Evaluation of the Efficacy of Topically Applied Melatonin Gel as Adjunctive Therapy in Chronic Periodontitis; Randomized Control Trial
Phase: PHASE4
Conditions: Chronic Periodontitis
Sponsor: Al-Azhar University

 
 
" S t u d y  p r o t o c o l  "  
 
Evaluation of the Efficacy of 
Topically Applied Melatonin Gel as 
Adjunctive Therapy in Chronic 
Periodontitis; (Randomized Control 
Trail) 
 
Manuscript ID: A A D J - 2 1 1 1 - 1 0 9 1  
Protocol
 
Result : 1/1/202o
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
                                                 Introduction 
Periodontal disease is a multifactorial disease. Etiopathogenesis 
of periodontal disease are not clear. However, it is known that 
the microorganisms in the mouth start a process and attack 
healthy tissue. The direct effect of bacterial-derived toxic 
products and the stimulation of the immunological system with 
bacterial infection results in damage to the periodontal tissue (1). 
Bacterial and products induce inflammatory responses in the 
tissues, resulting in polymorphonuclear leukocyte migration, 
differentiation into fibroblasts, activation of macrophages and a 
number of products such as Interleukin-1 (IL-1), Tumor necrosis 
factor-α (TNF-α), prostaglandins and hydrolytic enzymes 
leading to hard and soft tissue destruction (2). 
The receptor activation of nuclear factor-kappa B ligand 
(RANKL) is an important protein in osteoclastic differentiation 
and proliferation (3). Another protein, osteoprotegerin (OPG), 
interferes with its biologic potential. RANKL and OPG play 
critical roles in the development of periodontal disease, with 
periodontal bone destruction resulting from the upregulation of 
RANKL with downregulation of OPG (4) 
The first treatment goal in periodontal disease is changing or 
removing microbial origin and risk factors to prevent disease 
progression and maintain periodontal tissue healt2xh .then ,the 
recurrence of disease must be prevented and finally, restructured 
and reorganizing attachment has to be done (5). The knowledge 
that periodontitis is a chronic inflammatory disease provide us 
with options to consider using anti-inflammatory agents as 
therapeutic strategies additional to conventional periodontal 
treatment andrisk 
reduction strategies. This concept has been referred to as host 
response modulation or host modulation therapy, denoting that 
the treatment aims to modify the host response by reducing 
those damaging aspects of the inflammatory response that lead 
to tissue destruction (6) 
Melatonin (N-acetyl-5-methoxy-tryptamine), secreted from the 
pineal gland and other organs, is an antioxidant and anti-
inflammatory agent. Melatonin, first described in 1917, was not 

 
isolated until 1958 (7). Melatonin has been reported to be related 
to various biological events such as sleep, emotional state, 
immunity, 
thermoregulation, 
sexual 
maturation 
and 
reproduction, especially the circadian rhythm. In addition, it is 
thought that melatonin, which has been shown to have 
antiproliferative and antioxidant effects in studies, may be 
effective in the treatment of cancer and prevention of aging (8). 
The inflammatory process may trigger increased plasma melatonin 
concentration in periodontitis. This leads to an increase in melatonin in 
the oral cavity and indicating that plays a protective role. There is a 
significant increase in melatonin level in elderly patients with excessive 
periodontal insult. Thus, the increase in melatonin in periodontal disease 
may be secondary to the increase of free radical products in these 
pathologies (9). An increase in saline melatonin level can affect the 
periodontal inflammatory process and improve the defensive response of 
the organism due to the antioxidant and antiinflammatory effects of 
melatonin (10). 
Melatonin strongly suppresses nitric oxide (NO) and interleukin-6 (IL-6) 
production induced by lipopolysaccharide (LPS) from P. intermedia, a 
major cause of inflammatory periodontal disease, in macrophages (11). 
The administration of melatonin, in local or systemic form, might be 
indicated in chronic periodontitis patients, with the goal to protect their 
mouth against inflammatory and infectious processes of diverse nature. 
Aim of Study 
The aim of study is to evaluate the efficacy of Melatonin gel as 
adjunctive to scaling and root planning in the treatment of chronic 
periodontitis using clinical parameters as well as assess the level of 
RANKL in gingival crevicular fluid. 
Patients and Methods 
Study type: randomized clinical trial 
Study setting and population 
The present study will be carried out as split mouth design on 
chronicperiodontitis patients; those will be selected from the outpatient 
clinics of department of Oral Medicine and Periodontology, Faculty of 
Dental Medicine, Al-Azhar University, Assiut. 
Eligibility criteria of population: 
Inclusion criteria:- 
All chronic periodontitis patients to be included in this study should have 
pocket depth less than 6 mm. 
All patients should be free from any systemic diseases according to 
criteria of Cornell medical index (12) 

 
Exclusion criteria:- 
Smokers Patients, pregnant, received antibiotics or non-steroidal anti-
inflammatory drugs within 3 months before the beginning of the study or 
received periodontal treatment within 6 months before the beginning of 
study will be excluded. 
Ethical considerations:- 
The research protocol will be approved by the ethical committee, 
faculties of dental medicine, Al-Azhar University and the enrolled 
patients should sign written consent form. 
Grouping and intervention: 
Patients selected in this study will be classified into 2 groups: 
Group 1: twenty chronic periodontitis patients with pocket depth less than 
6mm will receive scaling and root planning combined with Melatonin gel 
adjunctive . Group 2: twenty chronic periodontitis patients with pocket 
depth less than 6 mm will receive scaling and root planning only 
Evaluation:- Clinical evaluation: Clinical parameters including 
Gingival index (GI) (Löe & Sillness) (13) , Plaque index (PI) (Sillness & 
Löe) (14) and clinical attachment loss will be taken for all patients at base 
line 1, 3 months after treatment. 
Biochemical evaluation: 
The level of RANKL in gingival crevicular fluid will be measured at 
baseline, 1, and 3 months using ELISA technique.  
Data analysis: The data will be collected, tabulated, computed and 
analyzed using suitable statistical program. 
References 
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Microbiological and immunological studies of adult periodontitis in 
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metalloproteinase-13, periodontal pathogens and inflammatory cells. J 
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Kim, “Melatonin inhibits Prevotella intermedia lipopolysaccharide-
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Results: 
 
 
 Table (1) Means ± SD of Gingival index ,Plaque 
index, Pocket depth ,Attachment level , RANKL , 
paired t- test and P- values in the two groups: 
Group I Group II t- test P-value 
Mean±SD Mean±SD 
GI 
Baseline  2.8±0.41 2.6±0.5 1.378 0.109 
1week     1.6±0.5 1±0 5.339 <0.0001*** 
1month    0.7±0.47 1.1±0.31 3.183 0.003** 
3month    0.8±0.41 1.85±0.37 8.536 <0.0001*** 
PI 
Baseline  2.5±0.51 2.6±0.5 0.623 0.205 
1week     1±0 1±0 6.332 <0.001** 
1month    1±0 1±0 6.332 <0.001** 
3month    1±0 1.9±0.55 7.285 <0.0001** 
PD 

 
Baseline  4.8±0.41 4.9±0.31 0.872 0.24 
1week     4.15±0.67 4.6±0.5 2.401 0.01* 
1month    2.55±0.51 3.7±0.47 7.411 <0.0001*** 
3 month   3.25±0.64 4.3±0.47 5.921 <0.0001*** 
Attachment level 
 Baseline 
                      2.8±0.41 2.9±0.31 0.872 0.24 
1week     2.15±0.67 2.6±0.5 2.401 0.01* 
1month    0.55±0.51 1.7±0.47 7.411 <0.0001*** 
3months   1.2±0.7 2.3±0.47 5.858 <0.0001*** 
RANKL 
Baseline   13.89±2.13 15.43±3.53 1.661 0.105 
1week      10.56±1.63 12.61±1.96 3.593 0.001** 
1month     10.33±0.82 12.81±2.42 4.343 <0.001*** 
3month     11.84±1.32 13.35±2.05 3.1 0.004**
 
Table (2) Correlation Coefficient (r) between 
RANKL levels & clinical parameter in both groups 
at different intervals 
     RANKLE              Plaque      Gingival                      Pocket                           Attachment 
   concentration           index          index                            depth                                  level 
 
                     
Group I 
Baseline            0.7        0.315    -0.218                  -0.218 
1 week              0         0.249     -0.453                  -0.453 
1month              0         0.199      0.148                   0.148 
3month              0         0.528      0.051                   0.107 
Group II 
Baseline           -0.568     0          0.406                 0.406 
1 week 
1month 
                   0          0        0.462                   0.462 
                   0        -0.467     0.535                   0.535 
3month          0.449       -0.061     0.532                   0.532