Journal of Dental Implants

: 2019  |  Volume : 9  |  Issue : 2  |  Page : 77--82

Managing perimucositis and peri-implantitis with melatonin: A new approach

Rosy Raheja, Tanu Mahajan 
 Department of Prosthodontics, Crown and Bridge and Implantology, Rama Dental College, Hospital and Research Centre, Kanpur, Uttar Pradesh, India

Correspondence Address:
Dr. Rosy Raheja
124/399, Block 11A, Govind Nagar, Kanpur, Uttar Pradesh


Melatonin (n-acetyl-5-methoxytryptamine) is a substance secreted by multiple organs including the pineal gland, retina, bone marrow, the gastrointestinal track, and the immune system. Its main function is the regulation of the circadian rhythm (day–night cycles). It plays an anti-inflammatory, antioncotic, and immunomodulatory role by scavenging free-radicals and through interactions with cell membrane and intracellular proteins. Melatonin is capable of entering the oral cavity by diffusing into the saliva from blood. As the majority of the melatonin remains bound to serum albumin, the amount of melatonin in saliva is approximately one-third of that present in the blood. The existence of MT1 receptors on healthy and cancerous oral mucosal cells is suggestive that melatonin may act as an anti-inflammatory or antioncotic agent in the oral cavity; for example, its anti-inflammatory effects have been reported on human gingival fibroblasts. Furthermore, intraperitoneal melatonin has been reported to reduce periodontitis in diabetic rats. Similarly, topical application of melatonin in diabetic patients has diminished the progression of periodontal bone loss as evident by the downregulation of pro-inflammatory factors. Hence, it has been suggested that melatonin may be used in the management of perimucositis and peri-implantitis in the field of dental implants. The aim of this review is to critically analyze and summarize the research focusing on the potential of melatonin in the fields of oral implantology.

How to cite this article:
Raheja R, Mahajan T. Managing perimucositis and peri-implantitis with melatonin: A new approach.J Dent Implant 2019;9:77-82

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Raheja R, Mahajan T. Managing perimucositis and peri-implantitis with melatonin: A new approach. J Dent Implant [serial online] 2019 [cited 2020 Aug 9 ];9:77-82
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The use of dental implants for supporting prosthetic rehabilitations has shown highly satisfactory results regarding restoration of the patient's function and esthetics, as well as in terms of long-term survival.[1] However, dental implants can lose supportive bone, even in cases of successful osseointegration. The main cause of this loss of crestal bone surrounding an implant is local inflammation during the course of peri-implant diseases. These diseases are defined as inflammatory lesions of the surrounding peri-implant tissues and include two different entities: peri-implant mucositis and peri-implantitis.[2] Peri-implant mucositis is defined as an inflammatory lesion limited to the surrounding mucosa of an implant, whereas peri-implantitis is an inflammatory lesion of the mucosa that affects the supporting bone with loss of osseointegration.[3] Both peri-implant diseases are infectious in nature and are caused by bacteria from dental biofilms.[4] A complex hypothesis has been proposed to elucidate the mechanism by which mucositis develops and resolves. Nowadays, there is considerable evidence supporting the view that proper soft tissue integration at the transmucosal part of a dental implant is a prerequisite to seal the adjacent alveolar bone from the oral environment. The accumulation of bacterial plaque biofilms on exposed surfaces may lead to inflammatory conditions of the implant-supporting soft and hard tissue.[5],[6] The hypothesis speculates on the importance of the inflammatory response induced in the involved tissues in peri-implantitis. Peri-implant inflammations represent serious diseases after dental implant treatment, which affect both the surrounding hard and soft tissue. Due to prevalence rates up to 56%, peri-implantitis can lead to the loss of the implant without multilateral prevention and therapy concepts.[7]

Mucositis and moderate forms of peri-implantitis can obviously be treated effectively using conservative methods. These include the utilization of different manual ablations, laser-supported systems as well as photodynamic therapy, which may be extended by local or systemic antibiotics. It is possible to regain osseointegration. In cases with advanced peri-implantitis, surgical therapies are more effective than conservative approaches. Depending on the configuration of the defects, resective surgery can be carried out for elimination of peri-implant lesions, whereas regenerative therapies may be applicable for defect filling.

Melatonin has several specific functions in the oral cavity, so its effects on oral health warrant further investigations. It acts as a potent antioxidant and free radical scavenger, immunomodulatory agent, strong promoter of bone formation, and anti-inflammatory factor in periodontal diseases (PDs).[8] Recently, it has been claimed that the imbalances in levels of free radicals and reactive oxygen species (ROS) with antioxidants may play an important role in the onset and development of several inflammatory oral pathologies.[9] On this purpose, the current evidences for oxidative damage in the most prevalent oral cavity diseases and the possible therapeutic effects of antioxidants like melatonin[10] have been extensively reviewed in the last years.

 History of Periodontitis: Microbiology of Peri-Implant Infections

PD is an oral inflammatory disorder of the periodontium that affects the supporting tissues of the teeth (alveolar bone, gums, and periodontal ligament), leading to progressive destruction of connective tissue attachment and alveolar bone. A consequence is the severe loss of supporting periodontal tissues and teeth, seen prevalently among adults and older people. Current information indicates that bacterial infection and accumulations on the teeth may be the primary causative agent of PD.[11],[12] Nowadays, PD represents one of the most commonly reported chronic inflammatory adult conditions. Approximately 48% of U.S. adults have chronic PD, and similar or higher rates (up to 70%) have been reported in other populations.[13] PD incidence is increased by several risk factors; in general, all those conditions that provide the anaerobes ample time to survive in periodontal tissue or any medical conditions (e.g., HIV infections) that trigger host antibacterial defense mechanisms will likely promote PDs.[14] The severity of periodontitis is characterized by the degree of marginal bone loss, depth of periodontal pockets, degree of attachment loss, and number of teeth with furcation development.[15] In diagnosing PD, the probing depth is a good indicator of the advance of the disease. In a healthy periodontium, there is no loss of epithelial attachment or pocket formation, and the periodontal pocket is <2 mm deep.[16] The disease state ranges from gingivitis to periodontitis and advanced periodontitis. Gingivitis, the most prevalent and mild form of PD, is characterized by the inflammation of the gums caused by plaque deposits, with possible bleeding when brushed or probed. Periodontitis can be identified by the hardening of plaque to form calculus, causing gum recession.

This results in the formation of pockets between 3.5 and 5.5 mm between the tooth surface and the gum.[17] The symptoms are similar to those of gingivitis but are more severe due to higher accumulation of bacteria and stronger inflammatory responses. Advanced forms of periodontitis are also prevalent, affecting approximately 10%–30% of the adult population in the United States.[18] Advanced periodontitis is distinguished by excessive tissue loss of gingiva and alveolar bone and pockets >5.5 mm in depth. This condition often leads to tooth exfoliation due to the destruction of the tooth connective ligaments.[19] The etiology and pathogenesis of PD are not completely clear. Human gingivitis and periodontitis are the results of an imbalance in the bacterial species that colonize the oral cavity and are characterized by complex interactions between pathogenic bacteria and the host's immunoinflammatory responses. In the past three decades, marked advances have occurred in our understanding of the infectious agents of PD. There are >300 distinct species of bacteria present in the gingival area of the mouth, most of which exist in a commensal relationship with the host. However, three Gram-negative, anaerobic, or microaerophilic bacteria species, known as periodontal pathogens (Actinobacillus actinomycetemcomitans, Bacteroides forsythus, and Porphyromonas gingivalis), have been identified as being ubiquitous in periodontal plaque formations.[19],[20],[21],[22] Moreover, within the past years, various herpes viruses, such as human cytomegalovirus and Epstein–Barr virus, have also emerged as pathogens in the destructive PD.[23] As reported above, the damage of periodontal tissues results both from a direct effect of the toxic products released by the bacteria and from the action of the immune system that, if stimulated by bacterial infection, produces and releases mediators that induce the effectors of connective tissue breakdown.[24],[25] Numerous studies have showed that the destruction of periodontal tissue in PD is mainly due to host-derived mediators and free radicals.[26],[27] Different mechanisms, including DNA damage, lipid peroxidation, protein damage, oxidation of important enzymes, and stimulation of pro-inflammatory cytokine release, have been implicated as causes of tissue damage by an increase in both ROS and reactive nitrogen species.[28],[29] An inverse relationship between peroxidation products and antioxidant molecules or enzymes in spontaneous or in experimental PD has been stressed.[30],[31],[32] Chapple et al. reported that total antioxidant activity is reduced in saliva of patients with periodontitis relative to that in nonperiodontitis individuals. The imbalance between oxidative stress induced by ROS and the concentrations (or activity) of the antioxidants may lead to a further oxidative attack and substantial deterioration of the periodontal tissues,[33],[34] resulting in tissue damage.[35],[36] Microbial components, especially lipopolysaccharide, have the capacity to induce an initial infiltrate of inflammatory cells. Activated macrophages synthesize and secrete a variety of pro-inflammatory molecules, including some interleukins (IL-1α, IL-β, IL-6, and IL-8), tumor necrosis factor α, prostaglandins (PGE2), and hydrolytic enzymes.[37] These cytokines recruit polymorphonuclear leukocytes (PMN) to the site of infection. PMN play a relevant role in the etiology of PD, as they are the predominant host immune response to oral bacterial infection.

On stimulation by bacterial antigens, cytokines promote the PMN to express adhesion molecules and move out of the circulation to the site of infection.[38] When PMN arrive here, they can induce an autoamplification effect producing IL-8 to attract more PMN into the infection site. This is exacerbated by the ability of P. gingivalis to modulate the mobility and function of PMN within the site of infection: a reduction of IL-8 secretion in epithelial cells, mediated by the bacterium, inhibits the recruitment of PMN to the infected area. At the site of infection, PMN produce proteolytic enzymes (e.g., elastase), but also ROS. Indeed, PMN in periodontal patients display an increased number, adhesion, and oxidative activity.[39] As the release of ROS is not target specific, damage to host tissue also occurs.[40] Human PMN produce in vitro desquamation (as a consequence of the digestion of extracellular matrix [ECM] constituents by PMN neutral proteases) and lysis of gingival epithelial cells (caused by PMN oxidants generated by myeloperoxidase). In PD, a number of proteases that degrade collagen and ECM play key roles in periodontal tissue breakdown.[41] A particular subgroup of matrix metalloproteinases (MMPs), called collagenases, is the major group of enzymes responsible for degradation of ECM and for collagen destruction in periodontitis. These latent collagenolytic enzymes are activated by ROS in the inflammatory environment, giving rise to elevated levels of interstitial collagenase in inflamed gingival tissue.[42] The attachment loss deepens the sulcus, creating a periodontal pocket. This pocket provides a microbial niche that can harbor on the order of 100 bacterial cells.[43]

PD is clearly an important and potentially life-threatening condition, often underestimated by health professionals and the general population. The available evidence implicating inflammatory mediators and cells in the disease process suggests that local antioxidant status may be of importance in determining susceptibility to the disease and its progression following initial bacterial colonization.[44]

 Gold Standard Therapies in Periodontal Disease

Due the minimal symptoms of gingival bleeding and attachment loss, many individuals neglect to treat their disease. Left untreated, gingivitis may progress to irreversible periodontitis, resulting in tooth loss [Figure 1]. Periodontal research has provided sufficient evidence indicating that, once diagnosed, chronic PD is successfully treatable.[45] The first therapeutic goal in the treatment of PD is to alter or eliminate the origin of the microbes as well as the contributing risk factors. The majority of periodontal treatment modalities, however, attempt to arrest the progression of periodontal destruction to avoid tooth loss and preserve the healthy state of the periodontium.[46] Furthermore, in severe cases, regeneration of the periodontal attachments must be attempted.[47]{Figure 1}

The first nonsurgical step of PD treatment involves special cleaning called scaling and root planing. Supplemental treatment may include antiseptic mouth medications, either to aid the healing process or to further control the bacterial infection. Often, antibiotics may be administered, which may offer an effective alternative. Doxycycline, a wide-spectrum antibiotic, and other tetracyclines are frequently used in dental treatments for soft tissue and bone regeneration after PD because of their strong activity against periodontal pathogens; they are able to inhibit the activity of human MMPs and reduce the severity and progression of PDs in animal models and humans.[48] Along with antibiotic therapy, if the periodontal pockets are not reduced or further loss of alveolar bone is observed, surgical treatment may therefore be beneficial to PD patients to prevent bone loss. If the PD has caused excessive loss of gum tissue or bone, then soft-tissue grafts or bone grafts may be performed to reduce further gum recession and bone loss. Basic concept of systematic treatment of peri-implant infections explained in [Figure 2].{Figure 2}

 New Perspectives in Periodontal Disease Treatment: Melatonin Supplementation

In recent years, the role of ROS, lipid peroxidation products, and antioxidant systems in the pathology of PD have been well clarified. It is now of importance to determine the possible contribution of diet to salivary antioxidant status because the use of antioxidant supplementation in the treatment or prevention of these chronic diseases of the oral cavity can be an excellent chance for preventing them. Recent medical and dental research in this area is geared toward the prevention of free radical-mediated diseases using specific nutrient antioxidant supplementation. Melatonin was found to be released with saliva into the oral cavity and to be implicated in various dental and PDs: for this reason, it is one of the more prominent antioxidants used for this purpose. In particular, melatonin possesses two functions of great interest to dental professionals: first of all, its capacity to scavenge free radicals, thereby exerting antioxidative action and second, the cell protective effect exerted by melatonin in situ ations of inflammation.[49]

Such beneficial effects of melatonin could open new perspectives for the treatment of oral inflammatory processes suggesting that this indole hormone could have a protective function in fighting periodontal infection. However, the relationship between PDs and melatonin level remains to be better understood.

According to Masaaki Takechi et al. in 2008, melatonin influences the release of growth hormone and cortisol in humans, and it was recently reported that it promoted bone formation. On the other hand, fibroblast growth factor-2 (FGF-2) was reported to facilitate the proliferation of osteoblasts. In the present study, we examined the effect of recombinant human FGF-2 and melatonin on the promotion of osteogenesis around titanium implants. Twenty-four 10-week-old female rats of the Wistar strain received titanium implants in both tibiae. In the experimental groups, 100 mg/kg body weight of melatonin was administered by intraperitoneal injection for 4 weeks after implantation, and 10 microgram of FGF-2 was locally injected around the implant sites 5 days after implantation. The control group was administered saline only. In the control group, few newly formed bone could be seen around the implants. It was observed to be in direct contact with the implant surface, but otherwise unmineralized connective tissue was occasionally interposed. In the experimental group, newly formed bone was observed around the titanium implant. In addition, in contrast to the control group, abutment bone trabeculae were seen in the medullary canal region. Bone trabeculae were seen in the medullary canal region. Bone trabeculae were directly connected to existing cortical bone. These results strongly suggested that ML and FGF-2 have the potential to promote osseointegration.[50]


In conclusion, a number of positive effects of melatonin on the periodontium and its potential therapeutic roles on peri-implantitis have been documented. Melatonin shows promise in the management of periodontitis, periodontal regeneration, oral implantology, and preventative dentistry. Implants made up of titanium coated with melatonin will have the direct effect on osseointegration. However, more clinical as well as animal studies are required to ascertain the use of melatonin in the clinical setting.

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Conflicts of interest

There are no conflicts of interest.


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