Efficacy of melatonin supplementation in the treatment of periodontitis: a systematic review and meta-analysis

Efficacy of melatonin supplementation in the treatment of periodontitis: a systematic review and meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Efficacy of melatonin supplementation in the treatment of periodontitis: a systematic review and meta-analysis Yuexiang Zhen, Hui Yue, Yiting Xiao, Qin Liu, Meilin Zhao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-376485/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background: The aim of this systematic review and meta-analysis was to analyze the additive effects of the melatonin supplementation with nonsurgical periodontal therapy (NSPT) on periodontal status in patients affected by chronic periodontitis. Methods: In December 2020, We searched PubMed, EMBASE, Web of Science, CENTRAL databases and Google Scholar databases. Four RCTs were recruited with the same inclusion criteria. PD and CAL were the primary outcome measures. Subgroup analyses were performed according to health statuses and follow-up times, and Cochran’s Q and I-square ( I 2 ) tests were used to assess heterogeneity. Results: This review included four RCTs. Four studies reported probing depth (PD) and 3 studies reported clinical attachment loss (CAL). Compared with the placebo groups, the melatonin groups showed a significant reduction in PD (weighted mean difference [WMD], -1.01; 95% confidence intervals [CI], -1.67 to -0.35; I 2 = 76%) and CAL (WMD, -1.08; 95% CI: -1.36 to -0.79, I 2 = 0%). Subgroup analyses revealed that the use of systemic melatonin + NSPT significantly reduced PD and CAL at the 2-, 3-, and 6-month follow-ups compared to NSPT alone, and stronger treatment effects of reducing PD were observed at shorter follow-ups than at longer follow-ups when adjunctive systemic melatonin was used. Conclusions: Melatonin supplementation in adjunct with nonsurgical periodontal therapy can moderately improve the efficacy of NSPT in reducing PD and greater CAL gain in patients with periodontitis. With the limited evidence available, it is evident that additional good quality RCTs are required to demonstrate additional beneficial effects of oral melatonin supplementation on periodontal clinical parameters after NSPT. General Biochemistry Dentistry Periodontitis Melatonin Nonsurgical periodontal therapy Meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background Chronic periodontitis (CP) is an inflammatory disease mainly caused by subgingival microbial plaque and characterized by the destruction of tooth-supporting tissues [ 1 , 2 ]. The damage to periodontal tissue is related to the production of certain harmful substances, including pro-inflammatory cytokines, free radicals, reactive oxygen species and reactive nitrogen, some of which are directly produced by periodontal bacteria and others of which are produced by the host immune response to dysbiotic microbial presence [ 3 , 4 ]. The release of these products is largely sustained, driving the progressive loss of connective tissue attachment and alveolar bone and even tooth loss if not treated promptly [ 3 , 5 ]. Nonsurgical periodontal therapy (NSPT), a standard treatment for periodontitis, mainly includes professional oral hygiene instructions (OHI) and full-mouth subgingival scaling and root planing (SRP), which mechanically removes dental plaque and calculus on the root surface. However, the limitations of inaccessible periodontal defects [ 6 ] and poor host inflammatory-immune response [ 7 ] can influence the effectiveness of periodontal healing. Although NSPT can successfully suppress the progression of inflammation and prevent progressive bone loss in some cases, the ability of the periodontium to their return to original form and function is still limited. Regarding these issues, periodontal clinicians have considered the use of host modulatory agents as adjuvant therapies to modulate the host immune response and boost the regeneration of periodontal tissue [ 8 , 9 ]. Host modulatory agents can affect the host immune response through different pharmacological mechanisms [ 4 , 9 ]. For example, tetracycline antibiotics inhibit the synthesis of matrix metalloproteinase [ 10 ], nonsteroidal anti-inflammatory drugs inhibit the release of pro-inflammatory cytokines and prostaglandins [ 11 ]. and bone-sparing agents block the expression of osteoclasts [ 12 , 13 ]. However, these drugs may cause resistance, opportunistic infections, and other side effects [ 14 , 15 ]. Melatonin (N-acetyl-5-methoxy-tryptamine) is an important hormone that is mainly secreted by the pineal gland and is associated with the circadian rhythm [ 16 , 17 ]. Melatonin can be correlated with the development and severity of periodontitis [ 18 ]. Previous studies have shown that the level of melatonin in plasma and saliva is significantly decreased in patients with periodontitis compared to healthy patients [ 19 , 20 ]. Melatonin can be used as a dietary supplement or as a prescription drug in different countries [ 4 ]. Melatonin possesses a wide spectrum of essential properties, such as anti-inflammatory, immunomodulatory [ 21 , 22 ] and antioxidant effects [ 22 , 23 ], free radical scavenging; bone metabolism regulation [ 24 ], As such, melatonin could be used as a novel host modulatory agent to modulate the host response in patients with destructive periodontitis [ 25 ]. Therefore, research on melatonin supplementation after NSPT in the treatment of periodontal disease has attracted the attention of clinicians. Currently, some publications have reported that systemic melatonin after NSPT in patients with periodontitis has advantages in reducing probing depth (PD) and clinical attachment loss (CAL) compared with NSPT alone [ 26 , 27 ]. However, other studies have noted no significant difference in the results of the clinical outcomes for NSPT combined with melatonin supplementation compared with NSPT alone [ 28 ]. This uncertain evidence is not conducive to the clinical application or promotion of melatonin in patients with periodontitis. To the best of our knowledge, there is no systematic review or meta-analysis of RCTs evaluating the effects of NSPT combined with melatonin on clinical outcomes in patients with periodontitis. Therefore, the primary purpose of this study was to summarize the available evidence and determine the effects of melatonin supplementation in combination with NSPT on clinical outcomes in patients with periodontitis. Methods Guidelines We conducted this study following the guidelines of the Transparent Reporting of Systematic Reviews and Meta-Analyses (PRISMA) statement [ 29 ]. Search plan We comprehensively searched the PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) databases for relevant articles published before April 2020 in the English language. We used the following terms (MeSH) and free text keywords: population [“periodontal disease” OR “chronic periodontitis”], intervention [“periodontal therapy” OR “periodontal debridement” OR “nonsurgical periodontal debridement” AND “melatonin”]. We also manually checked the reference lists of selected studies to identify any possible eligible citations. The detailed search strategy is illustrated in supplementary Table S1. Two investigators (YX.Z and H.Y.) independently conducted the study screening process. We deleted duplicate publications and excluded those that were ineligible by reviewing titles and abstracts. Finally, we read the full text carefully to identify eligible studies. Any disagreement during the study selection process was settled by discussion. To identify additional publications, we manually searched the reference lists of the included studies. We did not contact the original authors for further information. Inclusion and exclusion criteria We included RCTs with no minimum duration that evaluated the effects of systemic melatonin adjunctive to NSPT compared with NSPT plus a placebo or alone in patients with periodontitis. The primary outcome measures were PD and CAL. The secondary outcome measure was the occurrence of adverse effects related to melatonin administration.We excluded case reports, animal studies, and studies that used local melatonin delivery adjunctive to NSPT. In addition, we also excluded studies that used systemic melatonin with other concomitant oral medications. Data extraction Two investigators (ML.Z. and YX.Z.) independently collected and extracted the following data: first author’s name, publication date, study location, study design, participants’ characteristics, total sample size and dropouts, intervention (the treatment conditions of NSPT; dose, usage of melatonin, and duration of treatment), type of systematic disease, periodontitis definition, study duration, outcome measures, and sponsor. Disagreements regarding extracted information between the two reviewers were settled by discussion. Quality assessment Two investigators (Q.L. and YT.X.) individually performed the quality assessment of included trials based on the Cochrane Collaboration’s tool [ 30 ]. The third reviewer resolved any disagreements regarding the study quality assessment. The methodological quality included the following criteria: randomization generation, and allocation concealment; blinding of participants, personnel and examiners; outcome assessment; incomplete outcome data; selective outcome reporting; and other sources of bias. Overall, the risk of study bias was categorized as follows: 1) low risk of bias: there was a “low” risk answer for all domains; 2) moderate risk of bias: there was an “unclear” risk answer for one or more domains; 3) high risk of bias: there was a “high” risk answer for one or more domains. Statistical analysis Two investigators (Q.L. and H.Y.) determined the effects of NSPT plus melatonin supplementation and NSPT alone on periodontal parameter variables in patients with CP. Trial outcome data were pooled into weighted mean differences (WMDs) with 95% confidence intervals (CIs) using RevMan 5.3 software (Cochrane Collaboration). Heterogeneity among studies was estimated using the Cochran (Q) and I-square tests (I 2 ). P 50% indicated substantial heterogeneity. Otherwise, when P ≥ 0.1 and I 2 ≤ 50%, heterogeneity was acceptable [ 30 ]. We used a random-effects model for our meta-analysis. Owing to the small number of included studies, the assessment of publication bias by using a funnel plot was not evaluated [ 30 ]. Results Literature search A total of 151 potentially eligible publications were identified from the electronic databases search. Ninety-eight studies were screened after duplicate removal. The full texts of 10 studies were retrieved according to the established inclusion criteria. Ultimately, four studies [ 25 – 28 ] were finally considered eligible for inclusion in this review (Fig. 1 ). Characteristics of the included studies The detailed information of the included studies for the intervention and placebo groups is summarized in Table 1 , Table 2 and Table S2. Overall, four included RCTs [ 25 – 28 ] reported 198 patients who presented mild to severe CP. The investigators of four studies identified CP as involving at least one site with a PD of 4 millimetres or greater. The investigators of three studies provided the CAL threshold value in the definition of CP [ 28 ], while one study did not report CAL values or bone loss [ 28 ]. The investigators of two studies [ 25 , 28 ] recruited systematically healthy patients with CP. The remaining two studies recruited patients with comorbidities, one study recruited patients with primary insomnia [ 27 ], and the other study recruited patients with type 2 diabetes mellitus (DM) [ 26 ]. The dose of melatonin varied from 1 to 10 mg/day. The participants of two included studies received systemic melatonin for two months [ 26 – 28 ], while the participants of the other two studies received systemic melatonin for one month [ 25 ]. Tinto and colleagues [ 25 ] reported that SRP was performed in one-session in the full mouth under local anaesthesia and it took nearly 45 minutes per quadrant. EI-Sharkawy and colleagues [ 27 ] only reported SRP over two separate visits, but the investigators of three studies did not define SRP in detail [ 26 – 28 ]. The participants of 2 included studies did not receive local antimicrobials after SRP [ 26 , 28 ], but EI-Sharkawy [ 27 ] and Tinto [ 25 ] combined antimicrobial treatment with a 0.12% and 0.20% chlorhexidine rinse twice a day for two weeks for study participants after SRP, respectively. Table 1 Characteristics of the included studies Author year, country Country Study design Sample size (no. dropouts) Mean age or range (y) Smokers Other systemic condition Periodontitis definition (mm)/clinical examination Duration (mo) Sponsor Chitsazi et al. 2017 [ 28 ], Iran Iran RCT parallel design 60 (0) 23–65 No No Moderate to severe CP, PD ≥ 5 UNC-15 probe 3, 6 Tabriz University Dental and Periodontal Research Center El-Sharkawy et al. 2019 [ 27 ], Egypt Egypt RCT parallel design 80 (6) 38–55 No primary insomnia ≥ 20 teeth, moderate to severe CP, PD ≥ 5 and radiographic CAL ≥ 4 at least three sites in each quadrant Probe not reported 3, 6 No Bazyar et al. 2018 [ 26 ], Iran Iran RCT parallel design 50 (6) T: 53.72 ± 6.68 C: 51.45 ± 5.03 No type 2 Diabetes mellitus Mild and moderate CP, PD ≥ 4 and CAL = 1–4 UNC-15 probe 2 No Tinto et al. 2019 [ 25 ], Italy Italy RCT parallel design 20 (0) 30–70 No No Severe CP, CAL ≥ 5, ≥ 20 teeth, PD ≥ 6 Probe not reported 6 Periodontal Unit of Santa Apollonia Dental Center RCT Randomized controlled trial, T Test group, C Control group, PD probing depth, CAL clinical attachment loss, mm millimetre, mo months, CP chronic periodontitis Table 2 Participants, interventions, outcomes and results Author, year, country Participants Groups Interventions Outcome variables/adverse effects Results NSPT Drug usage and dosage Chitsazi et al. 2017 [ 28 ], Iran T : N = 40 C : N = 40 31 females, 29 males T: NSPT + melatonin C: NSPT OHI + SRP 2 mg melatonin a day for 1 mo PD, CAL None T VS. C in PD and CAL scores: P > 0.05 El-Sharkawy et al. 2019 [ 27 ], Egypt T: N = 38 C: N = 36 33 females, 41 males T: NSPT + melatonin capsule C: NSPT + Placebo OHI + two-session SRP + 0.12% chlorhexidine rinse for 2 weeks 10 mg melatonin once per day 1 hour before bedtime for 2 mo CAL, PD Cases of headache, dizziness,nausea, constipation, diarrhea,and abdominal cramp ≤ 2 T VS. C in PD and CAL: P < 0.01 Bazyar et al. 2018 [ 26 ], Iran T: N = 22 C: N = 22 30 females, 14 males T: NSPT + melatonin tablets C: NSPT + placebo OHI + SRP 3 mg melatonin once a day 1 hour before bedtime for 2 mo PD, CAL None T VS. C PD and CAL P < 0.01 Tinto et al. 2019 [ 25 ], Italy T: N = 10 C: N = 10 8 females, 12 males T: NSPT + melatonin tablets C: NSPT + placebo OHI + one-session SRP (1 quadrant per 45 minutes with local anesthesia) + 0.20% chlorhexidine rinse for 2 weeks 1 mg melatonin once a day at bedtime for 1 mo PD T: 20% sleepiness and 10% headache T VS. C in PD: P > 0.05 T test group, C control group, NSPT non-surgical periodontal therapy, PD probing depth, CAL clinical attachment loss, mo months, OHI oral hygiene instructions, SRP scaling and root planing Quality assessment of selected studies Of the four included RCTs, three had a low risk of bias [ 25 – 27 ], and one exhibited a moderate risk of bias [ 28 ]. The risk of bias quality assessments of the included RCTs is presented in Table 3 . All included studies received a “yes” answer for aspects of randomized sequence generation, allocation concealment, blinding of participants and personnel, complete data, and other bias. The risk answer was assigned because the blinding of allocation for the participants was not described. Overall, the quality of studies was considered moderate in 1 RCT and high in 3 RCTs. Table 3 Risk of quality assessment of the selected studies Author year, country Random sequence generation Allocation concealment Blinding of participants and personnel Blinding of outcome Incomplete outcome data Selective reporting Other biases Overall risk of bias Chitsazi et al. 2017 [ 28 ], Iran low unclear low low low low low moderate EI-Sharkawy et al. 2019 [ 27 ], Egypt low low low low low low low low Bazyar et al. 2018 [ 26 ], Iran low low low low low low low low Tinto et al. 2019 [ 25 ], Italy low low low low low low low low The primary outcomes The investigators of the four included studies reported PD [ 25 – 28 ] between baseline and follow-up visits, and the investigators of three studies reported CAL [ 26 – 28 ]. Overall, there were significant differences in reducing PD (WMD, -1.01; 95% CI, -1.67 to -0.35; I 2 = 76%) and CAL (WMD, -1.08; 95% CI: -1.36 to -0.79, I 2 = 0%), as presented in Fig. 2 and Fig. 3 . There was substantial heterogeneity in PD (I 2 = 76%) among the studies. Secondary outcome measures One study [ 25 ] mentioned that, in the melatonin group, two patients reported sleepiness, and one patient reported headache. One trial [ 27 ] reported cases of headache, dizziness, nausea, and gastrointestinal reaction that were less than or equal to two in number. The other two trials did not report adverse effects [ 26 , 28 ]. Subgroup analyses The findings of the subgroup analysis by health status demonstrated that the systemic melatonin adjunctive to NSPT group showed a significant difference in PD compared with the NSPT alone group with respect to patients with comorbidities (WMD, -1.01; 95% CI, -1.61 to -0.35; I 2 = 72%) and systemically healthy patients (WMD, -0.77; 95% CI, -1.91 to -0.36; I 2 = 88%) (Fig. 5 ). However, high degrees of heterogeneity were observed between studies. We also performed a subgroup analysis by follow-up period for CAL and found that melatonin supplementation after NSPT resulted in significantly less CAL at the 2- (WMD, -1.18; 95% CI, -1.56 to -0.80), 3- (WMD, -0.83; 95% CI, -1.23 to -0.43), and 6-month (WMD, -0.94; 95% CI, -1.38 to -0.51) visits than NSPT alone (Fig. 6 ). The subgroup analysis for CAL showed a low heterogeneity. Discussion Due to its antioxidant and anti-inflammatory properties, and modulatory effects on bone formation, periodontal practitioners have begun to consider the use of melatonin supplementation as an adjunctive therapeutic option with NSPT in the treatment of periodontitis [ 4 ]. However, some previous publications have reported that the effects of systemic melatonin on clinical periodontal parameters are controversial in patients with periodontitis [ 25 – 28 ]. This meta-analysis demonstrated that the use of systemic melatonin + NSPT showed modest additional benefits in reducing PD by 1.12 mm and in decreasing CAL by 1.02 mm compared to NSPT + a placebo or alone. The findings of the subgroup analysis also suggested stronger treatment effects of PD reduction in shorter follow-up periods than in longer follow-up periods when adjunctive systemic melatonin was used. It is worth noting that melatonin has a wide safety margin, but systemic melatonin may have some side effects, such as sleepiness and headache [ 25 , 27 ]. Thus, when using systemic melatonin, periodontal clinicians should consider its potentially undesired side effects. PD reduction and CAL gain are often considered clinical indicators of the successful treatment of periodontitis [ 31 ]. This systematic review and meta-analysis demonstrated that, compared with NSPT alone, the use of systemic melatonin + NSPT significantly reduced PD and CAL. Over the years, studies have demonstrated that the biological mechanisms of melatonin on the ability of periodontal healing could be attributed to the following. First, the intrinsic anti-inflammatory and antioxidant properties of melatonin can promote the early healing of periodontal tissue [ 32 ]. Studies have shown that melatonin can reduce highly destructive free radicals and oxygen and nitrogen reactive substances that cause oxidative damage to periodontal tissues, increase the antioxidant capacity of the host and depress pro-inflammatory cytokine production [ 21 , 33 ], thus reducing the adverse effects of the host’s immune system on periodontal tissues. On the other hand, melatonin plays an important role in regulating bone tissue formation and bone loss. Melatonin can effectively suppress the receptor activator of the nuclear factor-kappa B ligand/osteoprotegerin (RANKL/OPG) signalling pathway, which is activated by osteoclast receptors, potentially suppressing the progression of alveolar bone loss [ 34 ]. Melatonin can promote osteoblastic differentiation and stimulate the synthesis of new bone matrix [ 24 ], which is manifested in the improvement of new attachment generation. Additionally, melatonin exerts a direct antimicrobial effect on some periodontal cariogenic bacteria, potentially reducing the inflammatory response of periodontal tissue [ 35 ]. These mechanisms provide possible evidence for the potential therapeutic effect of melatonin on the healing of periodontal soft and hard tissues in patients with periodontitis. In the present study, the overall meta-analysis showed considerable heterogeneity across studies (PD, I 2 = 76.0%). The observed heterogeneity may also be attributed to differences in the participants’ characteristics, health statues, severity and range of periodontal disease, the dose and duration of melatonin, treatment conditions of NSPT, and follow-up periods among studies. First, we performed subgroup analyses of PD according to different follow-up times and health statuses. The health status subgroup analysis showed that patients with comorbidities and systemically healthy patients showed significant heterogeneity, and the follow-up time subgroup analysis suggested low heterogeneity at three months and moderate heterogeneity at six months. The follow-up time subgroup analysis showed that the heterogeneity in our study was acceptable according to the follow-up time. Therefore, the reason for the high heterogeneity may be that the follow-up time might account for more heterogeneity than the health status. Second, as for treatment conditions, Tinto and colleagues [ 25 ] carried out SRP in one-session in the full mouth under local anaesthesia and it took nearly 45 minutes per quadrant, while the investigators of three studies [ 26 – 28 ] did not mention the detailed treatment modality of SRP. In addition, EI-Sharkawy [ 27 ] and Tinto [ 25 ] used a 0.12% and 0.20% chlorhexidine rinse in both melatonin and placebo groups after SRP, respectively, but the remaining two studies [ 26 , 28 ] did not take any local antimicrobials after surgery. We also noted that the dose of melatonin ranged from 1 to 10 mg/day and the duration of melatonin supplementation of included studies varied from 4 weeks to 2 months. However, due to the paucity of studies, which provided limited information, we could not perform subgroup analyses of other potentially confounding factors. Further scientific RCTs are needed to provide additional information regarding the use of melatonin in the treatment of periodontitis. This investigation is the first systematic review and meta-analysis to determine the effects of systemic melatonin + NSPT compared to NSPT alone on clinical outcomes in patients with periodontitis. All the included studies were randomized, parallel-designed trials, and all of them were published in the last three years. We considered three included studies to have a low risk of bias and one study to have a moderate risk of bias. For analysis purposes, we performed subgroup analyses according to follow-up periods and health status. However, some of the limitations of our research should be recognized. Melatonin is a novel host modulatory agent for use in periodontal diseases, so the number of clinical studies is relatively small. We included only four RCTs and consequently we could not assess the publications by funnel plots. Conclusion The present meta-analysis shows that systemic melatonin as an adjunct to NSPT can moderately reduce PD and improve CAL in patients with CP. The use of systemic melatonin may improve the efficacy of NSPT for the treatment of CP and thereby promote improved capacity for periodontal healing. Considering the limitations of our study, it is recommended to conduct good quality RCTs with a large sample size to assess the safety and efficacy of oral melatonin. Based on data of future clinical trials, systemic melatonin might be used as a reliable adjunctive therapy for chronic periodontitis in patients. Abbreviations NSPT: Nonsurgical periodontal therapy; PD: Probing depth; CAL: Clinical attachment loss; WMD: Weighted mean difference; CI: Confidence interval; RCTs: Randomized clinical trials; I 2 : I-square; CP: Chronic periodontitis; OHI: Oral hygiene instructions; SRP: Scaling and root planning; PRISMA: Transparent Reporting of Systematic Reviews and Meta-analyses; CENTRAL: The Cochrane Central Register of Controlled Trials; WMDs: Weighted mean differences; DM: Diabetes mellitus; RANKL/OPG: Receptor activator of the nuclear factor-kappa B ligand/osteoprotegerin. Declarations Ethics approval and consent to participate Not applicable. Availability of data and materials The data supporting the findings are available in the databases PubMed, EMBASE and CENTRAL. Consent to publish Not applicable. Conflict of interest The authors declare no conflict of interest. Acknowledgements Not applicable Funding This study was supported by the Program for Innovation Team Building at Institutions of Higher Education in Chongqing in 2016 (CXTDG201602006) and Chongqing medical research project (2015msxm055). Authors’ contributions Yuexiang Zhen and Hui Yue searched the literature and selected the studies. Meilin Zhao and Yuexiang Zhen extracted the data. Qin Liu and Yiting Xiao assessed the quality of the included studies. Qin Liu and Hui Yue analysed the data. Yuexiang Zhen, Meilin Zhao, Hui Yue, Qin Liu and Yiting Xiao drafted the article. Yuexiang Zhen and Meilin Zhao designed the study, interpreted the data, and revised the article. All authors approved the submission. References Holtfreter B, Albandar JM, Dietrich T, Dye BA, Eaton KA, Eke PI, Papapanou PN, Kocher T: Standards for reporting chronic periodontitis prevalence and severity in epidemiologic studies: Proposed standards from the Joint EU/USA Periodontal Epidemiology Working Group. 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Renn TY, Huang YK, Feng SW, Wang HW, Lee WF, Lin CT, Burnouf T, Chen LY, Kao PF, Chang HM: Prophylactic supplement with melatonin successfully suppresses the pathogenesis of periodontitis through normalizing RANKL/OPG ratio and depressing the TLR4/MyD88 signaling pathway. Journal of pineal research 2018, 64(3). Vilar A, de Lemos L, Patraca I, Martinez N, Folch J, Junyent F, Verdaguer E, Pallas M, Auladell C, Camins A: Melatonin suppresses nitric oxide production in glial cultures by pro-inflammatory cytokines through p38 MAPK inhibition. Free radical research 2014, 48(2):119-128. Virto L, Cano P, Jimenez-Ortega V, Fernandez-Mateos P, Gonzalez J, Haugen HJ, Esquifino AI, Sanz M: Melatonin as adjunctive therapy in the treatment of periodontitis associated with obesity. Journal of clinical periodontology 2018, 45(11):1336-1346. Srinath R, Acharya AB, Thakur SL: Salivary and gingival crevicular fluid melatonin in periodontal health and disease. Journal of periodontology 2010, 81(2):277-283. Supplementary Files TableS1.docx TableS2.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 21 Dec, 2021 Editor assigned by journal 19 Dec, 2021 Editor invited by journal 18 Dec, 2021 Submission checks completed at journal 30 Mar, 2021 First submitted to journal 28 Mar, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-376485","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":19123791,"identity":"7e0e6605-f2b3-4b5a-b578-752d5190f54d","order_by":0,"name":"Yuexiang Zhen","email":"","orcid":"https://orcid.org/0000-0002-2105-3158","institution":"Chongqing Medical University Stomatology College: Stomatological Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuexiang","middleName":"","lastName":"Zhen","suffix":""},{"id":19123792,"identity":"8d24463c-6dc0-4cf8-8215-1654ff006253","order_by":1,"name":"Hui Yue","email":"","orcid":"","institution":"Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Yue","suffix":""},{"id":19123793,"identity":"e10084a7-b672-4ff3-9566-6892450d5245","order_by":2,"name":"Yiting Xiao","email":"","orcid":"","institution":"Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yiting","middleName":"","lastName":"Xiao","suffix":""},{"id":19123794,"identity":"4a7b8acc-09e9-440c-8df1-8a896c20ebb9","order_by":3,"name":"Qin Liu","email":"","orcid":"","institution":"Chongqing University of Medical Science: Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Liu","suffix":""},{"id":19123795,"identity":"24edef3f-9751-41a0-8844-41f031414411","order_by":4,"name":"Meilin Zhao","email":"data:image/png;base64,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","orcid":"","institution":"Chongqing Medical University Stomatology College: Stomatological Hospital of Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Meilin","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2021-03-30 12:48:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-376485/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-376485/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":7555983,"identity":"b4665b3d-00fe-4ef4-b41f-0e6dc747b7a9","added_by":"auto","created_at":"2021-04-01 01:28:43","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":307201,"visible":true,"origin":"","legend":"Flow diagram of the study selection process.","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-376485/v1/01efe40fee02cb5561e1cc16.jpg"},{"id":7556384,"identity":"0541c6a0-90a8-4f7e-b5c8-cf7311bdcd8c","added_by":"auto","created_at":"2021-04-01 01:34:43","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":129114,"visible":true,"origin":"","legend":"Forest plot presenting overall WMDs of post-therapy on probing depth by comparing melatonin + NSPT vs. NSPT. ","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-376485/v1/46e62612000e85727e704dd3.jpg"},{"id":7555985,"identity":"a5bf9002-4bc0-42ff-b5ff-cb8ac317f8d8","added_by":"auto","created_at":"2021-04-01 01:28:43","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":117947,"visible":true,"origin":"","legend":"Forest plot presenting overall WMDs of post-therapy on clinical attachment loss by comparing melatonin + NSPT vs. NSPT. ","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-376485/v1/b8ec2b90a8ffc4236c08c0d4.jpg"},{"id":7556331,"identity":"e129e50f-92db-4e7f-b6ce-e22a2142a909","added_by":"auto","created_at":"2021-04-01 01:31:43","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":233390,"visible":true,"origin":"","legend":"The subgroup analysis presenting the WMDs of post-therapy on probing depth by comparing melatonin + NSPT vs. NSPT only groups at 2-, 3- and 6-month follow-ups. ","description":"","filename":"figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-376485/v1/a2150b9274500a33085b7ee5.jpg"},{"id":7556332,"identity":"2e198d2e-5481-46f0-89ae-fbca2b73d077","added_by":"auto","created_at":"2021-04-01 01:31:43","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":205146,"visible":true,"origin":"","legend":"The subgroup analysis presenting the difference of post-therapy on clinical attachment loss by comparing melatonin + NSPT vs. NSPT only groups at 2-, 3- and 6-month follow-ups. ","description":"","filename":"figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-376485/v1/ce562c0fa56b062f5a56d843.jpg"},{"id":7556335,"identity":"a2849cb6-e86f-49b1-8f50-7ff21b8e42cd","added_by":"auto","created_at":"2021-04-01 01:31:43","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":204354,"visible":true,"origin":"","legend":"The subgroup analysis presenting the WMDs of post-therapy on probing depth by comparing melatonin + NSPT vs. NSPT only groups according health statuses. ","description":"","filename":"figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-376485/v1/eae5b606abb7a0d9c2c047ba.jpg"},{"id":13683556,"identity":"dc120486-91e6-4bab-8f69-e3b0a12515bc","added_by":"auto","created_at":"2021-09-17 12:03:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":914329,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-376485/v1/204abc1e-a4cd-4510-81d2-d98d8b95256d.pdf"},{"id":7555989,"identity":"1b437177-a7ef-46b7-b89d-62e15f46e397","added_by":"auto","created_at":"2021-04-01 01:28:43","extension":"docx","order_by":14,"title":"","display":"","copyAsset":false,"role":"supplement","size":15401,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-376485/v1/5119f91bc27fa066828e66a4.docx"},{"id":7556333,"identity":"83b3898a-e01f-471b-8ba3-2c07b42a1a00","added_by":"auto","created_at":"2021-04-01 01:31:43","extension":"docx","order_by":15,"title":"","display":"","copyAsset":false,"role":"supplement","size":19953,"visible":true,"origin":"","legend":"","description":"","filename":"TableS2.docx","url":"https://assets-eu.researchsquare.com/files/rs-376485/v1/cddbc138ab8f84b802b275dc.docx"}],"financialInterests":"","formattedTitle":"Efficacy of melatonin supplementation in the treatment of periodontitis: a systematic review and meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eChronic periodontitis (CP) is an inflammatory disease mainly caused by subgingival microbial plaque and characterized by the destruction of tooth-supporting tissues [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. The damage to periodontal tissue is related to the production of certain harmful substances, including pro-inflammatory cytokines, free radicals, reactive oxygen species and reactive nitrogen, some of which are directly produced by periodontal bacteria and others of which are produced by the host immune response to dysbiotic microbial presence [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. The release of these products is largely sustained, driving the progressive loss of connective tissue attachment and alveolar bone and even tooth loss if not treated promptly [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e]. Nonsurgical periodontal therapy (NSPT), a standard treatment for periodontitis, mainly includes professional oral hygiene instructions (OHI) and full-mouth subgingival scaling and root planing (SRP), which mechanically removes dental plaque and calculus on the root surface. However, the limitations of inaccessible periodontal defects [\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e] and poor host inflammatory-immune response [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e] can influence the effectiveness of periodontal healing. Although NSPT can successfully suppress the progression of inflammation and prevent progressive bone loss in some cases, the ability of the periodontium to their return to original form and function is still limited. Regarding these issues, periodontal clinicians have considered the use of host modulatory agents as adjuvant therapies to modulate the host immune response and boost the regeneration of periodontal tissue [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]. Host modulatory agents can affect the host immune response through different pharmacological mechanisms [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]. For example, tetracycline antibiotics inhibit the synthesis of matrix metalloproteinase [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e], nonsteroidal anti-inflammatory drugs inhibit the release of pro-inflammatory cytokines and prostaglandins [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. and bone-sparing agents block the expression of osteoclasts [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, these drugs may cause resistance, opportunistic infections, and other side effects [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eMelatonin (N-acetyl-5-methoxy-tryptamine) is an important hormone that is mainly secreted by the pineal gland and is associated with the circadian rhythm [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. Melatonin can be correlated with the development and severity of periodontitis [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. Previous studies have shown that the level of melatonin in plasma and saliva is significantly decreased in patients with periodontitis compared to healthy patients [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]. Melatonin can be used as a dietary supplement or as a prescription drug in different countries [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. Melatonin possesses a wide spectrum of essential properties, such as anti-inflammatory, immunomodulatory [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e] and antioxidant effects [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e], free radical scavenging; bone metabolism regulation [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e], As such, melatonin could be used as a novel host modulatory agent to modulate the host response in patients with destructive periodontitis [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]. Therefore, research on melatonin supplementation after NSPT in the treatment of periodontal disease has attracted the attention of clinicians.\u003c/p\u003e\n\u003cp\u003eCurrently, some publications have reported that systemic melatonin after NSPT in patients with periodontitis has advantages in reducing probing depth (PD) and clinical attachment loss (CAL) compared with NSPT alone [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. However, other studies have noted no significant difference in the results of the clinical outcomes for NSPT combined with melatonin supplementation compared with NSPT alone [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. This uncertain evidence is not conducive to the clinical application or promotion of melatonin in patients with periodontitis.\u003c/p\u003e\n\u003cp\u003eTo the best of our knowledge, there is no systematic review or meta-analysis of RCTs evaluating the effects of NSPT combined with melatonin on clinical outcomes in patients with periodontitis. Therefore, the primary purpose of this study was to summarize the available evidence and determine the effects of melatonin supplementation in combination with NSPT on clinical outcomes in patients with periodontitis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003cp\u003e\u003cstrong\u003eGuidelines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted this study following the guidelines of the Transparent Reporting of Systematic Reviews and Meta-Analyses (PRISMA) statement [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSearch plan\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003cp\u003eWe comprehensively searched the PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) databases for relevant articles published before April 2020 in the English language. We used the following terms (MeSH) and free text keywords: population [\u0026ldquo;periodontal disease\u0026rdquo; OR \u0026ldquo;chronic periodontitis\u0026rdquo;], intervention [\u0026ldquo;periodontal therapy\u0026rdquo; OR \u0026ldquo;periodontal debridement\u0026rdquo; OR \u0026ldquo;nonsurgical periodontal debridement\u0026rdquo; AND \u0026ldquo;melatonin\u0026rdquo;]. We also manually checked the reference lists of selected studies to identify any possible eligible citations. The detailed search strategy is illustrated in supplementary Table S1.\u003c/p\u003e\n\u003cp\u003eTwo investigators (YX.Z and H.Y.) independently conducted the study screening process. We deleted duplicate publications and excluded those that were ineligible by reviewing titles and abstracts. Finally, we read the full text carefully to identify eligible studies. Any disagreement during the study selection process was settled by discussion. To identify additional publications, we manually searched the reference lists of the included studies. We did not contact the original authors for further information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion and exclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003cp\u003eWe included RCTs with no minimum duration that evaluated the effects of systemic melatonin adjunctive to NSPT compared with NSPT plus a placebo or alone in patients with periodontitis. The primary outcome measures were PD and CAL. The secondary outcome measure was the occurrence of adverse effects related to melatonin administration.We excluded case reports, animal studies, and studies that used local melatonin delivery adjunctive to NSPT. In addition, we also excluded studies that used systemic melatonin with other concomitant oral medications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData extraction\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003cp\u003eTwo investigators (ML.Z. and YX.Z.) independently collected and extracted the following data: first author\u0026rsquo;s name, publication date, study location, study design, participants\u0026rsquo; characteristics, total sample size and dropouts, intervention (the treatment conditions of NSPT; dose, usage of melatonin, and duration of treatment), type of systematic disease, periodontitis definition, study duration, outcome measures, and sponsor. Disagreements regarding extracted information between the two reviewers were settled by discussion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality assessment\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003cp\u003eTwo investigators (Q.L. and YT.X.) individually performed the quality assessment of included trials based on the Cochrane Collaboration\u0026rsquo;s tool [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. The third reviewer resolved any disagreements regarding the study quality assessment. The methodological quality included the following criteria: randomization generation, and allocation concealment; blinding of participants, personnel and examiners; outcome assessment; incomplete outcome data; selective outcome reporting; and other sources of bias. Overall, the risk of study bias was categorized as follows: 1) low risk of bias: there was a \u0026ldquo;low\u0026rdquo; risk answer for all domains; 2) moderate risk of bias: there was an \u0026ldquo;unclear\u0026rdquo; risk answer for one or more domains; 3) high risk of bias: there was a \u0026ldquo;high\u0026rdquo; risk answer for one or more domains.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003cp\u003eTwo investigators (Q.L. and H.Y.) determined the effects of NSPT plus melatonin supplementation and NSPT alone on periodontal parameter variables in patients with CP. Trial outcome data were pooled into weighted mean differences (WMDs) with 95% confidence intervals (CIs) using RevMan 5.3 software (Cochrane Collaboration). Heterogeneity among studies was estimated using the Cochran (Q) and I-square tests (I\u003csup\u003e2\u003c/sup\u003e). \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1 and I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50% indicated substantial heterogeneity. Otherwise, when \u003cem\u003eP\u0026thinsp;\u0026ge;\u003c/em\u003e\u0026thinsp;0.1 and I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026le;\u0026thinsp;50%, heterogeneity was acceptable [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. We used a random-effects model for our meta-analysis. Owing to the small number of included studies, the assessment of publication bias by using a funnel plot was not evaluated [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eLiterature search\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 151 potentially eligible publications were identified from the electronic databases search. Ninety-eight studies were screened after duplicate removal. The full texts of 10 studies were retrieved according to the established inclusion criteria. Ultimately, four studies [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e] were finally considered eligible for inclusion in this review (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCharacteristics of the included studies\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003cp\u003eThe detailed information of the included studies for the intervention and placebo groups is summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table S2. Overall, four included RCTs [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e] reported 198 patients who presented mild to severe CP. The investigators of four studies identified CP as involving at least one site with a PD of 4 millimetres or greater. The investigators of three studies provided the CAL threshold value in the definition of CP [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e], while one study did not report CAL values or bone loss [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. The investigators of two studies [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e] recruited systematically healthy patients with CP. The remaining two studies recruited patients with comorbidities, one study recruited patients with primary insomnia [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], and the other study recruited patients with type 2 diabetes mellitus (DM) [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. The dose of melatonin varied from 1 to 10 mg/day. The participants of two included studies received systemic melatonin for two months [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e], while the participants of the other two studies received systemic melatonin for one month [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]. Tinto and colleagues [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e] reported that SRP was performed in one-session in the full mouth under local anaesthesia and it took nearly 45 minutes per quadrant. EI-Sharkawy and colleagues [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] only reported SRP over two separate visits, but the investigators of three studies did not define SRP in detail [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. The participants of 2 included studies did not receive local antimicrobials after SRP [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e], but EI-Sharkawy [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] and Tinto [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e] combined antimicrobial treatment with a 0.12% and 0.20% chlorhexidine rinse twice a day for two weeks for study participants after SRP, respectively.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics of the included studies\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAuthor\u003c/p\u003e\n\u003cp\u003eyear,\u003c/p\u003e\n\u003cp\u003ecountry\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCountry\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eStudy design\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSample size (no. dropouts)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMean age or range (y)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSmokers\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOther systemic condition\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePeriodontitis definition (mm)/clinical examination\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDuration (mo)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSponsor\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChitsazi et al.\u003c/p\u003e\n\u003cp\u003e2017 [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e], Iran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRCT\u003c/p\u003e\n\u003cp\u003eparallel design\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e60 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23\u0026ndash;65\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eModerate to severe CP, PD\u0026thinsp;\u0026ge;\u0026thinsp;5 UNC-15 probe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3, 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTabriz University Dental and\u003c/p\u003e\n\u003cp\u003ePeriodontal Research Center\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEl-Sharkawy et al.\u003c/p\u003e\n\u003cp\u003e2019 [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], Egypt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEgypt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRCT\u003c/p\u003e\n\u003cp\u003eparallel design\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e80 (6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38\u0026ndash;55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eprimary insomnia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;\u0026thinsp;20 teeth, moderate to severe CP, PD\u0026thinsp;\u0026ge;\u0026thinsp;5 and radiographic CAL\u0026thinsp;\u0026ge;\u0026thinsp;4 at least three sites in each quadrant\u003c/p\u003e\n\u003cp\u003eProbe not reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3, 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBazyar et al.\u003c/p\u003e\n\u003cp\u003e2018 [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e], Iran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRCT\u003c/p\u003e\n\u003cp\u003eparallel design\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50 (6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT: 53.72\u0026thinsp;\u0026plusmn;\u0026thinsp;6.68\u003c/p\u003e\n\u003cp\u003eC: 51.45\u0026thinsp;\u0026plusmn;\u0026thinsp;5.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003etype 2 Diabetes mellitus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMild and moderate CP, PD\u0026thinsp;\u0026ge;\u0026thinsp;4 and CAL\u0026thinsp;=\u0026thinsp;1\u0026ndash;4\u003c/p\u003e\n\u003cp\u003eUNC-15 probe\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTinto et al.\u003c/p\u003e\n\u003cp\u003e2019 [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e], Italy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eItaly\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRCT\u003c/p\u003e\n\u003cp\u003eparallel design\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30\u0026ndash;70\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSevere CP, CAL\u0026thinsp;\u0026ge;\u0026thinsp;5,\u003c/p\u003e\n\u003cp\u003e\u0026ge; 20 teeth, PD\u0026thinsp;\u0026ge;\u0026thinsp;6\u003c/p\u003e\n\u003cp\u003eProbe not reported\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePeriodontal Unit of Santa Apollonia Dental Center\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"10\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eRCT\u003c/em\u003e Randomized controlled trial, \u003cem\u003eT\u003c/em\u003e Test group, \u003cem\u003eC\u003c/em\u003e Control group, \u003cem\u003ePD\u003c/em\u003e probing depth, \u003cem\u003eCAL\u003c/em\u003e clinical attachment loss, \u003cem\u003emm\u003c/em\u003e millimetre, mo months, \u003cem\u003eCP\u003c/em\u003e chronic periodontitis\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eParticipants, interventions, outcomes and results\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eAuthor,\u003c/p\u003e\n\u003cp\u003eyear,\u003c/p\u003e\n\u003cp\u003ecountry\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eParticipants\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eGroups\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eInterventions\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eOutcome variables/adverse effects\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eResults\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNSPT\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDrug usage and dosage\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChitsazi et al.\u003c/p\u003e\n\u003cp\u003e2017 [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e], Iran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT : N\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e\n\u003cp\u003eC : N\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e\n\u003cp\u003e31 females,\u003c/p\u003e\n\u003cp\u003e29 males\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT: NSPT\u0026thinsp;+\u0026thinsp;melatonin\u003c/p\u003e\n\u003cp\u003eC: NSPT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOHI\u0026thinsp;+\u0026thinsp;SRP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 mg melatonin a day for 1 mo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePD, CAL\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT VS. C in PD and CAL scores: P\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEl-Sharkawy et al.\u003c/p\u003e\n\u003cp\u003e2019 [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], Egypt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT: N\u0026thinsp;=\u0026thinsp;38\u003c/p\u003e\n\u003cp\u003eC: N\u0026thinsp;=\u0026thinsp;36\u003c/p\u003e\n\u003cp\u003e33 females,\u003c/p\u003e\n\u003cp\u003e41 males\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT: NSPT\u0026thinsp;+\u0026thinsp;melatonin capsule\u003c/p\u003e\n\u003cp\u003eC: NSPT\u0026thinsp;+\u0026thinsp;Placebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOHI\u0026thinsp;+\u0026thinsp;two-session SRP\u0026thinsp;+\u0026thinsp;0.12% chlorhexidine rinse for 2 weeks\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 mg melatonin once per day 1 hour before bedtime for 2 mo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCAL, PD\u003c/p\u003e\n\u003cp\u003eCases of headache, dizziness,nausea, constipation, diarrhea,and abdominal cramp\u0026thinsp;\u0026le;\u0026thinsp;2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT VS. C in PD and CAL: \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBazyar et al.\u003c/p\u003e\n\u003cp\u003e2018 [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e], Iran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT: N\u0026thinsp;=\u0026thinsp;22\u003c/p\u003e\n\u003cp\u003eC: N\u0026thinsp;=\u0026thinsp;22\u003c/p\u003e\n\u003cp\u003e30 females,\u003c/p\u003e\n\u003cp\u003e14 males\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT: NSPT\u0026thinsp;+\u0026thinsp;melatonin tablets\u003c/p\u003e\n\u003cp\u003eC: NSPT\u0026thinsp;+\u0026thinsp;placebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOHI\u0026thinsp;+\u0026thinsp;SRP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 mg melatonin once a day 1 hour before bedtime for 2 mo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePD, CAL\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT VS. C PD and CAL \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTinto et al.\u003c/p\u003e\n\u003cp\u003e2019 [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e], Italy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT: N\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e\n\u003cp\u003eC: N\u0026thinsp;=\u0026thinsp;10\u003c/p\u003e\n\u003cp\u003e8 females,\u003c/p\u003e\n\u003cp\u003e12 males\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT: NSPT\u0026thinsp;+\u0026thinsp;melatonin tablets\u003c/p\u003e\n\u003cp\u003eC: NSPT\u0026thinsp;+\u0026thinsp;placebo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOHI\u0026thinsp;+\u0026thinsp;one-session SRP (1 quadrant per 45 minutes with local anesthesia)\u003c/p\u003e\n\u003cp\u003e+\u0026thinsp;0.20% chlorhexidine rinse for 2 weeks\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 mg melatonin once a day at bedtime for 1 mo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePD\u003c/p\u003e\n\u003cp\u003eT: 20% sleepiness and 10% headache\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eT VS. C in PD: P\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eT\u003c/em\u003e test group, \u003cem\u003eC\u003c/em\u003e control group, \u003cem\u003eNSPT\u003c/em\u003e non-surgical periodontal therapy, \u003cem\u003ePD\u003c/em\u003e probing depth, \u003cem\u003eCAL\u003c/em\u003e clinical attachment loss, \u003cem\u003emo\u003c/em\u003e months, \u003cem\u003eOHI\u003c/em\u003e oral hygiene instructions, \u003cem\u003eSRP\u003c/em\u003e scaling and root planing\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality assessment of selected studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the four included RCTs, three had a low risk of bias [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], and one exhibited a moderate risk of bias [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. The risk of bias quality assessments of the included RCTs is presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. All included studies received a \u0026ldquo;yes\u0026rdquo; answer for aspects of randomized sequence generation, allocation concealment, blinding of participants and personnel, complete data, and other bias. The risk answer was assigned because the blinding of allocation for the participants was not described. Overall, the quality of studies was considered moderate in 1 RCT and high in 3 RCTs.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eRisk of quality assessment of the selected studies\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAuthor\u003c/p\u003e\n\u003cp\u003eyear,\u003c/p\u003e\n\u003cp\u003ecountry\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRandom sequence generation\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAllocation concealment\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eBlinding of participants and personnel\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eBlinding of outcome\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIncomplete outcome data\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSelective reporting\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOther biases\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOverall risk of bias\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChitsazi et al.\u003c/p\u003e\n\u003cp\u003e2017 [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e], Iran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eunclear\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003emoderate\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEI-Sharkawy et al. 2019 [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], Egypt\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBazyar et al.\u003c/p\u003e\n\u003cp\u003e2018 [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e], Iran\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTinto et al.\u003c/p\u003e\n\u003cp\u003e2019 [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e], Italy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003elow\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe primary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe investigators of the four included studies reported PD [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e] between baseline and follow-up visits, and the investigators of three studies reported CAL [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. Overall, there were significant differences in reducing PD (WMD, -1.01; 95% CI, -1.67 to -0.35; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;76%) and CAL (WMD, -1.08; 95% CI: -1.36 to -0.79, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), as presented in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. There was substantial heterogeneity in PD (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;76%) among the studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcome measures\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003cp\u003eOne study [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e] mentioned that, in the melatonin group, two patients reported sleepiness, and one patient reported headache. One trial [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] reported cases of headache, dizziness, nausea, and gastrointestinal reaction that were less than or equal to two in number. The other two trials did not report adverse effects [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe findings of the subgroup analysis by health status demonstrated that the systemic melatonin adjunctive to NSPT group showed a significant difference in PD compared with the NSPT alone group with respect to patients with comorbidities (WMD, -1.01; 95% CI, -1.61 to -0.35; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;72%) and systemically healthy patients (WMD, -0.77; 95% CI, -1.91 to -0.36; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;88%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). However, high degrees of heterogeneity were observed between studies.\u003c/p\u003e\n\u003cp\u003eWe also performed a subgroup analysis by follow-up period for CAL and found that melatonin supplementation after NSPT resulted in significantly less CAL at the 2- (WMD, -1.18; 95% CI, -1.56 to -0.80), 3- (WMD, -0.83; 95% CI, -1.23 to -0.43), and 6-month (WMD, -0.94; 95% CI, -1.38 to -0.51) visits than NSPT alone (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e). The subgroup analysis for CAL showed a low heterogeneity.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDue to its antioxidant and anti-inflammatory properties, and modulatory effects on bone formation, periodontal practitioners have begun to consider the use of melatonin supplementation as an adjunctive therapeutic option with NSPT in the treatment of periodontitis [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, some previous publications have reported that the effects of systemic melatonin on clinical periodontal parameters are controversial in patients with periodontitis [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. This meta-analysis demonstrated that the use of systemic melatonin\u0026thinsp;+\u0026thinsp;NSPT showed modest additional benefits in reducing PD by 1.12 mm and in decreasing CAL by 1.02 mm compared to NSPT\u0026thinsp;+\u0026thinsp;a placebo or alone. The findings of the subgroup analysis also suggested stronger treatment effects of PD reduction in shorter follow-up periods than in longer follow-up periods when adjunctive systemic melatonin was used. It is worth noting that melatonin has a wide safety margin, but systemic melatonin may have some side effects, such as sleepiness and headache [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. Thus, when using systemic melatonin, periodontal clinicians should consider its potentially undesired side effects.\u003c/p\u003e\n\u003cp\u003ePD reduction and CAL gain are often considered clinical indicators of the successful treatment of periodontitis [\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]. This systematic review and meta-analysis demonstrated that, compared with NSPT alone, the use of systemic melatonin\u0026thinsp;+\u0026thinsp;NSPT significantly reduced PD and CAL. Over the years, studies have demonstrated that the biological mechanisms of melatonin on the ability of periodontal healing could be attributed to the following. First, the intrinsic anti-inflammatory and antioxidant properties of melatonin can promote the early healing of periodontal tissue [\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e]. Studies have shown that melatonin can reduce highly destructive free radicals and oxygen and nitrogen reactive substances that cause oxidative damage to periodontal tissues, increase the antioxidant capacity of the host and depress pro-inflammatory cytokine production [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e], thus reducing the adverse effects of the host\u0026rsquo;s immune system on periodontal tissues. On the other hand, melatonin plays an important role in regulating bone tissue formation and bone loss. Melatonin can effectively suppress the receptor activator of the nuclear factor-kappa B ligand/osteoprotegerin (RANKL/OPG) signalling pathway, which is activated by osteoclast receptors, potentially suppressing the progression of alveolar bone loss [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]. Melatonin can promote osteoblastic differentiation and stimulate the synthesis of new bone matrix [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e], which is manifested in the improvement of new attachment generation. Additionally, melatonin exerts a direct antimicrobial effect on some periodontal cariogenic bacteria, potentially reducing the inflammatory response of periodontal tissue [\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]. These mechanisms provide possible evidence for the potential therapeutic effect of melatonin on the healing of periodontal soft and hard tissues in patients with periodontitis.\u003c/p\u003e\n\u003cp\u003eIn the present study, the overall meta-analysis showed considerable heterogeneity across studies (PD, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;76.0%). The observed heterogeneity may also be attributed to differences in the participants\u0026rsquo; characteristics, health statues, severity and range of periodontal disease, the dose and duration of melatonin, treatment conditions of NSPT, and follow-up periods among studies. First, we performed subgroup analyses of PD according to different follow-up times and health statuses. The health status subgroup analysis showed that patients with comorbidities and systemically healthy patients showed significant heterogeneity, and the follow-up time subgroup analysis suggested low heterogeneity at three months and moderate heterogeneity at six months. The follow-up time subgroup analysis showed that the heterogeneity in our study was acceptable according to the follow-up time. Therefore, the reason for the high heterogeneity may be that the follow-up time might account for more heterogeneity than the health status. Second, as for treatment conditions, Tinto and colleagues [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e] carried out SRP in one-session in the full mouth under local anaesthesia and it took nearly 45 minutes per quadrant, while the investigators of three studies [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e] did not mention the detailed treatment modality of SRP. In addition, EI-Sharkawy [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e] and Tinto [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e] used a 0.12% and 0.20% chlorhexidine rinse in both melatonin and placebo groups after SRP, respectively, but the remaining two studies [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e] did not take any local antimicrobials after surgery. We also noted that the dose of melatonin ranged from 1 to 10 mg/day and the duration of melatonin supplementation of included studies varied from 4 weeks to 2 months. However, due to the paucity of studies, which provided limited information, we could not perform subgroup analyses of other potentially confounding factors. Further scientific RCTs are needed to provide additional information regarding the use of melatonin in the treatment of periodontitis.\u003c/p\u003e\n\u003cp\u003eThis investigation is the first systematic review and meta-analysis to determine the effects of systemic melatonin\u0026thinsp;+\u0026thinsp;NSPT compared to NSPT alone on clinical outcomes in patients with periodontitis. All the included studies were randomized, parallel-designed trials, and all of them were published in the last three years. We considered three included studies to have a low risk of bias and one study to have a moderate risk of bias. For analysis purposes, we performed subgroup analyses according to follow-up periods and health status. However, some of the limitations of our research should be recognized. Melatonin is a novel host modulatory agent for use in periodontal diseases, so the number of clinical studies is relatively small. We included only four RCTs and consequently we could not assess the publications by funnel plots.\u003c/p\u003e"},{"header":"Conclusion","content":" \u003cp\u003eThe present meta-analysis shows that systemic melatonin as an adjunct to NSPT can moderately reduce PD and improve CAL in patients with CP. The use of systemic melatonin may improve the efficacy of NSPT for the treatment of CP and thereby promote improved capacity for periodontal healing. Considering the limitations of our study, it is recommended to conduct good quality RCTs with a large sample size to assess the safety and efficacy of oral melatonin. Based on data of future clinical trials, systemic melatonin might be used as a reliable adjunctive therapy for chronic periodontitis in patients.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eNSPT: Nonsurgical periodontal therapy; PD: Probing depth; CAL: Clinical attachment loss; WMD: Weighted mean difference; CI: Confidence interval; RCTs: Randomized clinical trials; I\u003csup\u003e2\u003c/sup\u003e: I-square; CP: Chronic periodontitis; OHI: Oral hygiene instructions; SRP: Scaling and root planning; PRISMA: Transparent Reporting of Systematic Reviews and Meta-analyses; CENTRAL: The Cochrane Central Register of Controlled Trials; WMDs: Weighted mean differences; DM: Diabetes mellitus; RANKL/OPG: Receptor activator of the nuclear factor-kappa B ligand/osteoprotegerin.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings are available in the databases PubMed, EMBASE and CENTRAL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Program for Innovation Team Building at Institutions of Higher Education in Chongqing in 2016 (CXTDG201602006) and Chongqing medical research project (2015msxm055).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYuexiang Zhen and Hui Yue searched the literature and selected the studies. Meilin Zhao and Yuexiang Zhen extracted the data. Qin Liu and Yiting Xiao assessed the quality of the included studies. Qin Liu and Hui Yue analysed the data. Yuexiang Zhen, Meilin Zhao, Hui Yue, Qin Liu and Yiting Xiao drafted the article. Yuexiang Zhen and Meilin Zhao designed the study, interpreted the data, and revised the article. All authors approved the submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHoltfreter B, Albandar JM, Dietrich T, Dye BA, Eaton KA, Eke PI, Papapanou PN, Kocher T: Standards for reporting chronic periodontitis prevalence and severity in epidemiologic studies: Proposed standards from the Joint EU/USA Periodontal Epidemiology Working Group. Journal of clinical periodontology 2015, 42(5):407-412.\u003c/li\u003e\n\u003cli\u003eKinane DF, Stathopoulou PG, Papapanou PN: Periodontal diseases. 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Journal of periodontology 2010, 81(2):277-283.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Periodontitis, Melatonin, Nonsurgical periodontal therapy, Meta-analysis ","lastPublishedDoi":"10.21203/rs.3.rs-376485/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-376485/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e The aim of this systematic review and meta-analysis was to analyze the additive effects of the melatonin supplementation with nonsurgical periodontal therapy (NSPT) on periodontal status in patients affected by chronic periodontitis.\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In December 2020, We searched PubMed, EMBASE, Web of Science, CENTRAL databases and Google Scholar databases. Four RCTs were recruited with the same inclusion criteria. PD and CAL were the primary outcome measures. Subgroup analyses were performed according to health statuses and follow-up times, and Cochran’s Q and I-square ( I\u003csup\u003e2 \u003c/sup\u003e) tests were used to assess heterogeneity.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e This review included four RCTs. Four studies reported probing depth (PD) and 3 studies reported clinical attachment loss (CAL). Compared with the placebo groups, the melatonin groups showed a significant reduction in PD (weighted mean difference [WMD], -1.01; 95% confidence intervals [CI], -1.67 to -0.35; I\u003csup\u003e2\u003c/sup\u003e = 76%) and CAL (WMD, -1.08; 95% CI: -1.36 to -0.79, I\u003csup\u003e2\u003c/sup\u003e = 0%). Subgroup analyses revealed that the use of systemic melatonin + NSPT significantly reduced PD and CAL at the 2-, 3-, and 6-month follow-ups compared to NSPT alone, and stronger treatment effects of reducing PD were observed at shorter follow-ups than at longer follow-ups when adjunctive systemic melatonin was used.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e \u003c/p\u003e\u003cp\u003eMelatonin supplementation in adjunct with nonsurgical periodontal therapy can moderately improve the efficacy of NSPT in reducing PD and greater CAL gain in patients with periodontitis. With the limited evidence available, it is evident that additional good quality RCTs are required to demonstrate additional beneficial effects of oral melatonin supplementation on periodontal clinical parameters after NSPT.\u003c/p\u003e","manuscriptTitle":"Efficacy of melatonin supplementation in the treatment of periodontitis: a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-04-01 01:28:41","doi":"10.21203/rs.3.rs-376485/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2021-12-21T23:48:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-12-19T23:46:36+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-12-18T23:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-03-30T12:48:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2021-03-29T00:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d3017309-53e0-4dea-98a6-01bb82388a6c","owner":[],"postedDate":"April 1st, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":3338828,"name":"General Biochemistry"},{"id":3338829,"name":"Dentistry"}],"tags":[],"updatedAt":"2021-04-01T01:28:41+00:00","versionOfRecord":[],"versionCreatedAt":"2021-04-01 01:28:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-376485","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-376485","identity":"rs-376485","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}