were also collected and reviewed together by all the authors involved in the study to confirm whether the studies meet the specified inclusion criteria or not.

Eligibility criteria

Only the randomized controlled trials (RCTs) comparing A. vera to placebo, fluoride-containing triclosan, chlorhexidine, chlorine dioxide, Metformin, Alendronate, Ocimum sanctum, tea tree oil, Ornigreat in gel, mouthwash, or toothpaste were included. The case series, case reports, in vitro studies, uncontrolled clinical trials, review papers, letters to editor, monographs, and conference papers were excluded.

Inclusion criteria

In vivo study

Human trials, randomized clinical trials and studies published in English

Healthy adults

No limits on the number of patients were placed

Studies having a test group of A. vera in any form as Local drug delivery and a control group as placebo, fluoride-containing triclosan, chlorhexidine, chlorine dioxide, Metformin, Alendronate, O. sanctum, tea tree oil, Ornigreat in the form of gel, mouthwash or toothpaste.

Exclusion criteria

In vitro study

Nonhuman

Non-English

Systemically unhealthy adults

Case with aggressive periodontitis

Case reports

Case series

Retrospective studies

Technical studies

Animal studies and reviews.

Outcome variables

Two outcome variables evaluated in the present study were PI and GI.

Data extraction

Two distinct authors retrieved the data using a customized data extraction form that comprised the author's name, research nation, study design, number of participants, gender, age-range, clinical characteristics, and the two primary outcomes.

Quality assessment and risk of bias

The quality evaluation of individual studies was conducted by two reviewers (AJ, SR). The probability of bias assessment of all RCT's included was accomplished through the Cochrane Collaboration Guidelines, which was judged by six domains: (1) sequence generation (2) allocation concealment (3) blinding of participants and outcome assessors (4) incomplete outcome data (5) selective outcome reporting and (6) other sources of bias. During the judgment each “Yes” or “No” indicated low and high risk of bias respectively, while “Unclear” meant an uncertain risk of bias. A study was grouped as “Low risk of bias” when all the aspects were of low risk of bias and as high or uncertain when any one or more aspects were of “High or Unclear risk of bias” [Table 1].

Table 1

Risk of bias

Author (year)	Randomisation	Allocation concealment	Blinding	Incomplete outcome data addressed	Selective outcome reporting	Other risk of bias	Risk of bias of individual study
de Oliveira et al., (2008)[23]	Yes	Yes	Yes	Yes	Yes	No	Low risk
Pradeep et al., (2012)[7]	Yes	Unclear	Yes	Yes	Yes	No	Low risk
Yeturu et al., (2016)[24]	Yes	Yes	Yes	Yes	Yes	No	Low risk
Pradeep et al.(2016)[25]	Yes	Unclear	Yes	Yes	Yes	No	Low risk
Ipshita et al., (2018)[26]	Yes	Yes	Yes	Yes	Yes	No	Low risk
Kurian et al., (2018)[27]	Yes	Yes	Yes	Yes	Yes	No	Low risk
Deepu et al., (2018)[28]	Yes	Yes	Yes	Yes	Yes	No	Low risk
Kamath et al., (2020)[29]	Yes	Unclear	Yes	Yes	Yes	No	Low risk
Penmetsa et al., (2019)[30]	Yes	Unclear	Yes	Yes	Yes	No	Low risk

Statistical analysis

A meta-analysis was performed on the included studies for two parameters namely PI (n = 9 studies) and GI (n = 4 studies). Between the study, heterogeneity was assessed by Q statistics, and by I2 statistics. Both random-effects models and fixed effects models were used for the meta-analysis considering the significant role of heterogeneity in the models. Standardized effect size (i.e. standardized mean difference [SMD]) was estimated for each parameter along with 95% confidence intervals (CIs). Publications bias was examined using Funnel plot and Egger's test. P value was set at 0.05 level for deciding the statistical significance of the results.

RESULTS

The initial search yielded a total of 220 studies, out of which 122 were duplicate and so had to be removed [Figure 1]. The titles and abstracts of the 98 studies were screened by two independent reviewers, and 77 were found irrelevant and thus removed. Twenty full-text articles were obtained, eleven of these had to be excluded as they were animal studies, case series, review articles, and studies published in other languages. Some studies were excluded due to insufficient data available (the number of subjects included in these studies was showing varying results). Thus, finally, nine studies for PI and four studies for GI were considered for the meta-analysis.

Figure 1

Flowchart. n – number of studies

General characteristics of the included studies

Table 2 shows overall 9 RCTs[72324252627282930] with varying follow-up periods of 1 week to 12 months provided data from 256 participants in the test group which were compared to data from 457 participants in the control group. The minimum number of participants per group was 15 and maximum number of participants per group was 38. Regarding the control group, it was not the same in all the studies. Some studies had 2 or 3 control groups while the others had one control group but these were considered as one while comparing with the test group.

Table 2

Overview of basic and general characteristics of the reviewed studies

Author	Year	Age (years)	Number of patients		Parameters evaluated	Follow up
			Test	Control
Oliveria S M A et al.	2008	35-43	15	15	PI	1 month
Pradeep A R et al.	2012	25-40	30	30	PI, GI	6 weeks
						12 weeks
						24 weeks
Yeturu S K et al.	2016	Mean: 21	30	30	PI, GI	15 days
Pradeep A R et al.	2016	25-45	30	30	PI	3 months
						6 months
Ipshita S et al.	2018	-	30	30	PI	12 months
Kurian IG et al.	2018	Mean: 41	30	30	PI	6 months
						12 months
Deepu S L et al.	2018	-	33	38	PI, GI	4 months
Penmetsa G S et al.	2019	25-65	20	20	PI, GI	4 weeks
Kamath N. P et al.	2019	8-14	38	38	PI, GI	4 weeks

PI – Plaque index; GI – Gingival index

Type of interventions

Many of the studies compared one test group, i.e., A. vera in any form like denitrifies, mouthwash or gel with same form control group, i.e., Placebo, Fluoride containing triclosan, Chlorhexidine, Chlorine dioxide, Metformin, Alendronate, O. sanctum, tea tree oil or Ornigreat. Four studies had two control groups and one of the studies had 1 control group.

Aloe vera and plaque index

For the meta-analysis of PI few studies had more than one-time point as follow up period, hence separate studies were considered for each follow-up period. Pradeep AR et al. 2012 three follow-up, Pradeep A R et al. 2015 two follow-ups, Kurian T G et al. 2017 two follow-ups, Kamath N. P et al. 2019, two follow-ups rest studies had only one follow up period.

The descriptive statistics for PI obtained in the studies, along with the mean difference and weight of each study in the analysis are shown in Figure 2 and Table 3. The estimates of measures of heterogeneity for PI based on fourteen studies were: I2 = 67.38%, P < 0.001. Significant heterogeneity was observed with Q = 39.85, P = 0.0001. The estimates of SMD from fixed effects and random effects were found slightly different indicating that between-study heterogeneity has not influenced the results, Moreover, both the models showed consistent results yielding positive and significant treatment effects. Estimates from random effect model (SMD = 0.288, 95% CI = 0.048–0.529, P = 0.019) and fixed effect model (SMD = 0.271, 95% CI = 0.00134–0.407, P < 0.001) were almost similar. The forest plot provides the visualization of mean difference across studies [Table 3 and Figure 2].

Figure 2

Plaque index standardized mean difference

Table 3

Plaque index considered for data analysis

Study	SMD	SE	95% CI	t	P	Weight (%)
						Fixed	Random
Oliveria S M A et al., 2008	0.38	0.359	−0.354-1.115			3.76	5.58
Pradeep AR et al., 2012[7]	−0.00828	0.255	−0.518-0.502			7.45	7.32
Pradeep AR et al., 2012[7]	0.511	0.259	−0.00770-1.029			7.21	7.24
Pradeep AR et al., 2012[7]	0.986	0.27	0.445-1.527			6.62	7.04
Yeturu S K et al., 2016	−0.409	0.258	−0.925-0.107			7.29	7.27
Pradeep AR et al., 2016[25]	0.722	0.263	0.195-1.249			6.98	7.17
Pradeep AR et al., 2016[25]	0.112	0.255	−0.399-0.622			7.44	7.31
Sahu I et al., 2017	−0.0474	0.255	−0.558-0.463			7.45	7.32
Kurian IG et al., 2018[27]	0.744	0.264	0.216-1.272			6.96	7.16
Kurian IG et al., 2018[27]	1.173	0.276	0.620-1.727			6.33	6.93
Deepu S L et al., 2018	0.0187	0.235	−0.451-0.488			8.73	7.67
Penmetsa G S et al., 2019	−0.147	0.31	−0.776-0.481			5.02	6.35
Kamath NP et al., 2020[29]	0	0.227	−452-0.452			9.38	7.83
Kamath NP et al., 2020[29]	0.0991	0.227	−0.354-0.552			9.37	7.82
Total (fixed effects)	0.271	0.0696	0.134-0.407	3.893	<0.001	100	100
Total (random effects)	0.288	0.123	0.0476-0.529	2.351	0.019	100	100
Test for heterogeneity
Q	39.8501
DF	13
Significance level (P)	0.0001
I2 (%)	67.38
95% CI for I2	42.95-81.35

P<0.05 was considered as significant. SMD – Standardized mean difference; SE – Standard error; CI – Confidence interval; Q – Cochran’s quotient; DF – Degree of freedom; I2 – Inconsistency; t – Student’s t statistics; P – Probability

Aloe vera and gingival index

The descriptive statistics for GI obtained in the studies, along with mean difference and weight of each study in the analysis are shown in Figure 3 and Table 4. The estimates of measures of heterogeneity for GI based on thirteen studies were: I2 = 52.28%, P < 0.016.

Figure 3

Gingival index standardized mean difference

Table 4

Gingival index considered for data analysis

Study	SMD	SE	95% CI	t	P	Weight (%)
						Fixed	Random
Pradeep AR et al., 2012[7]	0.851	0.266	0.318-1.384			16.02	16.46
Pradeep AR et al., 2012[7]	0.377	0.257	−0.138-0.892			17.19	17.03
Pradeep AR et al., 2012[7]	0.339	0.257	−0.175-0.853			17.25	17.05
Yeturu SK et al., 2015	−0.26	0.256	−0.772-0.252			17.36	17.1
Deepu S L et al., 2018	0.0187	0.235	−0.451-0.488			20.53	18.43
Penmetsa GS et al., 2019	0.348	0.312	−0.284-0.980			11.65	13.93
Total (fixed effects)	0.259	0.107	0.0493-0.469	2.429	0.016	100	100
Total (random effects)	0.27	0.155	−0.0354-0.575	1.739	0.083	100	100
Test for heterogeneity
Q	10.4787
DF	5
Significance level (P)	0.0628
I2 (%)	52.28
95% CI for I2	0.00-80.97

P<0.05 was considered as significant. SMD – Standardized mean difference; SE – Standard error; CI – Confidence interval; Q – Cochran’s quotient; DF – Degree of freedom; I2 – Inconsistency; t – Student’s t statistics; P – Probability

No significant heterogeneity was observed with Q = 10.48, P = 0.0686. The standardized effect size, SMD from fixed effects, and random effects were found slightly different and positive. However, one model showed significantly and another model showed nonsignificant treatment effects. Results from random-effect model may be considered more appropriate (SMD = 0.259, 95% CI = 0.049–0.469, P = 0.016, significant) than fixed-effect model (SMD = 0.27, 95% CI = −0.035–0.575, P = 0.0803, not significant). The forest plot provides the visualization of mean differences across studies.

Publication bias

In each of the studies conducted in both the meta-analysis, Begg's funnel plot and Egger's test were both considered for their publication bias [Figures 4 and 5]. Observed symmetrical distribution of the estimates against their standard errors in the funnel plot indicates publication bias is unlikely to be a major issue in this meta-analysis.

Figure 4

Funnel plot for plaque index

Figure 5

Funnel plot for gingival index

DISCUSSION

The present systematic review and meta-analysis aimed to evaluate the efficacy of A. vera in the form of gel, mouthwash, and denitrifies in contrast to different herbal and allopathic products like fluoride-containing triclosan, chlorhexidine, chlorine dioxide, metformin, alendronate, O. sanctum, tea tree oil, ornigreat. Overall, the findings of this study have shown that A. vera is effective in reducing PI and GI.

It is widely acknowledged that effective plaque control is a critical aspect in the prevention and treatment of periodontal disorders.[3132] Although mechanical oral hygiene is the easiest and effective strategy for plaque control, additional local drug delivery systems in adjunct to it is beneficial in inhibiting and reducing gingival plaque formation[323334] A. vera in the form of chip has shown promising results in reducing the periodontal pockets.[17] The present meta-analysis focused on the local application of A. vera for the management of periodontal parameters. This review included the RCTs with nine studies for the PI and four for GI.

In terms of the intervention, the formulation, concentration, and sources of A. vera differed among the research. Moreover one of the studies included three controls,[29] four studies included two control groups[7242627] while four studies had only one follow-up.[23252830] Amongst these studies six studies had placebo as one of its control group,[72526272829] two studies had fluoridated toothpaste as a control group[723] two studies had chlorhexidine as a control group[2429] and the remaining ones had Chlorine dioxide,[24] alendronate gel,[26] metformin,[27] ornigreat[30] and tea tree oil[29] as one of the control groups.

The sorts of formulations utilized for the test as well as the control group differed between studies, such as the use of dentifrice in some.[723] Mouthwash was used in the other two studies[2429] and the rest studies used A. vera in the form of gel.

When compared to fluoridated dentifrice, A. vera seemed to have no additional effects on PI and GI,[23] but when compared to placebo, it showed a superior reduction in both the indices. However, when compared to Chlorhexidine,[2429] it showed much superior and comparable results. Nevertheless, when compared to Alendronate and Metformin, A. vera did not produce improved results.[2627] A. vera when used in contrast to ornigreat, was equally effective.[30]

In the present meta-analysis, we found a significant improvement in the PI amongst the Test group i.e., A. vera group with a mean difference of 0.271 and P < 0.001 and heterogeneity of 67.38%. This may be due to the variation in the sample size, number of control groups, number of follow-up periods and different forms of products used; unlike the other systematic reviews where AL-Maweri et al.[35] compared only one product like chlorhexidine with A. vera mouthwash. Furthermore, the meta-analysis showed a significant reduction in the GI amongst the test group compared to the control group with a mean difference of 0.259 and P = 0.016 and heterogeneity I2 = 52.28%. The trial meta-analysis performed for GI showed heterogeneity of I2 = 95.24%; hence, two of the studies were excluded Vangipuram S et al. 2016, Kamath N. P et al. 2019 and the analysis was reperformed for GI.

The study's overall findings demonstrated that A. vera may be utilized to successfully reduce PI and GI, improve overall oral hygiene, and hence aid in the prevention of periodontal diseases.

CONCLUSION

Although different adjunctive products like chlorhexidine show standard results in improving the periodontal parameters, A. vera shows promising results in reducing plaque and GI scores, without reported side effects. Results from our meta-analyses confirmed the beneficial effects of A. vera in improving the periodontal parameters and hence may be considered as a safe alternative drug delivery agent for the management of periodontal diseases in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.