The Effect of Carica Papaya on Periodontal Disease: A Systematic Review and Meta-Analysis

Abstract

Background:

The aim of the present systematic review and meta-analysis was to investigate the effect of Carica papaya on periodontal disease in the adult population.

Materials and Methods:

A systematic search was performed using the PubMed, Web of Science, Embase, and Cochrane library databases up to June 2021 using related keywords for randomized clinical trials that evaluated the effect of Carica papaya on gingival index (GI), plaque index (PI), and papilla bleeding index (PBI) in the intervention group compared to control group.

Results:

A total of five eligible studies involving 206 participants were included in the systematic review and meta-analysis. GI score significantly decreased in the intervention group at the end of the treatment compared to the baseline (ES = −0.64; 95% CI = −0.85–−0.42; I² = 90.4%; P < 0.001). Furthermore, patients in the intervention group had significantly lower GI (weighted mean difference = −0.28; 95% CI = −0.45–−0.10; I² = 98.2%; P < 0.001) and PI (weighted mean difference = −0.36; 95% CI = −0.59–−0.14; I² = 99.3; P < 0.001) scores compared with control individuals. However, no significant difference observed between the two groups regarding PBI score.

Conclusion:

Despite study limitations, this systematic review and meta-analysis highlighted the effective role of oral care products containing Carica papaya for the treatment of periodontal diseases by improving indices like GI and PI.

INTRODUCTION

Periodontal disease is a prevalent chronic inflammatory disease affecting gingiva, bone, and ligament surrounding the teeth as a consequence of complex interactions between microbiome and host inflammatory response.[1] Multiple risk factors such as genetic susceptibility and environmental or acquired conditions such as smoking and diabetes mellitus have been proposed to increase periodontal disease risk.[2] The prevalence of the periodontal disease has been reported to be between 2% to 76% in the adult population around the globe.[3] The periodontal disease initially presents as gingivitis which is caused by bacteria in dental plaque. If left untreated, gingivitis may progress to periodontitis which is a chronic inflammatory state of the disease.[4] A significant association has been found between chronic periodontal disease and chronic diseases such as diabetes mellitus and cardiovascular disease.[5,6] It is also known that periodontal disease negatively affects both health-related quality of life (HRQOL) and oral HRQOL in the adult population.[7,8] Therefore, periodontal disease is a major public health problem, and its early diagnosis and treatment are of great importance.

The main goal of periodontal disease management is to reduce the bacterial load and prevent the progression of the disease.[9] Therapeutic options include mechanical plaque and calculus removal through scaling and root planning (SRP) as well as maintaining oral hygiene.[10] However, SRP does not always lead to desirable clinical outcomes in all patients, mainly because of the difficulty to access deep periodontal pockets.[11] Thus, various adjunctive treatments such as antibiotics, photodynamic treatment, and antiseptics have been proposed to prevent bacterial recolonization and improve periodontal treatment outcomes, particularly in patients with suboptimal responses to traditional treatment modalities.[12,13,14] However, treatment-related adverse events such as antibiotic resistance, allergic reactions, and discoloration of teeth limit some adjunct treatments application.[15] As a result, recently, the use of natural compounds and their analogs has received much attention for the treatment of periodontal disease.

Carica papaya, usually known as papaya, is one of the most popular species of the Caricaceae family cultivated in tropical and subtropical countries. Extracts derived from different parts of the papaya plant such as leaves and seeds are used in the treatment of a wide range of diseases in traditional medicine.[16] The anti-inflammatory effect of Carica papaya has also been suggested in previous research.[16,17,18] Recent experimental and interventional studies have investigated the therapeutic effect of Carica papaya on periodontal disease. Animal studies have found that the alcoholic extract of papaya seeds promotes the healing of periodontal tissues by increasing the number of osteoclasts or anti-inflammatory processes.[19,20,21] Additionally, several human interventional studies have investigated the effect of chemical anti-plaque products containing Carica papaya on various dental indices in patients with periodontal disease.[22,23,24,25] However, to the best of our knowledge, no previous systematic review and meta-analysis have been reported on the effect of Carica papaya on periodontal disease. The aim of the present systematic review and meta-analysis was to investigate the therapeutic influence of Carica papaya on gingivitis and periodontitis indices.

METHODS

The review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline (PRISMA). The protocol of the study was also registered at Prospero (CRD42023432984).

Search strategy

The systematic search was conducted with no time or language restrictions in the PubMed, Web of Science, Embase, and Cochrane library databases up to June 2021. Furthermore, a manual search of eligible studies’ reference list was performed to find additional publications. The search processes were performed by two independent researchers (Z.S and Z.S) and were supervised by the principal investigator (Z.G). The combinations of keywords used in the systematic search strategy were outlined as follow: Gingivitis OR Periodontitis OR “Gingival index” OR “plaque index” OR “dental plaque” OR “gingival bleeding” OR “Tooth plaque” OR “Gingival enlargement” OR “Gingival Overgrowth” OR “Gingival Hemorrhage” OR “gingiva bleeding” OR “papillary bleeding index” OR “interdental gingival bleeding” OR “supragingival plaque index” OR “subgingival plaque index” OR “infragingival plaque index” AND Carica OR papaya OR Pawpaw OR papaw OR asimina AND Effect* OR reduc* OR therap* OR treatment OR healing OR decrease OR inhibit.

Eligibility criteria

An investigation was considered eligible if met the following criteria (1) was a randomized clinical trial; (2) evaluated chemical anti-plaque products containing Carica papaya as the exposure; (3) evaluated gingival index (GI), plaque index (PI), or papilla bleeding index in the intervention group compared with placebo and non-placebo control group as the outcome of interest. Experimental studies, case-reports, editorials, letters, commentaries, conference presentations, and reviews were excluded.

Data extraction and quality assessment

The following data were extracted from each eligible study by two independent researchers (Z.S and Z.S) using a pre-designed form: first author, study design, study location, sample size, sample sex, sample age, intervention duration, control group, and type of Carica papaya-containing oral care product. Any discrepancy was resolved through discussion with the principle investigator.

The quality assessment was conducted using 25-item comprehensive recommended guidelines of the Consolidated Standards of Reporting Trial (CONSORT) checklist by two independent researchers and any discrepancies resolved by a third reviewer.[26] The quality of included studies graded as poor (<25%), moderate (25–50%), good (50–75%), and high (>75%).

Statistical analysis

To conduct statistical analysis, the STATA software package (version 14, STATA inc., College Station, TX, USA) was applied. The standardized mean difference (SMD) and attributed 95% confidence intervals (95% CIs) were calculated. To calculate combined SMD with 95% CI, the random effect model was adopted. Heterogeneity was assessed by the Cochran Q test and a P value < 0.05 indicated as heterogeneity. Additionally, the degree of heterogeneity was quantified by the I² statistic. To evaluate the source of heterogeneity, subgroup analysis and sensitivity analysis were used. Publication bias was assessed by visual inspection of funnel plot, Egger’s, and Begg’s tests. Sensitivity analysis was performed in order to determine the effect of each study or a specific group of studies on the total effect.

RESULTS

Characteristics of included studies

The initial search yielded 347 publications. Following the screening of searched articles’ titles and abstracts, duplicates (n = 27) and irrelevant articles (n = 311) were excluded. The full text of the remaining articles (n = 9) was evaluated for eligibility. Finally, five randomized clinical trials involving 206 participants were included in the systematic review and meta-analyses[23,24,27,28,29] [Figure 1], and four experimental studies were excluded.[19,20,21,30]

Figure 1.

Flow diagram of search strategy and study selection

The characteristics of the included RCTs in the systematic review and meta-analysis are summarized in Table 1. Eligible studies were performed between 2016 and 2021. They were conducted in Russia (n = 1),[24] India (n = 2),[23,27] and Indonesia (n = 2).[28,29] The sample size of included studies ranged from 20 to 84. The Carica papaya-containing oral care products were used as the primary treatment in two studies[28,29]; however, they were used as adjunct treatment in three other studies.[23,24,27] Additionally, the intervention duration ranged from 5 to 30 days. Based on the CONSORT checklist of quality assessment, two studies showed high quality[23,27]; however, three studies showed good quality.[24]

Table 1.

Basic characteristics of eligible studies

Author		Year		Country		Study design		Population		Sample size				Samples traits				Intervention duration (days)		Intervention		Controls		Outcome measures		Quality
										Intervention		Control		Age (year)		Males (%)
Rangaraju. VM		2021		India		Randomized clinical trial		Subjects with oral malodor score ≥3		20		10		NR		NR		14		Carica papaya-containing mouthwash/scaling		Carica papaya-containing mouthwash in healthy subjects with oral malodor score ≥3/scaling		Gingival index/Papillary bleeding index		Excellent
Tadikonda. A		2017		India		Randomized clinical trial		Subjects with orthodontic therapy		26		26		18–24		35.6		30		Carica papaya-containing toothpaste/fixed orthodontic therapy		Standard fluoride toothpaste/fixed orthodontic therapy		Gingival index/Plaque index		Excellent
Ardyanti. R		2017		Indonesia		Randomized clinical trial		Subjects with Moderate Gingivitis		10		10		19–24		NR		5		Carica papaya-containing mouthwash		Chlorhexidine 0.2%		Gingival index		Good
Kharaeva. ZF		2016		Russia		Randomized clinical trial		Subjects with chronic moderate-to-severe Periodontitis subjects		39		45		38–62		46.4		10		Fermented papaya gel and conventional periodontal treatment		Conventional periodontal treatment		Gingival index/Plaque index/Gingival bleeding		good
Rohman. N		2016		Indonesia		Randomized clinical trial		Subjects with gingivitis		10		10		NR		NR		15		Carica papaya-containing mouthwash		Chlorhexidine 0.2%		Gingival index		Good

Changes of GI score in the intervention group

The changes in GI scores between the baseline and the end of the intervention in the treatment group ranged between −0.40 and −1.02. Combining six effect sizes from five studies revealed a statistically significant decrease in GI score in the treatment group (ES = −0.64; 95% CI = −0.85–−0.42) [Figure 2]. However, a between-study heterogeneity was observed (I² = 90.4%; P < 0.001). To discover the source of heterogeneity, subgroup analysis based on the type of treatment (adjuvant versus primary treatment) was performed. The use of Carica papaya as an adjunctive treatment caused a significant decrease in the GI score in the treatment group (ES = −0.75; 95% CI = −0.99–−0.51). The application of Carica papaya as a primary treatment also caused a significant decrease of 0.42 (95% CI = −0.53–−0.30) in the GI score in the treatment group [Figure 3]. The heterogeneity was totally removed in studies where Carica papaya was used as the main treatment (I² = 0.0%; P = 0.74). However, the heterogeneity remained significant in studies with Carica papaya adjuvant treatment (I² = 88.3%; P < 0.001). Additional subgroup analyses were performed for the type of Carica papaya-containing product (mouthwash, toothpaste, and gel) that has been used for treatment, and results are presented in Figure 4. Stratified analysis based on the type of Carica papaya-containing product indicated a statistically significant decrease of GI score in studies that used Carica papaya-containing mouthwash solution for the treatment (ES = −0.52, 95% CI = −0.68–−0.36; I² = 65.0, P = 0.036). A statistically significant decrease of 0.63 (95% CI = −0.76–−0.50) and 1.02 (95% CI = −1.15–−0.89) in the GI score was also observed, respectively, in studies that used Carica papaya-containing toothpaste and gel. A meta-regression analysis was also performed to explore the effect of treatment duration on GI score changes in the intervention group. Our results showed that treatment duration had no influence on GI score changes in the intervention group (regression coefficient = −0.01; P = 0.052; I² _residual = 67.77%) [Supplementary Figure 1 ^{(1.2MB, tif)} a]. The visual inspection of the funnel plot, as well as Begg’s (P = 1.00) and Egger’s (P = 0.53) tests, showed no evidence of publication bias [Supplementary Figure 1 ^{(1.2MB, tif)} b]. Furthermore, sensitivity analysis indicated that removing each included study at a time had no significant effect on the overall estimate [Supplementary Figure 1 ^{(1.2MB, tif)} c].

Figure 2.

Forest plot of GI score changes in the intervention group

Figure 3.

Forest plots of GI score changes in the intervention group, stratified by the type of intervention (primary versus adjunct)

Figure 4.

Forest plots of GI score changes in the intervention group, stratified by the type of Carica papaya-containing oral care product

Comparison of GI score between the intervention and control group patients

The meta-analysis on the mean difference of GI scores between individuals in the intervention group and those in the control group was conducted on four effect sizes from three studies. Our results showed that patients in the intervention group had significantly lower GI scores compared with control individuals (weighted mean difference = −0.28; 95% CI = −0.45–−0.10) [Figure 5]. There was a significant heterogeneity between studies (I² = 98.2%; P < 0.001). The results of the meta-regression test revealed that treatment duration had no influence on the mean difference of GI score between the two groups (regression coefficient = −0.009; P = 0.284; I²_residual = 29.86%) [Supplementary Figure 2 ^{(625.5KB, tif)} a]. No difference in the estimated mean difference of GI score was observed by excluding each included RCT in the sensitivity analysis [Supplementary Figure 2 ^{(625.5KB, tif)} b]. Given the limited number of effect sizes, no test for publication bias was performed.

Figure 5.

Forest plot of GI score comparison between intervention and control groups

The meta-analysis on the mean difference of GI score between individuals in the intervention group and chlorhexidine-treated controls was conducted on two effect sizes from two studies. According to our findings, there was no significant mean difference of GI scores between patients treated with Carica papaya and those treated with chlorhexidine (weighted mean difference = 0.30; 95% CI = −1.33–1.93; I² = 83.8; P = 0.013) [Figure 6].

Figure 6.

Forest plot of GI score comparison between intervention group and chlorhexidine control group

Comparison of PI score between the intervention and control group patients

The combination of two effect sizes from two studies showed that patients in the intervention group had a significantly lower PI score compared to controls (weighted mean difference = −0.36; 95% CI = −0.59–−0.14; I² = 99.3; P < 0.001) [Supplementary Figure 3 ^{(610KB, tif)} ].

Comparison of PBI score between the intervention and control group patients

The combination of two effect sizes from two studies indicated that patients in the intervention group had a non-significant lower PBI score compared to controls (weighted mean difference = −0.43; 95% CI = −0.96–0.10; I² = 99.3; P < 0.001) [Supplementary Figure 4 ^{(592.3KB, tif)} ].

DISCUSSION

To the best of our knowledge, this is the first systematic review and meta-analysis to investigate the effect of Carica papaya on periodontal disease. The current meta-analysis showed that the use of Carica papaya as a chemical plaque control agent in different oral healthcare products reduces the GI score significantly. Additionally, by comparing the GI score between the intervention and control groups, it was found that the GI score was significantly lower in the treatment group compared to the control group. However, no significant difference was found between the two groups in terms of PBI scores, which possibly can be explained by differences in the design of included studies, such as the studied population and type of oral health care product containing Carica papaya. This finding demonstrates the probable potency of Carica papaya for the treatment of gingival inflammation, which can mediate the progression of periodontal disease. No significant mean difference in GI scores was found between patients treated with Carica papaya and those treated with chlorhexidine. Chlorhexidine is a broad-spectrum anti-microbial agent that is considered the gold standard for chemical plaque control.[28,29,31] However, the use of chlorhexidine is associated with some adverse effects such as tooth staining, dry mouth, modified taste sensation, and oral mucosal desquamation.[32] Thus, finding alternative treatment strategies with fewer side effects is particularly important. Few studies with small sample sizes and short follow-up durations compare the therapeutic efficacy of Carica papaya and chlorhexidine on gingival inflammation, with controversial results.[28,29] The difference in the results of these studies can be due to the difference in the part of the plant from which the Carica papaya extract is prepared or the percentage of the extract used in the mouthwash solution. Therefore, more studies are needed to compare the therapeutic effect of Carica papaya with chlorhexidine on periodontal disease. The results of the present study also indicated that Carica papaya is effective in plaque control as a principal step in the treatment of periodontal disease. The PI score was significantly lower in patients treated with oral health products containing Carica papaya compared to controls.

The beneficial effect of Carica papaya on periodontal disease can be explained by several plausible mechanisms. Inflammation caused by oxidative stress is one of the proposed mechanisms that cause periodontal disease. Oxidative stress, defined as an imbalance between free reactive oxygen species (ROS) production and the antioxidant defense, can cause tissue destruction and damage to cells through lipid peroxidation and protein deactivation.[33,34] Furthermore, ROS can cause inflammation and cell death by activating inflammatory pathways such as NF-kb and JNK.[35] The anti-inflammatory and antioxidant effects of compounds such as vitamin C and phytochemicals found in different parts of the Carica papaya plant are probably one of the mechanisms through which this plant improves gingival inflammation and prevents the development of the disease.[36,37] Previous research has reported dental plaque as an important factor in the pathophysiology of periodontal disease. Antibacterial properties of phytochemical extracts of roots, leaves, and flowers of Carica papaya have been reported in previous studies.[38,39,40] However, further in vitro and in vivo research is required to detect the role of Carica papaya on bacterial profiles of periodontal disease.

The present study has some limitations that should be addressed. Firstly, a limited number of RCTs have examined the effect of Carica papaya on the indices of periodontal disease. Thus, larger-scale prospective population-based studies and RCTs are required to obtain robust findings on the favorable effect of Carica papaya on periodontal disease. Secondly, studies have been conducted in a limited number of countries, including India, Indonesia, and Russia, which limited the generalizability of our results to other populations. Finally, there were differences between the included studies regarding the type of health products containing Carica papaya, the type of treatment (main or adjuvant), and the control group. However, to the best of our knowledge, this is the first meta-analysis that investigated the effect of Carica papaya on periodontal disease. In summary, the results of the present systematic review and meta-analysis indicated that using Carica papaya in oral care products possibly improves gingival and periodontal indices. Further, well-designed RCTs and large-scale studies are required to confirm this finding.

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of Isfahan University of Medical Sciences.

Data availability

The data that support the findings of the present study are available from the corresponding author upon request.

Conflicts of interest

There are no conflicts of interest.

Supplementary Figure 1

(a) Meta-regression plot of GI score changes in the intervention group and follow-up duration. (b) Funnel plot for publication bias of GI score changes in the intervention group. (c) Sensitive analysis of GI score changes in the intervention group

Supplementary Figure 2

(a) Meta-regression plot of GI score difference between intervention and control group and follow-up duration. (b) Sensitive analysis of GI score difference between intervention and control group

Supplementary Figure 3

Forest plot of PI comparison between intervention and control groups

Supplementary Figure 4

Forest plot of PBI comparison between intervention and control groups

Funding Statement

The financial support for conception, design, data analysis, and manuscript drafting comes from Isfahan University of Medical Sciences, Isfahan, Iran.