Melatonin as an Adjunctive Therapy for Chronic Periodontitis.
Condition: Periodontal Diseases
MeSH terms: Periodontitis; Periodontal Diseases; Chronic Periodontitis
Study type: Interventional
Phase: Phase 4

Summary: 
      Background:

      Melatonin is an endogenous indoleamine synthesized mainly by pineal gland and showed
      anti-inflammatory and antioxidant properties. Moreover, melatonin promotes osteoblastic
      differentiation and suppresses osteoclastic formation. This randomized clinical trial (RCT)
      was aimed to assess the additive effect of melatonin supplementation in generalized chronic
      periodontitis (gCP) patients with insomnia who received scaling and root planing (SRP).

      Methods:

      Seventy four gCP patients with primary insomnia participated in this 6-month RCT and randomly
      distributed between two groups. Melatonin group (MTN+SRP group, n=38) included patients who
      were subjected to SRP with a 2- month regimen of 10 mg oral melatonin supplementation capsule
      once daily at bed-time. In the control group (Placebo+SRP group, n=36), SRP was performed for
      participants provided with matching placebo capsules. The primary treatment outcome included
      the clinical attachment gain (CAG) after 3 and 6 months of therapy, whereas, the changes in
      pocket depth ,bleeding on probing (BOP%) and salivary tumor-necrosis factor-α (TNF-α) levels
      represented the secondary outcomes.
    

Detailed description: 
      INTRODUCTION

      Chronic periodontitis is a local chronic inflammation of the tooth supporting apparatus
      initiated by specific microorganisms including Porphyromonas gingivalis, Tannerella
      forsythia, and Treponema denticola, which are collectively known as the "red complex". It was
      revealed that periodontal tissue damage begins as inflammatory neutrophil mediated reaction
      followed by chronic infiltration of monocytes. Previous investigations have reported that
      most of periodontal tissue destruction is directly caused by the host immune response to the
      aforementioned specific periodontopathogenic bacteria.

      Few years ago, host modulatory therapy (HMT) has emerged as a new concept for the treatment
      of destructive periodontal diseases. The aim of HMT is to decrease the periodontal tissue
      damage by reducing the destructive arm of the host immune response and boosting its
      regenerative features. HMT includes systemically or locally delivered therapeutics which are
      utilized as adjuncts to conventional periodontal treatment.

      A variety of different drugs have been assessed as host modulatory therapeutics such as
      non-steroidal anti-inflammatory drugs (NSAIDs), tetracyclines and bisphosphonates. Systemic
      or topical NSAIDs had significant serious adverse events when used for a long time and after
      stopping their use, a 'rebound' effect' was observed. Subantimicrobial dose of doxycycline
      (SDD) revealed beneficial outcomes when combined with non surgical treatment of chronic
      periodontitis; nevertheless, some adverse reactions associated with tetracyclines
      particularly photosensitivity were noted. Bisphosphonates were proven to significantly
      increase alveolar bone density and possess anticollgenase activity , however, their long term
      use could lead to avascular necrosis of jaw bones especially after tooth extraction. Thus,
      researchers worldwide are continually searching for new host modulatory agents to be used as
      adjunctive treatments for periodontal disease.

      To-date, melatonin (N-acetyl-5-methoxytryptamine) is a well-investigated, endogenous
      indoleamine which is primarily secreted from the pineal gland and responsible for regulation
      of sleep/waking cycle. Melatonin possesses a variety of essential properties such as
      anti-inflammatory, antioxidant, oncostatic and neuroprotective actions. Moreover, melatonin
      was recently found to promote osteoblastic differentiation and suppress osteoclastic
      formation through downregulation of the receptor activator of nuclear к-B ligand (RANKL). In
      lipopolysaccharide-induced experimental periodontitis in rats, locally applied melatonin
      significantly decreased bone resorption in comparison with rats which received no treatment.
      Thus, it was proposed that topically applied melatonin can serve as an adjunct to
      conventional periodontal treatments including scaling and root planing (SRP), as well as,
      surgical periodontal therapy.

      Recent studies have revealed that salivary melatonin levels were significantly reduced in
      subjects with periodontal disease, suggesting that melatonin could serve as a biomarker for
      periodontal diagnosis and used as a potential therapeutic in different periodontal diseases.
      Recently, topical application of 1% melatonin gel on the attached gingivae in diabetic
      individuals with periodontal disease resulted in significantly decreased pocket depth and
      gingival index as well as lower levels of serum IL-6 and C-reactive protein after therapy.

      Accordingly, we hypothesized that periodontal treatment with daily dietary supplementation of
      melatonin adjunctive to SRP in generalized chronic periodontitis (gCP) patients suffering
      from primary insomnia could improve the periodontal outcomes. Hence, the objective of the
      present clinical trial is to assess whether the adjunctive therapy of daily melatonin
      supplementation to SRP compared to placebo with SRP, ameliorates clinical periodontal
      parameters and reduces salivary TNF-α levels after 3 and 6 months of therapy in patients with
      gCP and primary insomnia.

      MATERIALS AND METHODS

      Study Population:

      The present study was conducted in accordance with the seventh revision of Helsinky
      declaration in 2013 and approved by the Institutional Review Board (IRB) of Mansoura
      University. Individuals were selected during their visits to the Periodontics clinics at the
      Faculty of Dentistry, Mansoura University, from July, 2016 till September , 2017. Individuals
      were asked to answer prepared questionnaires about their general medical status and
      sleep/awakening habits followed by diagnosing the periodontal condition to select eligible
      participants. Patients were considered eligible for participation if they had Athens Insomnia
      Scale (AIS) score ≥ 6 (provided that individuals have primary insomnia which not related to
      any other systemic causes or drug intake according to the International Classification of
      Sleep Disorders , ICSD-3). Each selected patient should have at least 20 teeth. The enrolled
      patients were diagnosed to have moderate to severe gCP based on Armitage's classification.
      Exclusion criteria included diabetes mellitus , smokers, individuals having night work
      shifts, cancer patients , patients with autoimmune diseases or osteoporosis, users of
      antibiotics or non-steroidal anti-inflammatory drugs within the last 3 months and patients
      who were subjected to any periodontal therapy during the last year. Enrolled patients signed
      informed consents prior to their participation in the clinical trial.

      Trial design:

      Seventy four patients diagnosed with gCP and primary insomnia were randomly assigned by a
      coin toss to either receive 10 mg oral melatonin capsule (Puritan's Pride, Inc., Holbrook,
      NY, USA) once per day at bedtime for two months in conjunction with SRP (MTN+SRP group, n =
      38), or matching placebo capsules for 2 months plus SRP (Placebo+SRP group, n = 36) in this
      double-blinded parallel randomized controlled trial (RCT). The randomization process was
      performed in absence of the working investigators. By a third party (pharmacist), sealed
      glass bottles were packed with 30 capsules of either melatonin or matching placebo and then
      coded with specific labels unknown to working investigators and patients. Patients in both
      groups were instructed to have one capsule at bedtime from the given bottle. Compliance of
      patients were assessed by counting the left capsules in the returned bottle at the end of
      each month. Adverse effects of the given drugs were monitored on a weekly basis for two
      months. All patients received meticulous thorough SRP with an ultrasonic scaler and hand
      curettes in a single visit by experienced periodontist. For all participants, strict oral
      hygiene instructions were given and 0.12% chlorhexidine mouthwash was prescribed for two
      weeks following SRP.

      Periodontal records:

      Periodontal measures including pocket depth (PD), clinical attachment level (CAL),
      dichotomous bleeding on probing (BOP) expressed as percentage, gingival (GI) and plaque (PI)
      indices were recorded at baseline, 3 and 6 months of therapy by a single examiner. To achieve
      intra-examiner calibration, periodontal mea-surements of 10 patients were performed twice
      within 2 days prior to RCT conduction. Calibration was approved when measurements of PD and
      CAL in the two times were within 1 mm variance in more than 90% of all measurements.

      Saliva Collection:

      Saliva samples were collected in the morning between 8 to 10 a.m. from all participants after
      fasting overnight. All participants were asked not to have any drinks except water after
      arousing. Whole unstimulated saliva samples were harvested by expectoration into 5 mL sterile
      polypropylene tubes before recording the clinical measurements. All saliva samples were
      centrifuged to remove debris, and immediately frozen and stored at -80οC until evaluation
      time.

      Biochemical Assessment:

      TNF-α level was determined in saliva by enzyme-linked immunosorbent assay (ELISA). Saliva
      samples were pipetted into clean microcap tubes and centrifuged at 10,000 × g for 5 minutes.
      Then, the supernatants were placed in clean microcap tubes and used immediately for ELISA
      assay. Human- TNF-α ELISA development kit (R&D systems, Abingdon Science Park,Abingdon, UK)
      was used to quantify this molecule in saliva samples according to the manufacturers'
      recommendations. The results of salivary TNF-α assay are expressed as concentrations in
      nanograms per milliliter.

      Trial outcomes:

      The primary outcome of the present RCT was the change in clinical attachment gain (CAG) after
      3 and 6 months of therapy, whereas, the secondary end-points included the change in pocket
      depth,BOP% and salivary TNF-α levels after 3 and 6 months.

      Assessment of untoward drug effects:

      Systemic signs and symptoms were recorded every week after SRP and initiation of medication
      intake during the first two months. At the end of RCT, patients indicated for additional
      periodontal treatments were scheduled as necessary.

      Statistical Analyses:

      This RCT was powered to 80% level to detect an average reduction of PD and CAL equal to 0.5
      mm variation between groups. The calculated minimum sample size required to achieve 80% power
      was 30 patients per group. Kolmogrov-Smirnov test of normality was used to explore data
      normality. Parametric data were presented as mean ± SD except salivary TNF-α concentrations
      which were expressed as mean± SEM (standard error of the mean). Baseline data were compared
      by using Student's t-test. One-way analysis of variance (ANOVA) with Holm-Sidak post hoc
      correction for multiple comparisons were used to determine significant differences at
      different time points. The level of significance was adjusted at 5%. Statistical analyses
      were performed by using the Statistical Package for the Social Sciences v. 20, SPSS,
      Chi-cago, IL.
    

Intervention name(s): Melatonin; Placebo
Intervention type(s): Dietary Supplement; Drug
Intervention description(s): After performing scaling and root planing (SRP) in the test group, melatonin 10 mg oral capsule was taken once daily at night prior to bedtime for only 2 months during the 6-month study period; After finishing scaling and root planing (SRP) in the control group, placebo capsule was taken once daily at bedtime for two months.
Other intervention name(s): N-acetyl-5-methoxytryptamine; starch capsule
Intervention MeSH terms: Melatonin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Melatonin; Chronic periodontitis; Host modulation therapy