5-1 Summary of the main findings
The results of the present study suggested that the adjunctive use of TCF and CHC provide significant additional clinical benefits to the treatment of patients in
maintenance phase of CP in follow-up period up to six months. Other adjunctive antimicrobial agents only showed limited clinical improvement.
5-2. Comparisons with other studies or reviews
Persisting periodontal pockets represent a risk factor for both progression of periodontitis and future tooth loss during maintenance care(Matuliene et al., 2008).
Primary effects of periodontal healing are yielded during cause related phase, such as oral hygiene reinforcement and non-surgical periodontal treatment. Sites that are poorly responded to initial therapy may require additional treatment. Thus, we conducted this research to investigate effects of various adjunctive localized antimicrobial agents compared to scaling and root planing alone. To avoid the possibly interference of the clinical outcomes , we exclude the studies that involved furcation sites due to its complex and irregular anatomy which might impair professional plaque control procedures(Cattabriga et al., 2000, Pihlstrom et al., 1984, Del Peloso Ribeiro et al., 2007).
In present network meta-analysis, we found that adjunctive localized antimicrobial agents do get better results in terms of PD reduction and CAL gain
compared to SRP alone in the follow-up period up to six months. This result was in line with previous published systematic reviews(Bonito et al., 2005, Xue and Zhao, 2017, Matesanz-Perez et al., 2013). In the systematic review, Bonito conducted separate analysis of tetracycline, minocycline, metronidazole, chlorhexidine, and other antimicrobials as locally delivered adjuncts to SRP. As a result, differences between treatment and SRP alone group in the baseline-to-follow-up period typically favored treatment groups but usually only modestly (from about 0.1 mm to near 0.5 mm). Xue and Zhao evaluated efficacy of PDT adjunctive to SRP in residual pockets in their study.
They found that additional clinical improvement in the maintenance of residual pockets in favor of SRP + PDT compared to SRP alone to an extent about two thirds of a
millimeter. In our study, however, only TCF and CHC yielded in statistically significant difference in PPD reduction and only CHC reaches that difference in CAL gain.
5-3. Clinical implication of the results
Antimicrobials must reach their target sites and be maintained there long enough to achieve sufficient concentration(Goodson, 1989). The concentration required for efficacy is often estimated from the minimum inhibitory concentration (MIC). Gel solution material generally maintained MIC in a shorter period of time compared to
agents fabricated in a more solid formulation. MTZ is reported to maintain MIC within 24 hours(Stoltze, 1995), whereas MIN can maintain its concentration in about 4
days(Satomi A, 1987). In contrast, concentration of CHC remains above MIC for more than 99% of the periodontal pocket flora for up to 9 days(Stanley et al., 1989).
Sustained concentration of TCF can be maintained over 10 days(Tonetti et al., 1990).
This may partly explain why TCF and CHC achieved better results than other gel solution antimicrobial agents. Changes in frequency of agent application and time interval between each application may be an alternative way to keep effective antimicrobial concentration on the subgingival microflora.
Besides, based on the fact that SRP + TCF group yielded in 0.57 mm of mean PPD reduction and 0.30 mm of mean CAL gain in 3 months follow-up period, 0.64 mm of mean PPD reduction and 0.31 mm of main CAL gain in 6 months follow-up period, we may assume that almost half of the reduction of PPD in SRP + TCF group were
attributed to gingival recession. This result is in accordance with a previous study which showed gingival recession contributed two-thirds of the pocket reduction in adjunctive TCF therapy(Wilson et al., 1997). The cause of greater gingival recession in SRP + TCF group may be related to the mechanical trauma caused by placement of the fibers in the sulcus for a prolonged period(Wong et al., 1998).
On the other hand, the adjunctive use of PDT only reach significant difference
compared to SRP alone in short-term follow-up. The effectiveness of PDT would depend on three factors: photosensitizer, visible light, and oxygen. Different types of photosensitizer, light application devices, output power, wavelengths, and duration of exposure vary in different studies. Photosensitizers may not be able to reach
concentrations high enough to be absorbed by bacteria. The microenvironment of residual pocket which contained fewer oxygen than healthy sites(Mettraux et al., 1984) might hinder effectiveness of PDT(Henry et al., 1996). Another reason that changes in periodontal parameters did not improve significantly might be the difference in
frequency of PDT application. Chondros et al. only applied PDT once at baseline as adjunct to SRP, and no additional benefits in PPD reduction and CAL gain is achieved.
In contrast, significant PPD reduction and CAL gain can be achieved after single use of adjunctive PDT in other studies(Campos et al., 2013, Goh et al., 2017). The effect of repeated application of PDT has also been studied. Lulic et al. performed repeated application of PDT five times in 14 days interval and found significant PPD reduction and CAL gain can be achieved in six months follow-up. However, in a study comparing different frequency of PDT application (once vs twice in one-week interval), no
significant difference between these two groups can be detected(Muller Campanile et al.,
2015). Based on abovementioned controversial results, more studies may be required to investigate frequency of PDT application to achieve the optimal effect.
In the medium-term follow-up, SRP + DOX achieved additional CAL gain (0.70 95%CI: 0.09-1.31) than SRP alone, which is not in line with the results in short-term and long-term follow-up. The reason why SRP + DOX got this result in the network meta-analysis may be attributed to two facts. First, the performance of SRP + DOX in the 3-arm study(Salvi et al., 2002) is significantly better than the other two treatments (SRP + MTZ and SRP + CHC). Secondly, clinical results of SRP + MTZ or SRP + CHC in other studies of medium-term follow-up group all resulted in better outcomes than they achieved in this 3-arm study (Table 2). The reason for inferior results obtained by SRP+ MTZ and SRP + CHC in this 3-arm study may be ascribed to involving
smokers in the investigation. However, since there is only one study included SRP + DOX in the medium-term follow-up, we should interpret this result with caution.
The efficacy of repeated SRP in residual pockets are rather limited compared to those following the initial phase of subgingival instrumentation(Badersten et al. 1984;
Wennstrom et al. 2005). In the sites respond poorly to initial mechanical debridement, only 11-16% might be brought to a successful treatment endpoint following mechanical re-instrumentation(Wennstrom et al. 2005). In another study evaluating the outcome of re-instrumentation of residual pockets, showed that the overall probability of achieving
pocket closure 3 months after retreatment was about 45%, while for sites with a PPD of
> 6 mm, the probability was only 12%(Tomasi et al. 2008). Surgical intervention of deep periodontal pockets with intrabony defects has demonstrated good performance in PPD reduction of about 3 mm(Laurell et al. 1998; Tu et al. 2012). However, patients may be hesitated in willingness to take surgery as a treatment option. In fact, according to a study(Stabholz and Peretz 1999) evaluating dental anxiety among patients in various dental treatments, periodontal surgery caused second highest dental anxiety score, next to tooth extraction. Periodontal surgery can be a stressful event for many patients, and post-operative period may be accompanied by significant pain and discomfort(Baume et al. 1995). Therefore, if adjunctive methods to SRP can reduce PPD to below 5 mm, it will avoid further necessity of surgery, and will benefit most patients who are afraid of surgery. Furthermore, when PPD of teeth under maintenance care can be maintained below 5 mm, the percentage of tooth loss can be drastically reduced(Matuliene et al. 2008) up to 11 years follow-up.
According to previous studies(Magnusson et al., 1984, Sbordone et al., 1990), after SRP, subgingival microbiota containing large numbers of pathogenic microorganisms repopulated within 2 months in the absence of improved plaque control. More recently, various studies has pointed out that application of adjunctive antimicrobial agents resulted in significant reduction of bacteria for six months follow-up period(Chondros et
al., 2009, Paolantonio et al., 2008, van Steenberghe et al., 1999). Therefore, we may speculate that in the person whose oral hygiene can be adequately achieved, locally delivered antimicrobial agents may help in maintaining low concentration of microorganisms for a longer period of time than SRP alone does.
In the follow-up period for shorter than six months, all adjunctive treatments showed better results than SRP alone, but there were no significant differences between
different adjunctive treatments (Table1, Table 2). Thus we may judge these treatments from other points of view, such as easy-handling characteristics, probability of adverse events or development of resistant bacteria. Typically, a gel-like biomaterial is more easily to inject into sulcus than fiber or chip. Adverse events may happen during or after placement of local antimicrobial agents. Previous studies reported various rates of side effects, from 0 % to more than 60 %.(Killeen et al., 2016, Kinane and Radvar, 1999, Matesanz et al., 2013, Muller Campanile et al., 2015, Tonetti et al., 2012, Williams et al., 2001). Generally, most of the studies did not report severe adverse event. Mostly reported events were temporary discomfort in tooth and gingival tissue (i.e. gingival redness, tooth pain, tooth hypersensitivity, stomatitis). The discomfort feeling will be alleviated or subsided even without use of analgesics in a short period of time.
Antibiotic resistance of periodontal pathogens may develop in the procedure of
systemically or locally administered antibiotics, whereas PDT or CHC should be free of this consideration.