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 . 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 . 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 . 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 . Melatonin can promote osteoblastic differentiation and stimulate the synthesis of new bone matrix , 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 . 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, I2 = 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  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  and Tinto  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.